ChooseTop of pageAbstract <<CASE PRESENTATIONCHALLENGES IN DIAGNOSIS A…SUMMARY OF THE RELEVANT L…NOVEL AGENTS FOR PROCSUGGESTED APPROACHES TO M…REFERENCES
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.
CASE PRESENTATIONChooseTop of pageAbstractCASE PRESENTATION <<CHALLENGES IN DIAGNOSIS A…SUMMARY OF THE RELEVANT L…NOVEL AGENTS FOR PROCSUGGESTED APPROACHES TO M…REFERENCES
A 59-year-old woman presents with recurrent high-grade serous ovarian carcinoma. At initial diagnosis, she underwent an optimal cytoreductive surgery and was diagnosed with stage IIIC, BRCA wild-type, homologous recombination deficiency (HRD) test–positive disease. She completed six cycles of adjuvant carboplatin and paclitaxel chemotherapy with normalization of her cancer antigen (CA)-125 and subsequently received olaparib maintenance. Five months after her last treatment with carboplatin and paclitaxel, she reported new abdominal bloating; her CA-125 was found to be 353. Computed tomography imaging revealed multiple new peritoneal nodules, serosal implants, and ascites, indicative of disease progression.
CHALLENGES IN DIAGNOSIS AND MANAGEMENTChooseTop of pageAbstractCASE PRESENTATIONCHALLENGES IN DIAGNOSIS A… <<SUMMARY OF THE RELEVANT L…NOVEL AGENTS FOR PROCSUGGESTED APPROACHES TO M…REFERENCES
After initial diagnosis and treatment with platinum-based chemotherapy, 85% of patients with epithelial ovarian cancer will experience recurrence and eventual treatment resistance. The platinum-free interval (PFI) is defined as the time from last platinum treatment to detection of recurrence. A PFI of <6 months has been historically used to identify patients who have <20% response rate with rechallenge with platinum-based therapy.1,2 Patients with a PFI of <6 months are considered to have platinum-resistant ovarian cancer (PROC). Given the limited efficacy of platinum in these cancers, treatment with nonplatinum therapy is often considered.
However, the introduction of maintenance therapies such as bevacizumab and poly (ADP-ribose) polymerase (PARP) inhibitors has added additional complexity into the interpretation of platinum resistance. For example, several retrospective studies, including retrospective analyses of the SOLO2 and PAOLA1 trials, have reported that receipt of previous PARP inhibitor treatment may modify the clinical relevance of the PFI.3–6 Additionally, patients with nominal PROC may still have disease response to platinum therapy. Recognizing that platinum sensitivity is therefore not a binary condition but a spectrum, the Gynecologic Cancer Intergroup (GCIG) moved away from a strict definition of platinum resistance in both the fifth and sixth Ovarian Cancer Consensus Conferences7,8 and recommends considering whether platinum remains a treatment option.7 Similarly, although the National Comprehensive Cancer Network (NCCN) Ovarian Cancer guidelines preserve a division between platinum-sensitive and platinum-resistant ovarian cancers, they caution that definitions of platinum sensitivity are imprecise, and that clinical judgment and flexibility should be used in determining treatment options.9
SUMMARY OF THE RELEVANT LITERATUREChooseTop of pageAbstractCASE PRESENTATIONCHALLENGES IN DIAGNOSIS A…SUMMARY OF THE RELEVANT L… <<NOVEL AGENTS FOR PROCSUGGESTED APPROACHES TO M…REFERENCES
Initial Studies
The mainstay of treatment for PROC has been sequential use of cytotoxic agents with monotherapy activity including pegylated liposomal doxorubicin (PLD), gemcitabine, paclitaxel, and topotecan. In general, the reported response rates in recent PROC trials have been 10%-15%, with a median progression-free survival (PFS) of approximately 3.5 months (Table 1).19–22
TABLE 1. Reported Response Rates in Recent PROC Trials
A significant advance in PROC treatment occurred with the AURELIA (Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer) study, which investigated the value of adding bevacizumab to nonplatinum chemotherapy in recurrent PROC. In this phase III study, 361 patients received either investigator’s choice chemotherapy (paclitaxel 80 mg/m2 once weekly, PLD 40 mg/m2 once every 4 weeks, or topotecan 4 mg/m2 once weekly) or investigator’s choice chemotherapy with bevacizumab.10 The primary end point was PFS, with secondary end points of objective response rate (ORR) and overall survival (OS). Eligible patients had PROC and no more than two previous anticancer treatments. The study met its primary end point of improved PFS, with patients in the chemotherapy plus bevacizumab arm demonstrating a statistically significant improvement of 6.7 months versus 3.4 months (hazard ratio [HR], 0.48 [95% CI, 0.38 to 0.60]) and ORR of 27.3% versus 11.8% (P = .001). No significant improvement in OS was observed.
AURELIA established the addition of bevacizumab to chemotherapy as a standard of care in PROC. Patients receiving chemotherapy plus bevacizumab experienced expected toxicity on the basis of previous studies including a 2% risk of GI perforation. Notably, the typical toxicity profiles for each chemotherapy cohort, including neuropathy with paclitaxel and hand-foot syndrome with PLD, were accentuated with the addition of bevacizumab. However, patients receiving bevacizumab with chemotherapy remained on treatment longer and reported a 15% or more improvement in patient-reported outcome measures of GI symptoms at 8 weeks, suggesting a patient-specific approach to choosing when to include bevacizumab with therapy.23
OVAL: A Randomized Trial of Ofranergene Obadenovec With Weekly Paclitaxel
Beyond the addition of bevacizumab to chemotherapy, therapeutic advances in PROC have been a challenge. The companion to this article16 reports the OVAL study, a phase III international randomized trial of ofranergene obadenovec (Ofra-vec) versus placebo in combination with weekly paclitaxel in PROC. In this trial, 409 patients with PROC were randomly assigned 1:1 to receive once weekly paclitaxel with placebo or Ofra-vec, a nonreplicating adenovirus-based therapy that promotes disruption of vascular growth and tumor immune infiltration, once every 8 weeks. Despite promising evidence of efficacy from the preceding phase I/II study,24 OVAL was closed early after failing to meet the coprimary end points of OS and PFS at the first unblinded analysis. The reported PFS for Ofra-vec in combination with paclitaxel was 5.29 months versus 5.36 months in the control arm (HR, 1.03 [95% CI, 0.83 to 1.29]), while OS for Ofra-vec plus paclitaxel was 13.13 months versus 13.14 months with paclitaxel alone (HR, 0.97 [95% CI, 0.75 to 1.27]).
A unique aspect of this trial was the inclusion of a planned unblinded interim futility analysis of CA-125 response in the study on the basis of GCIG consensus criteria.25 The end point for this analysis was included on the basis of the favorable CA-125 response rate of 58% with Ofra-vec plus weekly paclitaxel in the initial phase I/II study.24 In the OVAL interim futility analysis, which was conducted in the first 60 evaluable patients in the phase III study, 53% of patients had a CA-125 response, including 15% with a complete CA-125 response. The unblinded results were available only to the Data Safety Monitoring Committee, which recommended continuation of the study; of note, the prespecified criterion for continuation was an absolute percentage advantage in CA-125 response of 10% or higher for Ofra-vec with weekly paclitaxel compared with paclitaxel alone. Nonetheless, exploratory analyses at the conclusion of the study concluded no association between PFS or OS and CA-125 response. Although disappointing, the OVAL study results thus provide valuable evidence that CA-125 is not a reliable trial-level surrogate for survival outcomes.
Ongoing Studies and Approaches
Beyond the OVAL study, there are multiple ongoing clinical trials that look to improve therapeutic options for patients with PROC (Table 2). Just recently, however, the randomized phase III AXLerate-OC trial (ClinicalTrials.gov identifier: NCT04729608) of the GAS6/AXL decoy protein batiraxcept reported negative results for the combination of batiraxcept or placebo with once weekly paclitaxel in PROC. Notably, the PFS with weekly paclitaxel alone in the AXLerate-OC study was reported to be 5.5 months, similar to that observed in OVAL, and longer than the 3.5 months historically considered the benchmark for PFS with single-agent therapy in PROC. Interestingly, the activity observed with once weekly paclitaxel has consistently outperformed other single-agent regimens in numerous completed clinical trials, boasting response rates of approximately 30% and a PFS of 5.5 months irrespective of the number of previous lines of therapy.26 The results from OVAL and AXLerate-OC therefore reset the benchmark for expectations for standard-of-care weekly paclitaxel in PROC and should be considered in the development of clinical trials within this space.
TABLE 2. Recent or Ongoing Phase III Trials in Platinum-Resistant Ovarian Cancer
NOVEL AGENTS FOR PROCChooseTop of pageAbstractCASE PRESENTATIONCHALLENGES IN DIAGNOSIS A…SUMMARY OF THE RELEVANT L…NOVEL AGENTS FOR PROC <<SUGGESTED APPROACHES TO M…REFERENCES
Antibody-Drug Conjugates
Antibody-drug conjugates (ADC) are a rapidly evolving area of oncology drug development, and there has been high interest in developing these drugs in PROC. ADC targets of interest in PROC have included folate receptor alpha (FRα), NaPi2b, trophoblast cell surface antigen 2, mesothelin, and human epidermal growth factor receptor 2 (HER2). In November 2022, mirvetuximab soravtansine (MIRV) became the first ADC to receive accelerated approval from the US Food and Drug Administration (FDA) for ovarian cancer.
MIRV consists of a FRα-directed antibody conjugated to the cytotoxic maytansinoid effector molecule DM4, a tubulin-targeting antimitotic agent. In the phase II SORAYA study, 105 patients with FRα-high PROC (defined as 75% of viable tumor cells exhibiting at least 2+ membrane staining intensity by immunohistochemistry [IHC]) received MIRV at 6 mg/kg using adjusted ideal body weight administered intravenously once every 3 weeks. MIRV demonstrated substantial clinical activity, with an ORR of 32.4% (95% CI, 23.6 to 42.2; P < .0001) and a median duration of response (DOR) of 6.9 months.27 The confirmatory phase III trial MIRASOL randomly assigned 453 patients with FRα-high PROC and up to three previous lines of therapy to MIRV or investigator’s choice chemotherapy (paclitaxel, PLD, or topotecan). The primary end point of the study was PFS, with secondary end points of ORR, OS, and PROs. Excitingly, MIRASOL reported a PFS of 5.62 months with MIRV versus 3.98 months with chemotherapy (HR, 0.65 [95% CI 0.52 to 0.81]) and the first report of improved OS in a PROC trial, with an OS of 16.46 months with MIRV versus 12.75 months with chemotherapy (HR, 0.67 [95% CI, 0.50 to 0.88]).17 Low-grade ocular toxicities were reported in both studies, with blurry vision and keratopathy being the most common symptoms; 96% of cases resolved with dose hold or reduction.
Other ADCs remain under active development in PROC. The HER2-directed ADC trastuzumab deruxtecan (T-DXd) is approved in breast, gastric, and lung cancers, and has shown efficacy across multiple solid tumor types. Recent results from the DESTINY-PanTumor02 trial, a phase II trial of T-DXd in various cohorts of HER2-expressing advanced-stage solid tumors including ovarian cancer, reported an ORR of 57.5% and a DOR of 11.3 months in the ovarian cohort of 40 patients.28 These results are intriguing; however, development of T-DXd within the ovarian space will require further understanding of HER2 expression and biology in ovarian cancers. The results from an ovarian cancer expansion cohort of a separate FRα-directed ADC, luveltamab tazevibulin, were recently presented and reported an ORR of 37.5% with a median DOR of 5.5 months in 32 patients who had ovarian cancer with FRα of at least 25% by tumor proportion score.29 As more data become available, these ADCs or others may become part of the armamentarium for PROC, and this is an exciting and active area of ongoing investigation.
DNA Damage Response and Cell-Cycle Targeting Agents
DNA damage response (DDR) has been a target of growing interest, and agents under investigation in PROC include DDR and cell-cycle targeting drugs such as WEE1 kinase inhibitors, ATR inhibitors, and CDK2 inhibitors. In early-phase trials, inhibitors of WEE1, which modulates the G2/M cell-cycle checkpoint, have had reported activity as monotherapy in CCNE1-amplified ovarian cancers30 as well as in the setting of cyclin E-high PROC.31 A phase II study also reported significant activity of the WEE1 inhibitor adavosertib in patients with ovarian cancer who had previously received a PARP inhibitor, with an ORR of 23% as monotherapy and 29% when combined with olaparib.32 Significant clinical activity has also been reported with the combination of WEE1 inhibitors such as adavosertib or azenosertib with chemotherapy in PROC,33,34 and a phase II study of adavosertib together with gemcitabine reported improved PFS and OS compared with gemcitabine alone in PROC.35 Similarly, a study of the ATR inhibitor berzosertib together with gemcitabine reported improved PFS compared with gemcitabine alone.36
Immunomodulatory Approaches
Early studies suggested that the presence of tumor-infiltrating lymphocytes was a prognostic factor in epithelial ovarian cancer (EOC)37,38 and led to the hope that immunotherapy could be leveraged effectively in this disease. However, subsequent studies have found that the tumor microenvironment within EOCs is profoundly immunosuppressive,39,40 and thus far, trials involving immunotherapy either as a sole intervention (eg, NINJA) or in conjunction with chemotherapy (eg, JAVELIN 200 Ovarian) have failed to exhibit benefits for immunotherapy in PROC.14,15 Although these initial approaches to immunomodulatory strategies in PROC have not been successful, several phase I/II (ClinicalTrials.gov identifiers: NCT01685255, NCT04042116)41,42 and phase III trials (refer to Table 2) are currently in progress or have concluded, focusing on novel strategies to manipulate the composition of immune cells infiltrating the tumor. It remains to be seen whether such immunomodulatory strategies will be able to improve on our current therapies for PROC.
SUGGESTED APPROACHES TO MANAGEMENTChooseTop of pageAbstractCASE PRESENTATIONCHALLENGES IN DIAGNOSIS A…SUMMARY OF THE RELEVANT L…NOVEL AGENTS FOR PROCSUGGESTED APPROACHES TO M… <<REFERENCES
Although novel treatment modalities and approaches to PROC are under active study, the sequential use of noncarboplatin chemotherapy remains the standard of care for PROC. Considering the low response rates to available therapeutics, effective treatments for PROC continue to be an urgent unmet need, with the recent addition of MIRV in FRα-high PROC representing the first FDA approval in this space in almost 10 years. Consensus guidelines, including NCCN, European Society for Medical Oncology, and GCIG, encourage participation in clinical trials at all phases of PROC management.7,9,43
When considering therapy for patients with PROC, the determination to proceed with a particular treatment approach and the selection of therapeutic agents should be tailored to each patient, taking into account their individual symptoms and preexisting comorbidities. With the increasing accessibility of biomarker-guided therapies, consensus guidelines advocate for the consideration of tumor molecular analysis including but not limited to BRCA1/2 testing, HRD status, microsatellite stability status, mismatch repair deficiency, tumor mutational burden (TMB), and FRα testing.9 We routinely perform somatic tumor sequencing, if not already performed, as well as FRα IHC in our patients with PROC to direct therapeutic decision making. Where applicable, additional molecular testing and IHC (eg, HER2 testing) may be performed to guide trial eligibility.
The results of the MIRASOL trial, demonstrating improved PFS and OS of MIRV over other standard-of-care chemotherapies, emphasize the importance of understanding FRα status for all patients with PROC. For patients with FRα-high tumors, treatment with MIRV should be strongly considered, given the MIRASOL results. The FDA indication for use of MIRV is in patients with epithelial ovarian cancer with less than three previous lines of therapy; data suggest that approximately 35%-40% of ovarian cancer will be FRα-high and that FRα expression levels do not change significantly with increasing lines of treatment.17,27 Mitigation of ocular toxicity with this regimen requires ophthalmic or optometry examination with every other cycle and a strict regimen of daily eye drops. In addition to MIRV, several therapeutic approaches can be considered for PROC per the NCCN guidelines, including preferred therapies such as weekly paclitaxel, PLD, or topotecan (each with or without bevacizumab), or gemcitabine monotherapy. Consideration around side effects, including hair loss or worsened neuropathy, schedule of treatment, and patient preference may influence choice and order of these regimens. Additionally, given the overall limited activity of standard of care agents in PROC, we advocate for continuously reevaluating opportunities for clinical trial participation at decision-making junctures.
After somatic tumor testing, our patient’s genetic profile revealed a TP53 R223C mutation, along with loss of CDKN2B and CDKN2A. The TMB was measured at eight mutations per megabase, and her tumor was confirmed to be microsatellite stable. IHC demonstrated high FRα expression in 78% of cells and HER2 expression 1+.
Given a PFI of only 5 months, we opted to defer platinum-based therapy and considered single-agent nonplatinum regimens. In light of her tumor’s FRα-high status and after a thorough discussion about available treatment options, the patient made an informed decision to commence MIRV treatment. She reported significant improvement in abdominal bloating after her first cycle of treatment. Imaging after seven cycles (Fig 1) demonstrated near-resolution of abdominal ascites and improvement in peritoneal-based disease, and her CA-125 decreased to 14. On treatment, she reported mild neuropathy but no ocular symptoms with strict adherence to the recommended eye care regimen. She continues on MIRV treatment with good control of her PROC and excellent functional status.
FIG 1.Computed tomography images before treatment (left) and after seven cycles of MIRV treatment at 6 mg/kg (right). MIRV, mirvetuximab soravtansine.
Alcohol drinking is an established risk factor for several malignancies, and it is a potentially modifiable risk factor for cancer. The Cancer Prevention Committee of the American Society of Clinical Oncology (ASCO) believes that a proactive stance by the Society to minimize excessive exposure to alcohol has important implications for cancer prevention. In addition, the role of alcohol drinking on outcomes in patients with cancer is in its formative stages, and ASCO can play a key role by generating a research agenda. Also, ASCO could provide needed leadership in the cancer community on this issue. In the issuance of this statement, ASCO joins a growing number of international organizations by establishing a platform to support effective public health strategies in this area. The goals of this statement are to:
• Promote public education about the risks between alcohol abuse and certain types of cancer;
• Support policy efforts to reduce the risk of cancer through evidence-based strategies that prevent excessive use of alcohol;
• Provide education to oncology providers about the influence of excessive alcohol use and cancer risks and treatment complications, including clarification of conflicting evidence; and
• Identify areas of needed research regarding the relationship between alcohol use and cancer risk and outcomes.
INTRODUCTIONChooseTop of pageAbstractINTRODUCTION <<EPIDEMIOLOGY OF ALCOHOL U…DRINKING GUIDELINES AND D…ALCOHOL AND CANCERDISPARITIES IN ALCOHOL US…ALCOHOL AND CANCER: OUTCO…BARRIERS TO ADDRESSING AL…RESEARCH NEEDSPUBLIC HEALTH STRATEGIES …THE ROLE OF THE ONCOLOGIS…REFERENCES
The importance of alcohol drinking as a contributing factor to the overall cancer burden is often underappreciated. In fact, alcohol drinking is an established risk factor for several malignancies. As a potentially modifiable risk factor for cancer, addressing high-risk alcohol use is one strategy to reduce the burden of cancer. For example, in 2012, 5.5% of all new cancer occurrences and 5.8% of all cancer deaths worldwide were estimated to be attributable to alcohol.1 In the United States, it has been estimated that 3.5% of all cancer deaths are attributable to drinking alcohol.2 Alcohol is causally associated with oropharyngeal and larynx cancer, esophageal cancer, hepatocellular carcinoma, breast cancer, and colon cancer.3 Even modest use of alcohol may increase cancer risk, but the greatest risks are observed with heavy, long-term use.
Despite the evidence of a strong link between alcohol drinking and certain cancers, ASCO has not previously addressed the topic of alcohol and cancer. In addition, alcohol drinking is a potentially modifiable risk factor that can be targeted with preventive interventions at both the policy and the individual levels. Here, we provide an overview of the evidence of the links between alcohol drinking and cancer risk and cancer outcomes. The areas of greatest need for future research are highlighted. On the basis of this evidence and guidelines adopted by other cancer-focused organizations, ASCO-endorsed strategies for the reduction of high-risk alcohol consumption are presented.
EPIDEMIOLOGY OF ALCOHOL USEChooseTop of pageAbstractINTRODUCTIONEPIDEMIOLOGY OF ALCOHOL U… <<DRINKING GUIDELINES AND D…ALCOHOL AND CANCERDISPARITIES IN ALCOHOL US…ALCOHOL AND CANCER: OUTCO…BARRIERS TO ADDRESSING AL…RESEARCH NEEDSPUBLIC HEALTH STRATEGIES …THE ROLE OF THE ONCOLOGIS…REFERENCES
Beyond oncology, alcohol use and abuse together pose a significant public health problem. According to the Centers for Disease Control and Prevention, approximately 88,000 deaths were attributed to excessive alcohol use in the United States between 2006 and 2010.4 Approximately 3.3 million deaths worldwide result from the harmful use of alcohol each year.5 Population surveys demonstrate that 12% to 14% of adults have a current alcohol use disorder and that 29% have had such a disorder at some point in their lifetime.6,7 In addition to alcohol use disorder, other measures used to assess the impact of alcohol are excessive drinking, binge drinking, and heavy drinking. Excessive drinking includes binge drinking and is defined as consumption of four or more drinks during a single occasion for women, or five or more drinks during a single occasion for men. Binge drinking is the most common form of excessive drinking compared with heavy drinking, which is defined as eight or more drinks per week or three or more drinks per day for women, and as fifteen or more drinks per week or four or more drinks per day for men.8 Recent work has shown that the prevalence of adults who drink more than four to five drinks per occasion, defined as extreme binge drinking, has been increasing during the past decade.9 This study estimated that 13% of the US adult population engaged in extreme binge drinking on at least one occasion in the previous year. Moderate drinking is defined at up to one drink per day for women and up to two drinks per day for men.1,4 Most individuals who drink excessively do not meet the clinical criteria for alcoholism or alcohol dependence.10
Alcohol use during childhood and adolescence is a predictor of increased risk of alcohol use disorder as an adult.11 College-age and younger people who drink are prone to develop an alcohol use disorder later in life.7 Most adults who engage in high-risk alcohol drinking behavior started drinking before age 21 years. Among US youth age 12 to 20 years, 23% were current drinkers in the past 30 days, 10% were episodic drinkers, 2% were heavy episodic drinkers, and 6% met criteria for alcohol use disorder.11 Among childhood cancer survivors, the prevalence of alcohol use in the past 30 days in adulthood (7.8 mean years since diagnosis of their cancer) was 25%, which was lower than that observed in the general population.12 However, alcohol use among teenage patients with cancer is a common occurrence overall and has been observed to be as high among teens without cancer.13–15
DRINKING GUIDELINES AND DEFINITIONSChooseTop of pageAbstractINTRODUCTIONEPIDEMIOLOGY OF ALCOHOL U…DRINKING GUIDELINES AND D… <<ALCOHOL AND CANCERDISPARITIES IN ALCOHOL US…ALCOHOL AND CANCER: OUTCO…BARRIERS TO ADDRESSING AL…RESEARCH NEEDSPUBLIC HEALTH STRATEGIES …THE ROLE OF THE ONCOLOGIS…REFERENCES
Internationally, more than 40 countries have issued alcohol drinking guidelines; however, these vary substantially.16 The American Heart Association, American Cancer Society, and US Department of Health and Human Services all recommend that men drink no more than one to two drinks per day and that women drink no more than one drink per day.17–19 In addition, it is recommended that drinking alcohol should only be done by adults of legal age. People who do not currently drink alcohol should not start for any reason.
Defining risk-drinking can be challenging, because the amount of ethanol contained in an alcoholic beverage will vary considerably depending on the type of alcohol (eg, beer, wine, or spirits) and the size of the drink consumed. In addition, the definition of a standard drink varies among countries and ranges from 8 g to 14 g.20,21 The National Institute of Alcohol Abuse and Alcoholism (NIAAA) defines a standard drink as one that contains roughly 14 g of pure alcohol, which is the equivalent of 1.5 ounces of distilled spirits (approximately 40% alcohol by volume); 5 ounces of wine (approximately 12% alcohol by volume); or 12 ounces of regular beer (approximately 5% alcohol by volume).22 However, evidence shows that drinkers are often unaware of how standard drinks are defined and that these standard drink sizes are commonly exceeded.20
ALCOHOL AND CANCERChooseTop of pageAbstractINTRODUCTIONEPIDEMIOLOGY OF ALCOHOL U…DRINKING GUIDELINES AND D…ALCOHOL AND CANCER <<DISPARITIES IN ALCOHOL US…ALCOHOL AND CANCER: OUTCO…BARRIERS TO ADDRESSING AL…RESEARCH NEEDSPUBLIC HEALTH STRATEGIES …THE ROLE OF THE ONCOLOGIS…REFERENCES
Evidence to Link Alcohol Consumption to Specific Cancers
The relationship between drinking alcohol and cancer risk has been evaluated extensively in epidemiologic case-control and cohort studies. In a thorough systematic review of the world’s evidence that adhered to prespecified criteria for drawing inferences, a World Cancer Research Fund/American Institute for Cancer Research (AICR) report judged the evidence to be convincing that drinking alcohol was a cause of cancers of the oral cavity, pharynx, larynx, esophagus, breast, and colorectum (in men).23 Also, alcohol was judged to be a probable cause of increased risk of liver cancer and colorectal cancer (in women).23 An updated review of the evidence for liver cancer upgraded the conclusion for an association between alcohol drinking and liver cancer to convincing.24 The International Agency for Research on Cancer (IARC),25 a branch of WHO, has assessed the evidence and come to virtually identical conclusions: that alcohol is a cause of cancers of the oral cavity, pharynx, larynx, esophagus, colorectum, liver (ie, hepatocellular carcinoma), and female breast. For esophageal cancer, the association with alcohol drinking is largely specific to squamous cell carcinoma.25 The more that a person drinks, and the longer the period of time, the greater their risk of development of cancer, especially head and neck cancers.3
A valid question is whether these associations are specific to ethanol per se or whether they vary according to the type of alcoholic beverage (ie, beer, wine, or spirits/liquor). The answer is that the associations between alcohol drinking and cancer risk have been observed consistently regardless of the specific type of alcoholic beverage.25
The full range of cancers for which alcohol drinking represents a risk factor remains to be clarified. For example, the index of suspicion is high that alcohol drinking leads to excess risk of pancreatic cancer25 and gastric cancer.26 For some malignancies, alcohol drinking clearly is statistically associated with increased risk but, because of its strong correlation with other risk factors, it is difficult to discern if alcohol drinking is truly an independent risk factor. For example, alcohol drinking consistently has been statistically strongly associated with increased lung cancer risk.23 However, cigarette smokers also are more likely to be alcohol drinkers, and cigarette smoking is such an overwhelming lung cancer risk factor that confounding by cigarette smoking—rather than a direct association with alcohol drinking—currently cannot be ruled out as a possible explanation.27 As evidence continues to accumulate, the list of alcohol-associated cancers is likely to grow.
Magnitude of the Associations
Characterization of the dose-response relationship between alcohol and cancer is important for causal inference, because, if alcohol increases the risk for a specific cancer, one would expect the magnitude of the cancer risk to increase commensurate with increasing levels of alcohol consumption. Furthermore, the nature of the dose-response relationship provides useful information for communicating with patients about this issue. For alcohol-associated cancers, Table 1 summarizes results from a large-scale meta-analysis28 that show the relative risks of cancer in a comparison of nondrinkers with categories of people with light, moderate, and heavy alcohol consumption. The results summarized in Table 1 illustrate several key points. First, the magnitude of the association between alcohol drinking and cancer risk varied by type of cancer. Compared with nondrinkers, the summary relative risks (sRRs) for those classified as heavy drinkers ranged from 1.44 for colorectal cancer to 5.13 for cancer of the oral cavity and pharynx. The corresponding sRRs were 1.61, 2.07, 2.65, and 4.95 for cancers of the breast, liver, larynx, and esophagus, respectively. The strongest associations were observed for upper aerodigestive tract cancers (ie, larynx, esophagus, and oral cavity/pharynx), which involve tissues that come into direct contact with ingested alcohol. Second, monotonic dose-response relationships are evident for cancers of the oral cavity and pharynx, squamous cell carcinoma of the esophagus, and breast cancer. For liver, laryngeal, and colorectal cancers, the sRRs for the moderate category were intermediate between nondrinkers and heavy drinkers, but there was no evidence of increased risk in the light-drinker category. In a dose-response meta-analysis, the risk of secondary malignancies in patients with upper aerodigestive tract cancers increased incrementally by 9% for every increase in alcohol intake of 10 g/day.29
Table 1. Summary of Relative Risks From a Meta-Analysis for the Association Between Amount of Alcohol Drinking and Risk of Cancer
Clearly, the greatest cancer risks are concentrated in the heavy and moderate drinker categories. Nevertheless, some cancer risk persists even at low levels of consumption. A meta-analysis that focused solely on cancer risks associated with drinking one drink or fewer per day observed that this level of alcohol consumption was still associated with some elevated risk for squamous cell carcinoma of the esophagus (sRR, 1.30; 95% CI, 1.09 to 1.56), oropharyngeal cancer (sRR, 1.17; 95% CI, 1.06 to 1.29), and breast cancer (sRR, 1.05; 95% CI, 1.02 to 1.08), but no discernable associations were seen for cancers of the colorectum, larynx, and liver.30 On the basis of the lesser overall cancer risk at the lower end of the dose-response continuum, the World Cancer Research Fund/AICR made the following recommendation: “If alcoholic drinks are consumed, limit consumption to two drinks a day for men and one drink a day for women.”23 They also recommend that, “for cancer prevention, it’s best not to drink alcohol.” Recent updates to the AICR report estimate a 5% increase in premenopausal breast cancer per 10 grams of ethanol consumed per day (pooled relative risk [RR], 1.05; 95% CI, 1.02 to 1.08). The risk was even greater for postmenopausal breast cancer, which had an RR of 1.09 (95% CI, 1.07 to 1.12) for each 10 grams of ethanol per day.31
Does Cessation of Alcohol Consumption Lead to Lower Cancer Risk?
A key question relevant both to the assessment of causality and the provision of advice and effective interventions to patients is whether the risk of developing an alcohol-associated cancer is reduced after one stops drinking alcohol. The results of meta-analyses and pooled analyses that have focused directly on this question for upper aerodigestive tract cancers indicate that risk of these cancers declines in those who quit drinking alcohol compared with those who remain alcohol drinkers.32–35 The evidence from these studies suggests that the risk of cancer may be reduced to that seen in never drinkers after long-term (≥ 20 years) cessation from alcohol drinking. Unfortunately, there are limited existing data on the impact of alcohol cessation on the risk of other alcohol-related cancers. This important topic is in need of more thorough investigation, particularly because those who quit drinking alcohol may differ from current drinkers in important ways that are also associated with cancer risk. For example, similar to smoking cessation, an increased short-term risk of cancer after alcohol cessation may be due to the onset of cancer-related symptoms that contribute to the individual’s decision to stop drinking. Studies that carefully assess the time period between alcohol cessation and cancer diagnosis will help disentangle these complex methodological issues. Another potential bias is introduced by the finding that the category of former drinkers can be overrepresented by former heavy drinkers or alcoholics.36 When present, the risk of cancer after alcohol cessation may be higher than that observed for current drinkers because of the high alcohol exposure doses of those classified as former drinkers. Carefully designed prospective cohort studies will help overcome these bias-based limitations and will lead to a more refined characterization of the impact of cessation of alcohol drinking on cancer risk by longitudinally quantifying the amount of alcohol consumed and the duration of cessation.
Impact of Smoking in Combination With Alcohol Consumption
Some malignancies are causally linked to both alcohol drinking and cigarette smoking; in some cases, an established synergistic interaction between alcohol drinking and cigarette smoking exists. This means that, in cancers for which both alcohol drinking and cigarette smoking are causal factors, the cancer risks in those who are both alcohol drinkers and cigarette smokers are much larger than the risks seen for those who only drink alcohol or only smoke cigarettes. Specific upper aerodigestive tract cancers provide the strongest examples of robust synergistic interactions between alcohol drinking and cigarette smoking. A pooled analysis of 17 case-control studies identified a potent interaction between alcohol drinking and cigarette smoking in cancers of the oral cavity, pharynx, and larynx,37 and a review identified evidence of robust interaction in 22 of 24 published studies on oral, pharyngeal, laryngeal, and esophageal cancers.38 Despite the clear presence of synergistic interaction, the biologic underpinnings of the interaction between alcohol drinking and cigarette smoking are not well understood.
The Mechanistic Role of Alcohol in Carcinogenesis
When the evidence of alcohol’s role in carcinogenesis is considered, a key point is that, in biochemical reactions that are sequentially catalyzed by alcohol dehydrogenase and aldehyde dehydrogenase, ethanol is eliminated from the body by its oxidation first to acetaldehyde and then to acetate. Ethanol per se is not mutagenic, but acetaldehyde is carcinogenic and mutagenic, by binding to DNA and protein.39
The IARC reviewed the potential role of alcohol in carcinogenesis by synthesizing multiple bodies of evidence that included (1) experiments in which ethanol (or aldehyde) is administered to mice and rats in drinking water; (2) the absorption, distribution, metabolism, and excretion of ethanol and its metabolites; and (3) the genotoxicity of alcohol in various experimental systems, including biomarkers in humans.23 One key conclusion of the review was that, in animal models, administration of ethanol or acetaldehyde in drinking water increased the incidence of various tumors in mice and rats; also administration of other known carcinogens with ethanol in drinking water enhanced tumor development more.23 Another key conclusion was that “the role of ethanol metabolism in tumor initiation is implied by the associations observed between different forms of cancer and polymorphisms in genes involved in the oxidation of ethanol.”23 This point about polymorphisms is premised on the fact that genetic predisposition may amplify the toxic and mutagenic effects of alcohol consumption. A specific example of this line of reasoning is that most of the acetaldehyde generated during alcohol metabolism in vivo is eliminated promptly by aldehyde dehydrogenase-2 (ALDH2). However, a genetic variant of ALDH2 exists ([(rs671]*2) that encodes a catalytically inactive protein. Alcohol drinkers with the inactive form of ALDH2 experience excessive accumulation of acetaldehyde, which amplifies its toxic and mutagenic effects, and the amplification would be expected to lead to greater susceptibility to alcohol-induced cancer. Several studies in East Asian populations, who have the highest prevalence of this high-risk genotype, have documented that alcohol drinking is more strongly associated with cancers of the upper aerodigestive tract among those with a high-risk genotype.40 The IARC review also invoked mechanisms that included oxidative stress, sex hormones, folate metabolism, and DNA methylation as well as cirrhosis for hepatocellular carcinoma. Alcohol-induced oxidative stress, via the CYP2E1 pathway, for example, can result in chronic tissue inflammation.23 Alcohol drinking affects circulating concentrations of androgens and estrogens, which is a pathway of particular relevance to breast cancer.23 Consumption of alcohol is associated with lower folate concentrations—a relationship that has been extensively studied in relation to the etiology of colon cancer.41
Classification of Alcohol as a Carcinogen by the WHO
On the basis of the sum total of the evidence from research on mechanistic studies of the carcinogenicity of alcohol and the epidemiologic evidence to link alcohol with increased risk of multiple forms of cancer, the IARC classified alcohol as a group 1 carcinogen, because they found that it causes cancer in humans.41 Specifically, IARC concluded that there is sufficient evidence in humans for the carcinogenicity not only of alcohol consumption but also for the carcinogenicity of acetaldehyde associated with alcoholic beverage consumption.41
DISPARITIES IN ALCOHOL USE AND RELATED CANCERSChooseTop of pageAbstractINTRODUCTIONEPIDEMIOLOGY OF ALCOHOL U…DRINKING GUIDELINES AND D…ALCOHOL AND CANCERDISPARITIES IN ALCOHOL US… <<ALCOHOL AND CANCER: OUTCO…BARRIERS TO ADDRESSING AL…RESEARCH NEEDSPUBLIC HEALTH STRATEGIES …THE ROLE OF THE ONCOLOGIS…REFERENCES
Blacks, Asian Americans, and Hispanic individuals have lower rates of current alcohol use disorder than whites. However, rates among these groups appear to be increasing overall. The NIAAA has accumulated data during two decades by conducting large general-population surveys among US adults age 18 years and older. Their longitudinal surveys from 1991 to 1992 and 2001 to 2002 showed increases in alcohol abuse among men, women, and young black and Hispanic minorities. Rates of dependence also increased among men, young black women, and Asian men, which underscores the need to continue monitoring of prevalence and trends. It is now known that Hispanics and blacks have a higher risk than whites for developing alcohol-related liver disease.42 The longitudinal design of the NIAAA surveys enable the collection of data on cultural variables, such as acculturation. In addition to increasing overall rates, blacks and Hispanics are less likely to use alcohol treatment when it is available.43
All segments of US social strata are affected by alcohol abuse, but the prevalence of alcohol abuse is particularly high within American Indian and Alaska Native (AIAN) populations. AIAN people drink more alcohol and are more highly affected by alcohol-related illness than other populations.44 Among people age 12 years and older, the prevalence of binge drinking was 28% for AIAN people compared with 23% for whites, 22% for blacks, and 14% for Asian Americans. Findings from the 2000 to 2006 Behavioral Risk Factor Surveillance System showed that the rate of binge drinking was a major difference between non-Hispanic white and AIAN people, especially men.45 Similarly, rates of heavy drinking were highest (9%) among AIAN people and lowest (2%) among Asian Americans.44 The Indian Health Service, which provides a large amount of the health care to the AIAN community, addresses alcohol from a disease-model perspective.46 The Indian Health Service identifies alcoholism as a chronic disease with genetic, psychosocial, and environmental factors.47 Individuals with cirrhosis and chronic liver disease are at much higher risk of liver cancer, and the main preventable causes of these conditions are chronic infection with hepatitis B and C, chronic alcohol abuse, and nonalcoholic fatty liver disease. Though viral hepatitis prevention and treatment may be making a significant health difference already, addressing chronic alcohol abuse would be an important cancer prevention strategy.
Differential rates of alcohol use according to socioeconomic status hypothetically could contribute to cancer disparities. In reality, the relationship between alcohol drinking and socioeconomic status is complex, because it depends on how alcohol drinking is measured. When measures of alcohol use are used, those of a higher socioeconomic status are more likely to drink and to drink more heavily.48 However, for reasons that are poorly understood, measures of adverse consequences of alcohol tend to concentrate more among those of a lower socioeconomic status.48 A disproportionate share of the overall burden of cancer occurs in those of a lower socioeconomic status, so alcohol drinking may be a contributing factor to cancer disparities observed across the spectrum of socioeconomic status; however, this remains a relatively unexplored topic.49
Patterns of alcohol use and treatment also vary by sex and sexual orientation; higher rates are seen in sexual and gender minority populations (ie, lesbian, gay, bisexual, transgender, and intersex).50 This population also is known to bear a greater burden of cancer incidence.50 For example, although men have a higher prevalence of heavy drinking, women are less likely to use alcohol treatment services,43 even among those with alcohol dependence.51 Lesbian or bisexual female veterans had higher rates of alcohol misuse than heterosexual female veterans did, which may result at least in part from higher rates of trauma exposure and mental health difficulties experienced by the lesbian/bisexual women.52 Lesbian, gay, and bisexual young adults (ages 17 to 19 years) consume more alcohol both in high school and in college.53 A study of the National Longitudinal Study of Adolescent Health also confirmed significantly increased alcohol use and abuse among lesbian, gay, and bisexual youth.54 A recent ASCO position statement recommended increased cancer prevention education efforts, including reduction in high-risk alcohol use as a target effort.50
ALCOHOL AND CANCER: OUTCOMES AND EFFECT ON TREATMENTChooseTop of pageAbstractINTRODUCTIONEPIDEMIOLOGY OF ALCOHOL U…DRINKING GUIDELINES AND D…ALCOHOL AND CANCERDISPARITIES IN ALCOHOL US…ALCOHOL AND CANCER: OUTCO… <<BARRIERS TO ADDRESSING AL…RESEARCH NEEDSPUBLIC HEALTH STRATEGIES …THE ROLE OF THE ONCOLOGIS…REFERENCES
Compared with the wealth of evidence about the associations between alcohol drinking and the risk of developing cancer, research on the impact of alcohol drinking on outcomes in patients with cancer is still in its nascent stages. For cancers that have known associations with alcohol drinking, it would be expected that alcohol drinking at the time of diagnosis also would be associated with risk of cancer recurrence and/or secondary primary tumors (SPTs). This association has been observed for patients with upper aerodigestive tract cancer when nondrinkers are compared with occasional drinkers. The risk of cancer-specific mortality is increased significantly in moderate drinkers (RR, 1.79; 95% CI, 1.26 to 2.53) and heavy drinkers (RR, 3.63; 95% CI, 2.63 to 5.0).55 Among survivors of upper aerodigestive tract cancer, continued alcohol use after diagnosis is associated with a three-fold increased risk of upper aerodigestive tract second primary tumors,56 and cessation may reduce the increased risk for SPTs in pre-diagnosis drinkers compared with pre-diagnosis nondrinkers.29 In breast cancer survivors, several studies suggest that alcohol drinking is not associated with decreased overall survival,57 whereas other studies indicate that breast cancer–specific mortality may be increased in at least some subgroups of the patient population.58–60 The increase in breast cancer–specific mortality or risk of recurrence has been observed with moderate to heavy levels of alcohol drinking.60,61 Li et al showed that, among women with estrogen receptor–positive breast cancer, consumers of seven or more drinks per week versus none had a 90% increased risk of asynchronous contralateral breast cancer,62 which was higher than the 30% increased risk observed in a multicentered case-control study.63 Other SPTs in patients with breast cancer that have been associated with greater alcohol consumption (> 7 drinks per week versus none) include an increased risk of subsequent colorectal cancer (hazard ratio [HR], 1.92; 95% CI, 1.07 to 3.43) and a decreased risk of ovarian cancer (HR, 0.45; 95% CI, 0.21 to 0.98).64 Results of studies to evaluate the relationship between alcohol consumption and colorectal cancer have been mixed; one study observed that heavy drinking was associated with poorer survival,65 whereas the majority of studies have demonstrated either no association between alcohol drinking overall and colorectal cancer outcomes66 or a suggestion of better overall survival with higher levels of wine consumption.67 A recent meta-analysis of cohort studies among 209,597 cancer survivors showed a statistically significant 8% increase in overall mortality and a 17% increased risk for recurrence in the highest versus lowest alcohol consumers.68 More evidence is needed to clarify the impact of both alcohol drinking and cessation on cancer outcomes.
The majority of studies to evaluate the direct effects of alcohol use on cancer treatment have focused on patients with upper aerodigestive tract cancer, because 34% to 57% continue to drink after diagnosis.69 Smoking and alcohol use during and after radiation therapy have been associated with an increased risk of osteoradionecrosis of the jaw in patients with oral and oropharyngeal cancers.70–73
Alcohol abuse also complicates treatment outcomes among patients with cancer by contributing to longer hospitalizations, increased surgical procedures, prolonged recovery, higher health care costs,74–76 and higher mortality.77 Heavy alcohol use and abuse are important modifiable risk factors for postoperative morbidity.78 Heavy alcohol use79 and alcohol abuse,80 compared with no alcohol use, are associated with higher risks of anastomotic complications after colorectal surgery. Alcohol abuse, compared with no abuse, also has been shown to contribute to low quality-of-life outcomes in patients with head and neck cancer after treatment.81,82 Patients with cancer who abuse alcohol have increased comorbidities that can complicate treatment choices and that are affected by alcohol-related subclinical factors, including nutritional deficiencies, immunosuppression, and cardiovascular insufficiencies that increase treatment morbidity.83–85
Light alcohol use among cancer survivors has been perceived as potentially beneficial for treatment-related adverse effects, although there is little evidence to support this concept. A cross-sectional study of patients with head and neck cancer showed that patients who reported drinking at least one serving of alcohol in the past month reported better functional scores and lower levels of symptoms, such as fatigue, pain, dysphagia or dry mouth after treatment than those who reported that they had not used alcohol.86 Given the inability to distinguish the sequence of events in a cross-sectional study design, it is unclear whether light alcohol use promotes treatment recovery and well-being or is the result of improved health-related quality of life among survivors. The consumption of light alcohol for increasing appetite has been regarded as potentially beneficial for patients with cancer,87 because alcohol can stimulate appetite and snacking in cancer-free individuals.88 However, a recent study of patients with advanced cancer who had self-reported loss of appetite and who were randomly assigned to white wine with ≤ 15% alcohol content twice a day for 3 to 4 weeks versus a nutritional supplement showed no improvement in appetite or weight.89
BARRIERS TO ADDRESSING ALCOHOL AND CANCER IN THE ONCOLOGY SETTINGChooseTop of pageAbstractINTRODUCTIONEPIDEMIOLOGY OF ALCOHOL U…DRINKING GUIDELINES AND D…ALCOHOL AND CANCERDISPARITIES IN ALCOHOL US…ALCOHOL AND CANCER: OUTCO…BARRIERS TO ADDRESSING AL… <<RESEARCH NEEDSPUBLIC HEALTH STRATEGIES …THE ROLE OF THE ONCOLOGIS…REFERENCES
In addition to the perception that light alcohol use may have a beneficial effect on appetite and tolerance of cancer treatment, conflicting data about the heart health of alcohol, especially red wine, is one additional barrier to addressing alcohol and cancer risk in the oncology setting. However, subsequent work has revealed multiple confounders to this conclusion about heart health, including frequent classification of former and occasional alcohol drinkers as nondrinkers.90 For example, people who now abstain from alcohol often have underlying health concerns, which explains their reasons to cut down on alcohol and thereby makes the current alcohol drinkers appear healthier than former and occasional drinkers—a so-called abstainer bias.90 In addition, larger studies and meta-analyses have failed to show an all-cause mortality benefit for low-volume alcohol use compared with abstinence or intermittent use, which suggests the lack of a true benefit to daily alcohol use.91,92 Differences in alcohol dehydrogenase variants are associated with nondrinking, and nondrinkers have had lower rates of coronary heart disease and stroke than even light drinkers.93 As such, the benefit of alcohol consumption on cardiovascular health likely has been overstated.94,95 As reviewed in the Magnitude of the Association section, the risk of cancer is increased even with low levels of alcohol consumption,30 so the net effect of alcohol is harmful. Thus, alcohol consumption should not be recommended to prevent cardiovascular disease or all-cause mortality.
Low physician knowledge of alcohol use and cancer risk is another barrier to addressing alcohol use with patients. This lack of knowledge has been demonstrated among general practitioners, who were aware of an association of alcohol with cardiovascular health and obesity and who also felt that preventive health was an important aspect of their work; however, the majority of providers did not ask their patients about alcohol consumption, and most were unaware of alcohol as a carcinogen.96,97 A knowledge deficit was also seen among medical students relative to the role of alcohol as a risk factor in head and neck cancers.98 Knowledge of the association between cancer and alcohol also has been shown to be low among dentists and allied health professionals, who may be evaluating patients for these cancers. For example, dentists and dental hygienists have lower awareness of the association between alcohol use and head and neck cancers than family physician do (40% for dentists v 94% for family physicians), and this lack of knowledge would hamper their ability to counsel patients about alcohol-related cancers.99
In addition to a lack of knowledge of alcohol use as a cancer risk factor, physicians use different approaches to counseling patients about alcohol use. Just as overweight or obese physicians are less likely to counsel their patients about obesity,100 alcohol use among physicians may make them less likely to counsel patients about the risks of alcohol use. In one study of Danish physicians, 18.8% of physicians met criteria for risky alcohol consumption.101 Estimates indicate that up to 14% of American physicians will have an alcohol use disorder in their lifetime, which is a rate similar to the general population.102 Burnout, which is very common among oncology providers, also is strongly associated with high-risk alcohol use.103–107
RESEARCH NEEDSChooseTop of pageAbstractINTRODUCTIONEPIDEMIOLOGY OF ALCOHOL U…DRINKING GUIDELINES AND D…ALCOHOL AND CANCERDISPARITIES IN ALCOHOL US…ALCOHOL AND CANCER: OUTCO…BARRIERS TO ADDRESSING AL…RESEARCH NEEDS <<PUBLIC HEALTH STRATEGIES …THE ROLE OF THE ONCOLOGIS…REFERENCES
Although alcohol is a well-established risk factor for the development of certain cancers, very little is known about how current alcohol use affects cancer treatment delivery. Thus, the most compelling and urgent research need for the oncology community with regard to alcohol is better definition of the effect of concurrent alcohol use on cancer treatments, including chemotherapy, radiation, and surgery, as well as on cancer outcomes. Anecdotal stories from providers about the effect of alcohol on cancer treatment are intriguing, but rigorous scientific studies are needed to accurately quantify the effect. Underexplored research areas include the effects of alcohol exposure on postoperative morbidity; on the efficacy of chemotherapy and radiation; and on novel targeted therapies, such as immunotherapy and radiation.
Increased knowledge about the mechanistic effects of alcohol on cancer-related pathways and treatments may improve understanding of its role in disease progression and therapeutic responsiveness and toxicity. For example, a preclinical study demonstrated overlap between alcohol responsive genes and genes that are involved in responsiveness to endocrine therapy in breast cancer cells.108 The insufficient knowledge about the detrimental or potentially beneficial effects of alcohol use overall, as well as effects of its dose and frequency, among patients with cancer creates missed opportunities to intervene to improve overall quality of life and to educate patients about the cancer-specific prognostic role of alcohol.
Systems-based research, including research into successful means for the oncology community to identify patients who are currently using alcohol or who may be at high risk for alcohol relapse, will be critical. How to effectively apply evidence-based clinical interventions to assist patients in reduction of abstention from alcohol use also should be explored.
PUBLIC HEALTH STRATEGIES TO REDUCE HIGH-RISK ALCOHOL CONSUMPTIONChooseTop of pageAbstractINTRODUCTIONEPIDEMIOLOGY OF ALCOHOL U…DRINKING GUIDELINES AND D…ALCOHOL AND CANCERDISPARITIES IN ALCOHOL US…ALCOHOL AND CANCER: OUTCO…BARRIERS TO ADDRESSING AL…RESEARCH NEEDSPUBLIC HEALTH STRATEGIES … <<THE ROLE OF THE ONCOLOGIS…REFERENCES
Policies to reduce excessive alcohol consumption should be evidence based (such as those identified by WHO109 or the Community Preventive Services Task Force110), culturally sensitive, and equitable in their implementation. Recognizing that excessive alcohol use can delay or negatively impact cancer treatment and that reducing high-risk alcohol consumption is cancer prevention, ASCO joins the growing number of cancer care and public health organizations to support strategies designed to prevent high-risk alcohol consumption such as the following and those in Table 2.111–129
Table 2. Policy Recommendations of International Cancer Care and Public Health Organizations
Clinical strategies of alcohol screening and brief intervention provided in clinical settings: Health care providers can screen adults, including pregnant women, for excessive alcohol use to identify people whose levels or patterns of alcohol use place them at increased risk of alcohol-related harms. Health care providers can then recommend or offer treatment services to those at risk. Brief counseling interventions for adults who drink excessively have been found to positively affect several patterns of excessive drinking, including heavy episodic (binge) drinking and high average weekly intake of alcohol.130
Regulate alcohol outlet density: An alcohol outlet is defined as any site where alcohol may be legally sold to an individual to either consume on premises (eg, bars or restaurants) or off premises (eg, liquor stores or other retail settings).131 Using regulatory authority to reduce the number of alcohol outlets in a given area (ie, density) has proven to be an effective strategy for reducing excessive alcohol consumption.131–134 This is frequently executed through outlet licensing or zoning processes.
Increase alcohol taxes and prices: Taxes are placed on all alcohol beverages by both individual states and the federal government, and a portion of the federal excise tax may or may not be used to support treatment programs. Alcohol taxes vary from state to state and also differ in the amount applied based on the type of alcohol (eg, beer, wine, or spirits/hard liquor). Increasing taxes, and therefore the overall price of alcohol, has been shown to inversely effect levels of excessive consumption and related health harms.135–137 Other regulations that may directly or indirectly affect the price of alcoholic beverages, including regulations on wholesale distribution and bans on price-related promotions, may have some impact on excessive consumption, though more research is needed.137,138
Maintain limits on days and hours of sale: Limiting the days or hours during which alcoholic beverages can be sold can be applied to both outlets where the alcohol is consumed on premises and retail outlets where the alcohol is consumed off premises. These policies, made at the state and local levels, are intended to prevent excessive consumption by reducing access to the alcohol.139 Evidence from several studies has demonstrated the positive impact that reducing the number of days or hours that alcoholic beverages are sold generally result in a decrease in related harms.140,141
Enhance enforcement of laws prohibiting sales to minors: The minimum legal drinking age is 21 years in all US states. Enhanced enforcement of the minimum legal drinking age can reduce sales to minors (younger than 21 years) in retail settings (such as, bars, restaurants, liquor stores), thereby helping to reduce youth access to alcohol.130
Restrict youth exposure to advertising of alcoholic beverages: Early onset of drinking has been associated with an increased likelihood of developing dependence on alcohol later in life,142 and studies have demonstrated that youth exposed to more advertisements also show increases in drinking levels.143,144 The alcohol industry has only voluntary advertising codes created by the major trade groups, and are not subjected to federal restrictions. Currently, industry codes require that at least 70% of the audience of the advertisements (including print, radio, television, and internet/digital) consists of adults of legal drinking age.145–147 However, the alcohol industry is frequently noncompliant with its own self-regulation guidelines.148
Resist further privatization of retail alcohol sales in communities with current government control. Following the end of Prohibition in 1933, all states had wholesale of alcoholic beverages under state control. “License” states allowed retail sales by commercial interests, while some “control” states allowed alcohol to be sold, but only through government-run retail stores that restrict off-premises sales outlets (ie, outlets where alcohol is sold for consumption elsewhere). In the United States, all states and counties that permit the sale of alcohol allow privatized retail sales of beer, and most allow privatized retail sale of all alcoholic beverages. Privatization most often affects wine and spirits (eg, vodka and whiskey) in the control states.149
Include alcohol control strategies in comprehensive cancer control plans: State, tribal, and territorial comprehensive alcohol control strategies are not commonly included in comprehensive cancer control plans. Supporting the implementation of evidence-based strategies to prevent the excessive use of alcohol is one tool the cancer control community can use to reduce the risk of cancer.150
In addition to these strategies, ASCO supports efforts to eliminate pinkwashing in the marketing of alcoholic beverages. Pinkwashing is a form of cause marketing in which a company uses the color pink and/or pink ribbons to show a commitment to finding a cure for breast cancer. Given the consistent evidence that shows the link between alcohol consumption and an increased risk of breast cancer,25,151 alcoholic beverage companies should be discouraged from using the symbols of the battle against breast cancer to market their products.
THE ROLE OF THE ONCOLOGISTChooseTop of pageAbstractINTRODUCTIONEPIDEMIOLOGY OF ALCOHOL U…DRINKING GUIDELINES AND D…ALCOHOL AND CANCERDISPARITIES IN ALCOHOL US…ALCOHOL AND CANCER: OUTCO…BARRIERS TO ADDRESSING AL…RESEARCH NEEDSPUBLIC HEALTH STRATEGIES …THE ROLE OF THE ONCOLOGIS… <<REFERENCES
Worldwide, alcohol-related cancers are estimated to be 5.5% of all cancers treated annually, which represents a large number of patients. Oncologists frequently are the ones who manage the treatment of these patients, and they have a direct interest in promotion of the health of patients. Such promotion likely will include helping patients reduce high-risk alcohol use. Oncologists also stand in a position to drive the alcohol-related research agenda as it affects patients with cancer. The most pressing questions include how active alcohol use affects cancer treatments, how alcohol use affects risk of recurrence and overall prognosis, and how alcohol interacts with oral chemotherapy and supportive care medications. As front-line providers for these patients, another need to support is identification of the most effective strategies to help patients reduce their alcohol use. Ways to address racial, ethnic, sex, and sexual orientation disparities that will place these populations at increased rates for cancer also are needed. Oncology providers can serve as community advisors and leaders and can help raise the awareness of alcohol as a cancer risk behavior. Finally, because alcohol use is quite common, an initiative to address alcohol use (particularly high-risk alcohol use) is a potential preventive strategy to decrease the burden of cancer. Policy efforts are likely to be the most effective way to address this need.
Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)–directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and HER2-mutant non–small-cell lung cancer. Treatments are limited for other HER2-expressing solid tumors.
METHODS
This open-label phase II study evaluated T-DXd (5.4 mg/kg once every 3 weeks) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic treatment or without alternative treatments. The primary end point was investigator-assessed confirmed objective response rate (ORR). Secondary end points included safety, duration of response, progression-free survival (PFS), and overall survival (OS).
RESULTS
At primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. The median follow-up was 12.75 months. In all patients, the ORR was 37.1% (n = 99; [95% CI, 31.3 to 43.2]), with responses in all cohorts; the median DOR was 11.3 months (95% CI, 9.6 to 17.8); the median PFS was 6.9 months (95% CI, 5.6 to 8.0); and the median OS was 13.4 months (95% CI, 11.9 to 15.5). In patients with central HER2 IHC 3+ expression (n = 75), the ORR was 61.3% (95% CI, 49.4 to 72.4), the median DOR was 22.1 months (95% CI, 9.6 to not reached), the median PFS was 11.9 months (95% CI, 8.2 to 13.0), and the median OS was 21.1 months (95% CI, 15.3 to 29.6). Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths.
CONCLUSION
Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pretreated patients with HER2-expressing tumors receiving T-DXd. Greatest benefit was observed for the IHC 3+ population. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with HER2-expressing solid tumors.
INTRODUCTIONChooseTop of pageAbstractINTRODUCTION <<METHODSRESULTSDISCUSSIONREFERENCES
Human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor involved in the stimulation of cell proliferation, differentiation, and survival.1 HER2 overexpression can occur in a range of solid tumors, including breast, gastric, biliary tract, bladder, pancreatic, and gynecological tumors.2 HER2 overexpression is associated with a biologically aggressive tumor phenotype, poor prognosis, increased risk of disease recurrence, and limited benefit from chemotherapy.1,3–5 HER2-directed therapy is standard of care for HER2-expressing unresectable or metastatic breast cancer, HER2-positive locally advanced or metastatic gastric cancers, colorectal and gastroesophageal junction adenocarcinomas, and HER2-mutant non–small-cell lung cancer.6–9 However, many patients with other HER2-expressing solid tumors will progress on standard therapy, with poor prognosis and limited alternatives.5,10–13 This represents an opportunity to improve outcomes for such patients with novel HER2-targeted therapeutics.
CONTEXT
Key Objective
What is the efficacy and safety of trastuzumab deruxtecan (T-DXd; 5.4 mg/kg once every 3 weeks) in previously treated patients with locally advanced or metastatic human epidermal growth factor 2 (HER2)–expressing (immunohistochemistry [IHC] 3+/2+) solid tumors?
Knowledge Generated
DESTINY-PanTumor02 demonstrated that treatment with T-DXd resulted in durable responses across multiple tumor types, alongside clinically meaningful rates of progression-free survival and overall survival, with the greatest benefit observed in the HER2 IHC 3+ population. The safety profile was consistent with the known profile for T-DXd, including the incidence of interstitial lung disease (ILD).
Relevance (G.F. Fleming)
T-DXd provides meaningful benefit for patients with multiple types of solid tumors that express HER2, particularly for those whose tumors express HER2 at the 3+ level on central review.**Relevance section written by JCO Associate Editor Gini F. Fleming, MD.
Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate composed of a humanized immunoglobulin G1 anti-HER2 monoclonal antibody, a tetrapeptide-based cleavable linker, and a potent topoisomerase I inhibitor payload.14 T-DXd is currently approved in the United States and European Union for treatment of HER2-expressing breast cancer and HER2-positive gastric or gastroesophageal junction adenocarcinoma and in the United States and Japan for HER2-mutant non–small cell lung cancer.15–17 In early-phase studies, T-DXd demonstrated antitumor activity in a range of HER2–expressing malignancies, including colorectal, salivary gland, biliary tract, and endometrial cancer.18 In August 2023, T-DXd was granted breakthrough therapy designations in the United States for adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors that have progressed after prior treatment and have no satisfactory alternatives and for patients with HER2-positive (IHC 3+) metastatic colorectal cancer who have received ≥2 prior treatment regimens.19 The aim of this study (ClinicalTrials.gov identifier: NCT04482309) was to assess the efficacy and safety of T-DXd in patients with selected, locally advanced, metastatic, or unresectable HER2-expressing solid tumors.
METHODSChooseTop of pageAbstractINTRODUCTIONMETHODS <<RESULTSDISCUSSIONREFERENCES
Study Design and Participants
This open-label, multicenter, phase II study (ClinicalTrials.gov identifier: NCT04482309) evaluated the efficacy and safety of T-DXd 5.4 mg/kg once every 3 weeks in patients with previously treated HER2-expressing solid tumors in seven cohorts.
Eligible patients were age 18 years or older; had histologically confirmed locally advanced, unresectable, or metastatic biliary tract, bladder, cervical, endometrial, ovarian, pancreatic, or other solid cancers (excluding breast, colorectal, gastric, and non–small-cell lung cancers); who progressed after ≥1 systemic treatment or had no satisfactory alternative treatment options; Eastern Cooperative Oncology Group performance status of 0-120; HER2-overexpressing tumors with IHC 3+/2+ (local or central testing) scored using current ASCO/College of American Pathology guidelines for scoring HER2 in gastric cancer21; and had ≥1 investigator-assessed measurable lesion on the basis of RECIST 1.1.22 Patients with noninfectious interstitial lung disease (ILD)/pneumonitis requiring steroids, or if suspected ILD/pneumonitis could not be ruled out by imaging at screening, were excluded. HER2 expression for eligibility was based on local assessment, where available. Otherwise, eligibility was determined by central testing. HER2 IHC status was assessed centrally using HER2 HercepTest (DAKO) and scored according to gastric-specific criteria. Prior HER2-targeted therapy was permitted. Eligibility criteria are provided in Appendix 2, online only.
The study Protocol (online only) was approved by the institutional review board at each site and was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice, the Declaration of Helsinki, and local regulations on the conduct of clinical research. All patients provided written informed consent before study participation.
Procedures
T-DXd was administered intravenously once every 3 weeks at 5.4 mg/kg of body weight. RECIST scans were performed at screening and every 6 weeks until documented disease progression (RECIST 1.1) or withdrawal of consent. Treatment continued until documented disease progression (RECIST 1.1), withdrawal of consent, or when discontinuation criteria were met. Dose interruptions and/or reduction and supportive therapy were permitted for clinically significant and/or unacceptable toxicity. For suspected ILD/pneumonitis, treatment was interrupted pending evaluation, and all events were followed until resolution (including after discontinuation) regardless of severity (Appendix 2).
End Points
The primary end point was investigator-assessed confirmed objective response rate (ORR), defined as the proportion of patients with a confirmed complete or partial response by RECIST 1.1 (Appendix 2). Secondary efficacy end points included duration of response (DOR; time from date of first documented response [complete or partial] until the date of documented progression or death in the absence of disease progression); disease control rate (percentage of patients with a best objective response of confirmed complete response or partial response, or with stable disease for at least 5 weeks after first dose); progression-free survival (PFS; time from first dose until date of objective disease progression or death regardless of withdrawal or receipt of another cancer therapy); and overall survival (OS; time from date of first dose until death due to any cause). An independent central review per RECIST 1.1 was performed and reported alongside the investigator-assessed results for secondary outcomes. Exploratory endpoints included subgroup analysis by HER2 status.
Secondary safety end points included the occurrence of adverse events (including drug-related adverse events, serious adverse events, and adverse events of special interest [ILD/pneumonitis and left ventricular dysfunction]) and changes in vital sign measurements and standard clinical laboratory parameters. Adverse events were coded and graded according to the Medical Dictionary for Regulatory Activities (version 26.0) and National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Potential cases of ILD/pneumonitis were evaluated by an independent adjudication committee.
Statistical Analysis
A sample size of 40 patients per cohort was determined to provide sufficient precision for the estimation of objective response in each cohort (eg, for ORR 35%, exact CI would be 20.6 to 51.7). Efficacy and safety results are presented by cohort and overall on the basis of the full analysis set (patients who received at least one dose of study medication). Outcomes are reported in all patients enrolled by local and central testing; subgroup analyses by HER2 status are reported as confirmed by central testing alone. Descriptive statistics were used to summarize each end point. Kaplan-Meier estimations were used to describe DOR, PFS, and OS. Exact 95% CIs for binomial proportions were calculated using the Clopper-Pearson method.
RESULTSChooseTop of pageAbstractINTRODUCTIONMETHODSRESULTS <<DISCUSSIONREFERENCES
Between October 7, 2020, and July 7, 2022, a total of 268 patients with HER2-expressing solid tumors were enrolled from >120 sites across 15 countries. Of them, 267 (99.6%) patients received at least one dose of study treatment and were included in the full analysis set; one patient withdrew before receiving treatment (Appendix Fig A1).
The median age was 62 (range, 23-85) years. Patients had received a median of two lines of prior therapy (range, 0-12; Table 1). Across all cohorts, 40.8% had received ≥three prior lines, and 14.2% had received prior HER2 therapy (trastuzumab [12.4%], pertuzumab [1.9%], zanidatamab [1.5%], trastuzumab emtansine [1.1%], trastuzumab duocarmazine [0.4%], and/or tucatinib [0.4%]). The other tumors cohort included patients with salivary gland cancer (n = 19), malignant neoplasm of unknown primary site (n = 5), extramammary Paget disease (n = 3), cutaneous melanoma (n = 2), oropharyngeal neoplasm (n = 2), adenoid cystic carcinoma, head and neck cancer, lip and/or oral cavity cancer, esophageal adenocarcinoma, intestinal adenocarcinoma, appendiceal adenocarcinoma, esophageal squamous cell carcinoma, testicular cancer, and vulvar carcinoma (all n = 1).
TABLE 1. Demographics and Baseline Clinical Characteristics
In total, 202 patients were enrolled on the basis of local HER2 testing, and 65 patients were enrolled on the basis of central HER2 testing. According to HER2 testing for eligibility, 111 patients were enrolled with IHC 3+ expression, 151 with IHC 2+ expression, and five with IHC 1+ expression (Table 1). On the basis of central testing, there were 75 patients with IHC 3+ expression, 125 with IHC 2+ expression, 25 with IHC 1+ expression, 30 with IHC 0 expression, and 12 patients were unknown, owing to unavailable/unevaluable samples for central testing (Appendix Table A1).
At data cutoff (June 8, 2023), the median follow-up duration across all cohorts was 12.75 months (range, 0.4-31.6); 235 patients had discontinued treatment (progressive disease [n = 167, 62.5%], any adverse event [n = 32, 12.0%], death during study [n = 18, 6.7%], patient decision [n = 11, 4.1%], investigator decision [n = 4, 1.5%], unknown [n = 2, 0.7%], lost to follow-up [n = 1, 0.4%]), and 32 (12.0%) patients remained on treatment. The median number of 21-day treatment cycles for all patients was eight.
Among the 267 patients, 99 patients (37.1%; [95% CI, 31.3 to 43.2]) had a confirmed objective response by investigator assessment. Investigator-assessed ORRs in all patients by cohort (Fig 1 and Appendix Table A2) were 57.5% for endometrial (95% CI, 40.9 to 73.0), 50.0% for cervical (95% CI, 33.8 to 66.2), 45.0% for ovarian (95% CI, 29.3 to 61.5), 39.0% for bladder (95% CI, 24.2 to 55.5), 30.0% for other tumors (95% CI, 16.6 to 46.5), 22.0% for biliary tract (95% CI, 10.6 to 37.6), and 4.0% for pancreatic (95% CI, 0.1 to 20.4). In patients with centrally confirmed HER2 IHC 3+ expression (n = 75), investigator-assessed ORRs by cohort (Fig 1) were 84.6% for endometrial (n = 13 [95% CI, 54.6 to 98.1]), 75.0% for cervical (n = 8 [95% CI, 34.9 to 96.8]), 63.6% for ovarian (n = 11 [95% CI, 30.8 to 89.1]), 56.3% for bladder (n = 16 [95% CI, 29.9 to 80.2]), 44.4% for other tumors (n = 9 [95% CI, 13.7 to 78.8]), 56.3% for biliary tract (n = 16 [95% CI, 29.9 to 80.2]), and 0% for pancreatic cancer (n = 2). In the pancreatic cohort, no objective response was observed in the first 15 patients, and the cohort was closed for further recruitment according to prespecified futility criterion, by which time 25 patients had been enrolled. Investigator-assessed ORRs by central IHC 3+/2+ status are provided in Figure 1A.
FIG 1.Investigator-assessed responses as per RECIST 1.1. (A) ORR across tumor cohorts, according to HER2 status by central testing. aResponses in the other tumors cohort include responses in extramammary Paget disease, oropharyngeal neoplasm, head and neck cancer, and salivary gland cancer. (B) The maximum change in tumor size, according to tumor type. Patients with IHC 3+ status (central testing) are marked with a dot. The other tumors cohort includes responses in extramammary Paget disease, head and neck cancer, oropharyngeal neoplasm, and salivary gland cancer. (C) DOR in patients with an objective response, according to tumor type. DOR was defined as the time from the date of first documented response (complete response or partial response) until the date of documented progression, or death in the absence of disease progression. Response was determined by investigator assessment according to RECIST 1.1 and required confirmation after the first observed response at least 4 weeks later. Censored patients are marked with a rounded dot, patients who stopped responding are marked with a triangular dot, and patients with a complete response are marked with a square dot. BTC, biliary tract cancer; DOR, duration of response; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ORR, objective response rate.
Responses were observed in patients who received (n = 38; 36.8% [95% CI, 21.8 to 54.0]) or did not receive (n = 227; 37.4% [95% CI, 31.1 to 44.1]) prior HER2 therapy. Across all tumor types, 100 patients (37.5% [95% CI, 31.6 to 43.6]) had a confirmed ORR by independent central review. By cohort, ORRs by independent central review in all patients were 57.5% for endometrial (95% CI, 40.9 to 73.0), 37.5% for cervical (95% CI, 22.7 to 54.2), 42.5% for ovarian (95% CI, 27.0 to 59.1), 41.5% for bladder (95% CI, 26.3 to 57.9), 35.0% for other tumors (95% CI, 20.6 to 51.7), 26.8% for biliary tract (95% CI, 14.2 to 42.9), and 12.0% for pancreatic (95% CI, 2.5 to 31.2).
The investigator-assessed median DOR (Fig 1C and Appendix Table A2) across all cohorts was 11.3 months (95% CI, 9.6 to 17.8), ranging from 5.7 months in the pancreatic cohort to 22.1 months in the other tumors cohort; median DOR was not reached in the endometrial cohort. In all HER2 subgroups, the longest median DOR was in patients with IHC 3+ (22.1 months [95% CI, 9.6 to not reached]).
The investigator-assessed median PFS (Fig 2 and Appendix Table A2) was 6.9 months (95% CI, 5.6 to 8.0), ranging from 3.2 months in the pancreatic cohort to 11.1 months in the endometrial cohort. In all HER2 subgroups, the longest median PFS was in patients with IHC 3+ (11.9 months [95% CI, 8.2 to 13.0]). PFS by tumor cohort and HER2 status is provided in Figure 2 and Appendix Table A2.
FIG 2.Kaplan-Meier estimates of PFS, according to tumor type. (A) Endometrial cancer, (B) cervical cancer, (C) ovarian cancer, (D) bladder cancer, (E) other tumors, (F) biliary tract cancer, and (G) pancreatic cancer. IHC, immunohistochemistry; NR, not reached; PFS, progression-free survival.
Across all cohorts, the median OS (Fig 3 and Appendix Table A2) was 13.4 months (95% CI, 11.9 to 15.5; 66% maturity), ranging from 5.0 months in the pancreatic cohort to 26.0 months in the endometrial cohort. In all HER2 subgroups, the longest median OS was in patients with IHC 3+ (21.1 months [95% CI, 15.3 to 29.6]). OS by tumor cohort and HER2 status is provided in Figure 3 and Appendix Table A2.
FIG 3.Kaplan-Meier estimates of OS, according to tumor type. (A) Endometrial cancer, (B) cervical cancer, (C) ovarian cancer, (D) bladder cancer, (E) other tumors, (F) biliary tract cancer, and (G) pancreatic cancer. IHC, immunohistochemistry; NR, not reached; OS, overall survival.
Percentage change of target lesion size from baseline and a full breakdown of efficacy in the other tumors cohort are shown in Appendix Fig A2 and Appendix Table A3, respectively.
Among 267 treated patients (median follow-up of 12.75 months), ≥1 investigator-assessed drug-related adverse event was experienced by 226 (84.6%) patients (Table 2), with the most common being nausea (55.1%), anemia (27.7%), diarrhea (25.8%), vomiting (24.7%), and fatigue (24.7%). Grade 3 or higher drug-related adverse events occurred in 109 (40.8%) patients, with the most common being neutropenia (10.9%) and anemia (10.9%). Serious drug-related adverse events occurred in 36 (13.5%) patients. Drug-related adverse events led to discontinuation in 23 (8.6%) patients and dose reduction in 54 (20.2%) patients. Drug-related adverse events and non–drug-related adverse events resulting in death occurred in four (1.5%) and 19 (7.1%) patients, respectively. Adjudicated drug-related events of ILD/pneumonitis occurred in 28 (10.5%) patients, with the majority as low grade (grade 1, n = 7 [2.6%]; grade 2, n = 17 [6.4%]). There was one (0.4%) grade 3 event and three (1.1%) fatal adjudicated drug-related cases of ILD/pneumonitis, one each in the biliary tract, endometrial, and other tumors cohorts. Non-drug–related adverse events are provided in Appendix Table A4.
DISCUSSIONChooseTop of pageAbstractINTRODUCTIONMETHODSRESULTSDISCUSSION <<REFERENCES
In this phase II study, T-DXd demonstrated durable responses across multiple tumor types, alongside clinically meaningful PFS and OS in pretreated patients. The highest response rates and longest DOR, PFS, and OS were observed in tumors with IHC 3+ expression. Responses were also observed irrespective of prior HER2 therapy.
HER2 protein expression, gene amplification, and gene mutation have been identified as therapeutic targets in multiple tumor types.23 However, HER2-targeted therapy is not currently approved beyond breast, gastric, colorectal, and lung cancer.5,15,24 The tumor types investigated here were predefined on the basis of epidemiological frequency, prevalence of HER2 expression, and unmet medical need.2,5 Investigations are supported by phase I clinical data of T-DXd and encouraging results from the HERALD phase II basket trial which assessed T-DXd in advanced solid tumors with HER2 amplification.18,25
Of note are the magnitudes of benefit observed in the endometrial, cervical, and ovarian cohorts; the highest ORRs were observed in these cohorts across all studied tumor types (57.5% for endometrial, 50.0% for cervical, 45.0% for ovarian). To the best of our knowledge, this is the first report of a HER2-directed antibody-drug conjugate in these gynecological tumors. In the endometrial cohort, 77.5% of patients had ≥two prior lines of therapy. The ORR in patients with HER2 IHC 3+ expression was 84.6%. In all patients with endometrial cancer, median PFS and OS were 11.1 months and 26.0 months, respectively. The clinically significant response and survival rates observed in this study are encouraging for HER2-expressing endometrial cancers, which are typically associated with high risk for progression and poor survival rates.10 In the cervical cohort, 85.0% of patients had ≥two prior lines of therapy, and the ORR in patients with HER2 IHC 3+ expression was 75.0%. The median OS in this cohort was 13.6 months in all patients, not reached in IHC 3+ patients, and 11.5 months in IHC 2+ patients. These data are promising in a cohort with few treatment options and a typically low response rate to treatment.11 The median number of prior treatments in the ovarian cohort was three, and 35.0% of patients had five or more prior lines of therapy; the median OS was 13.2 months in all patients and 20.0 months in patients with HER2 IHC 3+ expression. The results from this study further support use of a HER2 antibody-drug conjugate for treating ovarian cancer, and the outcomes are promising for a disease subgroup with a high mortality rate.12,26
Although there was only one investigator-assessed responder in the pancreatic cohort (4.0%; closed to recruitment with 25 patients enrolled), when assessed by independent central review, three responses were observed (12.0%). PFS and OS results showed potential in the late-line pancreatic cancer setting; however, it is challenging to draw conclusions from this cohort owing to the low patient numbers, particularly in the IHC 3+ group.
Biliary tract cancer (BTC) is uncommon12 but has a high mortality rate13 and limited clinical benefit from second-line chemotherapy.27 The phase II trial of T-DXd in patients with unresectable or recurrent HER2-expressing BTCs showed promising activity in patients with HER2-positive (IHC 3+ and IHC 2+/in-situ hybridization+) BTC.28 The data in the DESTINY-PanTumor02 trial further support HER2 as a therapeutic target in BTC where an ORR of 56.3% and OS of 12.4 months were observed in patients with IHC 3+ tumors.
Safety findings for T-DXd in this trial were consistent with the established safety profile.15 A risk of pulmonary adverse events, primarily ILD/pneumonitis, has been observed in patients receiving T-DXd and is an important consideration for these patients.29,30 Although most cases of adjudicated drug-related ILD in this trial were low-grade and manageable and overall incidence was consistent with that in previous studies,31 three adjudicated drug-related ILD/pneumonitis-related deaths occurred. Multidisciplinary guidelines for diagnosing and managing T-DXd–related ILD/pneumonitis have been published.29 T-DXd–related ILD/pneumonitis can be safely managed with a multidisciplinary team, who should manage the ILD/pneumonitis jointly with the medical oncologist and may include a primary care physician, nurse practitioner, pulmonologist, pathologist, pharmacist, infectious disease specialist, and radiologist. Patients should be proactively monitored for ILD/pneumonitis, and suspected cases should be actively managed by a multidisciplinary team; T-DXd treatment should be interrupted in the event of grade 1 ILD/pneumonitis, and the event must resolve before treatment may resume.29
This tumor-agnostic biomarker-driven approach represents an innovative application of the principles of precision medicine.5 Despite the prospects of the tumor-agnostic strategy, only six drugs have received US Food and Drug Administration approval on the following basis: pembrolizumab for microsatellite instability high, mismatch repair deficient, or tumor mutational burden high tumors; dostarlimab for mismatch repair deficient tumors; larotrectinib or entrectinib for tumors with NTRK gene fusions; dabrafenib plus trametinib for tumors with BRAF V600E mutations; and selpercatinib for tumors with RET gene fusions.32 As with those studies, this trial has a clear rationale on the basis of preclinical/clinical data and demonstrates meaningful antitumor activity across endometrial, cervical, ovarian, bladder, biliary tract, and other tumor cohorts.
A tumor-agnostic investigative approach has some limitations, most notably the single-arm nature of the studies. It was not possible to include a single comparator, given the range of tumor types that were included. Another potential limitation is the few patients included with HER2 IHC 1+ tumors. The protocol allowed for recruitment of patients with HER2 IHC 1+ tumors once 3 of 15 responders within a cohort had been observed in centrally confirmed HER2 IHC 3+ or IHC 2+ tumors. However, only the cervical cohort prospectively opened enrollment to patients with IHC 1+ tumors as recruitment in other cohorts was complete by the time response rate data were available on the first 15 patients. There is limited evidence available from this study in HER2-low patients, a population of growing clinical interest after the approval of T-DXd in HER2-low breast cancer.15 The few responses in patients who were determined to be IHC 1+/0 on retrospective central testing suggest that further exploration in patients with IHC 1+ tumors is warranted beyond breast cancer.
In this global, multicenter phase II study, treatment with T-DXd demonstrated robust clinical activity providing durable clinical benefit for pretreated patients with selected HER2-expressing solid tumors. The observed safety profile, including ILD, was consistent with that in previously reported studies of T-DXd. These data provide clinical evidence for antitumor activity of T-DXd across multiple tumor types, suggesting potential tumor-agnostic activity in patients with HER2-expressing solid tumors.
External-beam radiation therapy (RT) is standard of care (SOC) for pain relief of symptomatic bone metastases. We aimed to evaluate the efficacy of radiation to asymptomatic bone metastases in preventing skeletal-related events (SRE).
METHODS
In a multicenter randomized controlled trial, adult patients with widely metastatic solid tumor malignancies were stratified by histology and planned SOC (systemic therapy or observation) and randomly assigned in a 1:1 ratio to receive RT to asymptomatic high-risk bone metastases or SOC alone. The primary outcome of the trial was SRE. Secondary outcomes included hospitalizations for SRE and overall survival (OS).
RESULTS
A total of 78 patients with 122 high-risk bone metastases were enrolled between May 8, 2018, and August 9, 2021, at three institutions across an affiliated cancer network in the United States. Seventy-three patients were evaluable for the primary end point. The most common primary cancer types were lung (27%), breast (24%), and prostate (22%). At 1 year, SRE occurred in one of 62 bone metastases (1.6%) in the RT arm and 14 of 49 bone metastases (29%) in the SOC arm (P < .001). There were significantly fewer patients hospitalized for SRE in the RT arm compared with the SOC arm (0 v 4, P = .045). At a median follow-up of 2.5 years, OS was significantly longer in the RT arm (hazard ratio [HR], 0.49; 95% CI, 0.27 to 0.89; P = .018), which persisted on multivariable Cox regression analysis (HR, 0.46; 95% CI, 0.23 to 0.85; P = .01).
CONCLUSION
Radiation delivered prophylactically to asymptomatic, high-risk bone metastases reduced SRE and hospitalizations. We also observed an improvement in OS with prophylactic radiation, although a confirmatory phase III trial is warranted.
To determine if prophylactic radiation to asymptomatic high-risk bone metastases reduces the incidence of skeletal-related events (SRE), including pathologic fracture, spinal cord compression, orthopedic surgery to bone, and/or palliative radiation therapy for pain.
Knowledge Generated
In this multicenter randomized controlled trial conducted in the United States that included 78 adult patients with metastatic solid tumor malignancies, radiation reduced SRE at 1 year from 29% to 1.6% compared with standard of care. Additionally, overall survival was extended with use of radiation (median 1.7 v 1.0 years) with a hazard ratio 0.49, which maintained significance on adjusted analysis.
Relevance (B.G. Haffty)
This randomized phase II trial is relevant in demonstrating statistically and clinically significant decreases in SRE including pathological fracture, spinal cord compression, or orthopedic intervention with prophylactic radiation to asymptomatic but high risk bone metastasis.*
In the article that accompanies this editorial, Leypoldt et al1 describe the results of a forward-thinking study focused on the management of high-risk newly diagnosed multiple myeloma (HR NDMM) using the quadruplet (quad) regimen: isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd). This multicenter, phase II trial enrolled patients with HR NDMM, cytogenetically defined as the presence of del17p, t(4;14), t(14;16), or more than three copies of 1q21. Patients were not eligible if they had Revised International Staging System (R-ISS) stage I disease. Both transplant-eligible (TE) and transplant-ineligible (TIE) patients received continuous therapy with Isa-KRd induction followed by Isa-KR maintenance interrupted by an autologous stem cell transplant (ASCT) among TE patients or two further cycles of Isa-KRd among TIE patients. Leypoldt et al1 report the results of the primary end point, which is minimal residual disease (MRD) negativity (<10–5 MRD by next-generation flow [NGF]) at the end of consolidation. The secondary end point was progression-free survival (PFS). While this was a concept study, how does this set us up for the future in managing patients with HR NDMM? German lore tells us of the good fortune of the Glücksklee, the four-leaf clover. Is this trial using a quad regimen for HR NDMM the answer we have been seeking? Let us consider four (lucky) points.
THE TAKEAWAY
In the article that accompanies this editorial, Leypoldt et al1 describe the results of a forward-thinking study focused on the management of patients with high-risk newly diagnosed multiple myeloma using the quadruplet regimen isatuximab, carfilzomib, lenalidomide, and dexamethasone. The results of this study mimic other data taking advantage not only of the addition of a CD38 monoclonal antibody, but also the use of long term combination maintenance therapy, a concept championed by our group over a decade ago.1 The result of this trial is an impressive depth of response as measured by minimal residual disease negativity and impressive progression-free survival (PFS) for a very challenging group of patients who are known to have poor PFS and overall survival with standard treatment approaches.
First, how do we measure and compare outcomes for a heterogeneous group of patients? The study population included patients with R-ISS II/III disease and presence of fluorescent in situ hybridization/cytogenetics abnormalities of del17p, t(4;14), t(14;16), or 1q21 (>3 copies). The assumption is that all are equally bad, but we now know that is not the case. In the era of immunomodulatory agent (IMiD)/proteasome inhibitor (PI) induction, isolated 1q amp does not carry the same risk as del17p or the combination of amp 1q and del17p. Several trials have confirmed that ≥two high-risk cytogenetic abnormalities (HRCAs) do extremely poorly even with triplet maintenance (IMiD/PI/steroids). Are there data demonstrating that CD38 monoclonal antibody (mAB) improves outcomes in HR NDMM? In the MASTER study, it did not appear to, but that may have been confounded by early discontinuation among patients achieving sustained MRD negativity (threshold of 10−5 as well, but by next-generation sequencing [NGS]) early.2 A study from our group using carfilzomib, pomalidomide, and dexamethasone as combination maintenance therapy post-ASCT resulted in higher rates of MRD negativity by NGS (10−6, not 10−5), but even here, patients with ≥two HRCAs did worse compared with those who carried only one HRCA.3 In summary, can we call this study a win when isolated 1q21 (>three copies) accounted for a third of the patient population (20% of TE and 45% of TIE) and two thirds of patients had one HRCA (60 of 99 TE patients and 17 of 26 TIE patients), which is considerably higher than what is presented in most studies. In the GRIFFIN trial, 15% had HRCAs (del17p, t[4;14], or t[14;16], or a combination of the above), but this number was upgraded to 41% with the inclusion of 1q21 (≥3 copies).4 The heterogeneity of the population may call for redefining our risk groups rather than broadening the definition of high risk, raising a question of patient selection affecting the reported outcomes.
Second, what is the optimal end point for measuring success in high-risk disease? The primary end point in this trial is MRD negativity (<10−5 MRD by NGF cytometry) at the end of consolidation. The secondary end point was PFS. This raises the question of the optimal measure of success (the ideal end point). Achieving MRD negativity is prognostic for PFS and overall survival (OS) in large studies and meta-analyses, but the consistency of when this is measured is variable and often represents the best response.5,6 In high-risk disease, declaring victory early on the basis of the depth of response alone is a dangerous game.2 This may apply to studies involving patients with long-term remissions, where surrogate end points make sense. Unfortunately, it is not the case here where high-risk patients develop early progression, with early defined as progression much sooner than standard-risk patients. The utility of a surrogate end point is unclear here, especially when the study presented a median follow-up of 44 months for TE patients and 33 months for TIE patients. MRD as a surrogate end point for PFS in high-risk myeloma remains a challenge, particularly when the definition of high risk is evolving. In the current study and DETERMINATION trial,7 MRD as a surrogate end point for PFS and OS among patients with del17p (44% of the current study population) was not confirmed. Until we have clarity on how best to define risk groups to reduce variability in outcomes, PFS should remain the primary goal with a focus on validating the surrogacy of MRD in a better-defined group of patients. The challenge with HR NDMM is the potential clonal evolution, so maintenance of a deep response at late time points is likely more important than early time points. Instead, sustained MRD negativity (preferably at a threshold of 10−6) at defined time points (12 and 24 months) likely represents potential surrogate end points that may better allow us to differentiate between maintenance approaches for high-risk patients. To appreciate the impact of novel treatments, we need a tighter definition of high-risk disease where the outcomes are more homogeneous.
Third, what is an acceptable toxicity and death rate? Given that the stakes are higher for high-risk myeloma, we are willing to accept a higher toxicity rate, particularly among younger patients. However, for older patients, the tolerance for toxicity is lower. The CLARION trial evaluated carfilzomib, melphalan, and prednisone versus bortezomib, melphalan, and prednisone among 955 elderly patients and did not demonstrate benefit for carfilzomib over bortezomib. Carfilzomib was associated with higher-grade adverse events (AEs; grade ≥3: acute renal failure in 7.4% v 2.1%, cardiac failure in 8.2% v 2.8%) and higher treatment-emergent AE (TEAE)–related discontinuation rates (15.5% v 13.5%).8 A decade later, the myeloma community continues to struggle with four issues related to carfilzomib (yes, four again): (1) optimal dosing (different studies evaluated dosing that ranged from 20/27 mg/m2 to 20/70 mg/m2, and the current dosing is still physician-dependent),9 (2) optimal schedule (weekly v biweekly schedule10v alternate week schedule as proposed in the FORTE trial11 and the current maintenance strategy), (3) cardiac toxicities (approximately 10% of patients have grade ≥3 cardiac AEs),12 and (4) the role of carfilzomib in elderly patients with myeloma. An independent predictor of higher-grade toxicities was older age, with elderly patients more prone to cardiovascular risks,12 which may explain why the previous studies failed to demonstrate the benefit of carfilzomib among elderly patients.8,13 While only three TIE patients discontinued due to TEAEs, it represents 12% of the TIE patient population, which is more in line with what was reported in other frontline studies of elderly patients with NDMM8,13 and significantly higher than the TEAE discontinuation among TE patients (3%). In the current study, 20% of the TIE patients experienced grade ≥3 cardiac AEs, compared with 2.1% among TE patients. The likelihood of the intention-to-treat population making it to maintenance is 16 of 26 among TIE patients versus 73 of 99 in the TE population. The concept of using a carfilzomib-containing quad among frail patients likely is not a sustainable option, and if a patient can tolerate an intensive regimen, they are likely TE using the US standards of treatment.
Fourth, how to optimally define TIE for global use? Defining transplant eligibility remains the most ambiguous question in today’s myeloma treatment paradigm, both in and outside the United States. During the past decade, we have transitioned from reliance on numeric age to more dependence on the physiologic assessment of patient fitness to tolerate the conditioning regimen (melphalan). In recent years, we have pushed the envelope to offer transplants to much older patients, often into their late 70s. It is clear that older patients gain the same relative benefit of high-dose therapy as their younger counterparts.14–16 The DETERMINATION trial7 tested the role of early transplant among a younger group of patients, and the group that achieved the maximal PFS benefit from early transplant were patients with high-risk myeloma (median PFS, transplant v no transplant: 55 v 17.1 months).7 These results underscore the need for optimally defining transplant eligibility, more so in the high-risk patient population that can gain the full benefit from this approach even in an era of newer immune treatments. The median age (range) in the current study for the TIE population was 74 years (64-87), and at our center and others, this would be potentially TE if fitness was not a major concern. If fitness is a major concern, the quad regimen is not a suitable solution.
Nevertheless, this is one of the few early prospective trials demonstrating excellent outcomes in patients with HR NDMM using CD38 mAB combinations. Recently, the multicenter OPTIMUM (MUKnine) trial investigated daratumumab, cyclophosphamide, bortezomib, lenalidomide, and dexamethasone as induction and extended consolidation among ultra–HR NDMM or plasma cell leukemia and reported a 3-year PFS of 77% and 3-year OS of 83.5%.17 These results are outstanding and occur in the context of a more narrowly defined high-risk population, and one that has historically experienced short remission durations and early death. We have also learned that interrupting maintenance based on early and short interval MRD testing is not a good choice either, with poor outcomes for high risk myeloma.2 As a result, the jury remains out in terms of the optimal approach for managing a more uniformly defined group of high-risk patients. Data from the current study supports the use of CD38 mAB as part of the induction therapy, but effective induction alone is not enough. The emphasis on continuous maintenance therapy with at least a triplet therapy seems to be the best current approach, although how the use of modern immune treatments such as bispecific monoclonal antibodies or chimeric antigen receptor T cells will likely continue to make a difference among these patients.
The road ahead for high-risk patients remains a challenge, but we have science and outstanding clinical trials like this one on our side: improved definitions, better agents and targets, and ultimately better tools to assess success. These results form the basis for a new direction in myeloma trials, and with Glücksklee as a start, we have a new direction to pursue going forward.
Several studies show family history alone is insufficient for determining the population with germline alterations associated with increased risk of pancreatic adenocarcinoma (PDAC).
Therefore, based on growing evidence, National Comprehensive Cancer Network guidelines adopted universal germline BRCA testing for patients with PDAC regardless of disease stage at diagnosis.
Germline BRCA testing will not only define screening recommendations but also guide therapeutic approaches for patients with all-stages of PDAC given platinum-based treatments associated with improved survival outcomes.
Question: What is your recommendation for germline BRCA testing before starting first-line treatment for PDAC?
Answer: Historically, germline genetic testing for deleterious alterations was offered based on a personal and family history of cancer, which defines the population at risk for testing. Similarly, BRCA testing was offered to patients based on their personal and family history of cancer. However, emerging data have shown that even reliably good family history is insufficient to capture patients with germline alterations associated with increased risk of PDAC.1,2 One landmark study investigated deleterious germline alterations, including BRCA mutations, among patients with “sporadic” PDAC.1 In this study, 33 out of 854 (3.9%) patients were found to carry germline alterations linked to PDAC, including BRCA1/2 mutations (15), and only 3 out of 33 patients had a family history of PDAC indicating several presumed instances of “sporadic PDAC” were driven by a germline alteration. A case-controlled study identified that 5.2% of patients with PDAC without a family history of cancer carry pathogenic germline alterations, including BRCA mutations.2 These data indicate that family history is not reliable for determining whether germline testing of BRCA alterations is needed. Therefore, all patients with PDAC, regardless of stage of disease, should undergo germline BRCA testing at the time of diagnosis.
[Based on the data], all patients with PDAC, regardless of stage of disease, should undergo germline BRCA testing at the time of diagnosis.
Increasing next-generation sequencing–based molecular profiling has uncovered potentially pathogenic BRCA variants that were not otherwise recognized as pathogenic in germline testing. This resulted in the expansion of recognized germline BRCA alterations that may directly impact screening recommendations for unaffected family members of affected individuals. It is important to note that germline testing with variant of uncertain significance results should prompt genetic counseling, given conflicting reports of the pathogenicity of these alterations and dynamic change in the classification of variant of uncertain significance alterations. Genetic counseling can also provide further insights for specific risk assessment for pancreatic cancer associated with each BRCA alteration, given that pancreatic cancer risk is higher with pathogenic germline BRCA2 alteration compared with germline BRCA1 alterations.
Dr. Sara Elrefai
Why Is Germline Genetic Testing Important?
Currently, National Comprehensive Cancer Network guidelines recommend germline genetic testing for all patients with PDAC, preferably with the use of a comprehensive panel of genes that are associated with pancreatic cancer, including but not limited to BRCA1/2, PALB2, ATM, CDKN2A,STK11, P53, MLH1, PMS2, MSH2, and MSH6.3 If germline testing reveals any pathogenic alteration, patients should be referred for genetic counseling for further recommendations for the implication of the individual germline alteration detected. It is important to note that germline BRCA alterations would not only impact testing the rest of the family but also may define therapeutic approaches for patients with PDAC. For example, platinum-based chemotherapy has been shown to induce deeper and more durable responses in the setting of pathogenic germline BRCA alterations.4,5 Several studies suggest that the earlier use of platinum-based therapy is also associated with prolonged survival among patients with PDAC with germline BRCA alterations.6,7 Moreover, PARP inhibitors induce synthetic lethality in cancer cells carrying pathogenic BRCA and PALB2 mutations, resulting in the death of cancer cells. This mechanism created a novel therapeutic opportunity for the use of PARP inhibitors for patients with PDAC. Olaparib has been approved as maintenance therapy for patients with germline BRCA-mutant metastatic PDAC who did not experience progression on platinum-based front-line therapy based on the POLO trial.8,9
Dr. Mohamed E. Salem
Concluding Remarks
Advances in next-generation sequencing may uncover previously unknown germline BRCA alterations, prompting an expansion of available platforms for comprehensive germline testing. This evolving landscape emphasizes the role of genetic counseling and informs not only family screening but also therapeutic choices. Platinum-based chemotherapy and PARP inhibitors show promise in improving responses and prolonging survival in patients with PDAC with germline alterations, highlighting the growing impact of genetic testing on precision medicine in pancreatic cancer.
Circulating tumor DNA (ctDNA) is considered to be a surrogate marker for minimal residual disease (MRD) and a predictive marker to determine the risk of colon cancer recurrence.
Patients with colon cancer with detectable ctDNA post–curative-intent therapy (MRD-positive) are at a remarkable risk of recurrence (95% to 100%) if not offered systemic therapy, which suggests that MRD positivity is not just a high-risk marker for recurrence but also a measure of persistent disease.
ctDNA-guided management can be considered to identify the cohort of patients with stage II colon cancer who may not benefit from adjuvant therapy, based on the DYNAMIC study.
Surgery followed by adjuvant chemotherapy based on clinical and pathologic risk stratification is the recommended approach for all patients with stage II (ie, high-risk stage II) and stage III colon cancer. Despite this approach, approximately 15% and 30% of patients with stage II and III disease, respectively, may experience recurrence, while 40% to 50% of the patients are cured by surgery alone.1-3 Biomarker-guided follow-up and personalized treatment are vital for patients with resected colon cancer to aid in clinical decision-making and appropriate risk stratification.
Dr. Midhun Malla
Recent Data Support the Predictive and Prognostic Utility of ctDNA as a Biomarker
ctDNA is considered a surrogate marker for MRD and a predictive marker to determine the risk of recurrence. Tumor-informed and tumor-agnostic testing strategies are currently available for ctDNA assessment.3 Both have demonstrated improved specificity and sensitivity of ctDNA as a strong predictive and prognostic biomarker compared with carcinoembryonic antigen across multiple studies.4-8 There is strong evidence to suggest that MRD status outperforms known clinicopathologic factors in predicting relapse. However, it is important to note that improved sensitivity and specificity are associated with serial testing of ctDNA, while single timepoint testing has similar sensitivity and specificity to carcinoembryonic antigen. Patients with colon cancer with detectable ctDNA post–curative-intent therapy, defined as MRD-positive, are at a remarkable risk of recurrence (95% to 100%) if not offered systemic therapy, which suggests that MRD positivity is not just a high-risk marker for recurrence but also a measure of persistent disease. Furthermore, the growth rate of ctDNA is also prognostic of outcomes, with exponential growth associated with significantly inferior survival outcomes compared with a slow rise in ctDNA.7 The optimal timing of ctDNA is essential for a reliable test with improved sensitivity. Historically, ctDNA testing was advised to be performed at least 4 weeks following surgery, as the increased shed of cell-free DNA in the immediate postoperative period could lead to false-negative results. However, a real-world analysis of patients who received commercial, tumor-informed ctDNA testing at 2 to 4 weeks postoperatively demonstrated similar sensitivity for MRD detection compared with 4 to 8 weeks postoperatively despite the presence of detectable cell-free DNA levels.9
The updated results of the GALAXY arm of the CIRCULATE-Japan study, which prospectively followed serial ctDNA in patients with stage I-III colorectal cancer (CRC), were presented at the European Society for Medical Oncology Congress 2023.10 Detectable postoperative ctDNA was the most significant prognostic factor for disease recurrence (HR 10.44). Adjuvant chemotherapy prolonged disease-free survival (DFS) in patients who were MRD-positive compared with no therapy (38.6% vs 16.1%; P < .01). Furthermore, no significant difference in DFS at 2 years was observed in patients with ctDNA-negative stage I-III CRC, either with or without adjuvant chemotherapy (88.3% vs 89.9%; P = .156).
How Can ctDNA Be Used in Routine Practice to Personalize Treatment?
Prospective clinical trials on ctDNA-guided management of colon cancer using adjuvant therapy is the perceivable next step after establishing ctDNA as a strong biomarker (Table 1).11-12 The DYNAMIC trial led by Tie et al compared tumor-informed, ctDNA-guided adjuvant treatment to standard treatment in patients with stage II colon cancer postoperatively.11 The primary endpoint of recurrence-free survival (RFS) at 2 years with ctDNA-directed management was noninferior to standard management, reminiscent of the fact that a ctDNA-guided approach can perhaps limit the use of adjuvant chemotherapy without compromising RFS in stage II colon cancer.11 PEGASUS is a multicenter prospective trial that used ctDNA-guided (tumor-agnostic) adjuvant treatment for patients with high-risk stage II or stage III colon cancer.12 Patients who were MRD-positive were treated with CAPOX for 3 months, while patients that were MRD-negative were treated with capecitabine for 6 months. Out of 135 patients, 35 patients had detectable postoperative ctDNA (26%). Patients with persistent ctDNA despite CAPOX received FOLFIRI. Seroconversion after CAPOX or FOLFIRI was observed in 14 out of 35 patients (40%) after a median follow-up of 21.2 months. Interestingly, patients with MRD-negative stage III and high-risk stage II disease demonstrated a low relapse rate of 7% despite de-escalated treatment with capecitabine. It is important to note that the false-positive test results associated with plasma-based assay can lead to overtreatment; 7 patients demonstrated persistent ctDNA positivity with no evidence of disease recurrence after the completion of the CAPOX and FOLFIRI treatment regimens.12
Can ctDNA Identify Patients Who May Not Derive Benefit From Adjuvant Therapy Without Compromising RFS?
Tumor-informed, ctDNA-guided treatment can be considered to help determine the cohort of patients with stage II colon cancer who may not benefit from adjuvant therapy based on existing prospective data. However, we need long-term follow-up and prospective confirmatory data from larger phase 3 trials to consolidate this evidence. Multiple prospective trials focused on ctDNA-guided management have been ongoing in the MRD space of adjuvant treatment of colon cancer (Table 2). Unfortunately, the COBRA study (NCT04068103) has been terminated because of higher-than-expected false-positive ctDNA results with tumor-agnostic assay, likely attributed to methylation and epigenomic markers that could have limited the sensitivity of the assay. An ideal assay should provide greater than 90% sensitivity and specificity, with minimal false-positive and -negative test results; this is onerous given the setting of limited ctDNA quantity across limited-stage (I, II, III) colon cancer.
[ctDNA] is on the path to revolutionize the adjuvant treatment of patients with colon cancer by minimizing the risk of both under- and overtreatment.
Ongoing Education and Clinical Trial Efforts Continue to Improve ctDNA Use
ctDNA continues to evolve as a tool to assess MRD and treatment response monitoring and is on the path to revolutionize the adjuvant treatment of patients with colon cancer by minimizing the risk of both under- and overtreatment. Ideal testing assay with excellent sensitivity and specificity; interpretation and application of testing results in the clinical context; patient anxiety associated with a positive test; availability; and health care reimbursement across the world are some of the challenges that remain toward its incorporation into clinical practice. Although both tumor-informed and -uninformed assays are available commercially, tumor-informed assay seems to have stronger data, with the availability of larger datasets to date, as well as improved sensitivity and specificity of the assay. Ongoing educational efforts through international organizations such as ASCO and the European Society for Medical Oncology, along with the involvement of patient advocate societies, continue to be immensely helpful in improving the interpretation and application of ctDNA testing. Ongoing clinical trials can help answer the question of whether ctDNA can be a surrogate marker for DFS and whether earlier initiation of treatment for patients at high risk for recurrence can lead to prolonged survival outcomes.
Intermittent fasting is a dietary pattern that has seen an increase in popularity in recent years, especially for weight management. But what actually is it, and is it right for you? This article aims to answer your questions, so you can feel ready for a conversation about weight management.
It may often seem like there is always a ‘new kid on the block’ when it comes to weight management methods, and intermittent fasting is one that has been slowly increasing in popularity in recent years, in particular the catchy 5:2 method. For those who have tried and tested several weight management approaches, it may be difficult to navigate the truth, and to try and understand what works best for you. The FAQs below are based on the science (albeit limited science so far!), so you can get a better understanding of the benefits and limitations of intermittent fasting.
It’s important to remember that people living with obesity are more likely to have micronutrient deficiencies, including an iron or vitamin D deficiency. Therefore, please speak to your healthcare provider before you start to restrict your diet, as they can perform the necessary assessments to support your health.
FAQs:
1. What is intermittent fasting, and how do you do it?
Intermittent fasting is a sweeping term that can be used when describing a program to restrict calorie-intake at certain times of the day, or week. This leads to periods of time known as extended fasting, where intake is typically around 25% of your energy needs.
One of the most popular and well known intermittent fasting methods is the 5:2 approach, where the extended fasting occurs on 2 non-consecutive days in the week. Another common approach is to follow ‘time-restricted eating’ where consumption is restricted to an 8-hour period within the day, and therefore the extended fast period is 16 hours daily.
It is important to understand that many people around the world also fast for religious reasons, and this should not be confused with intermittent fasting. For example, during the holy month of Ramadan, many complete a 12 hour fast each day, from sun rise to sunset.
2. How does intermittent fasting compare to popular diets?
It is important to remember that the scientific research for intermittent fasting is still evolving. Most recently, researchers who studied around 600 participants with overweight or obesity, have found that when following an intermittent fasting approach, people lost on average between 4-8% of their body weight over a six-month period. When compared to other diets that require a continuous restriction on energy intake, similar levels of weight loss were achieved.
When comparing weight management approaches, it is important to not just look at how much weight is possible to lose. The popular and well researched Mediterranean diet, where food intake can be characterised by a high level of plant-oriented food, and low levels of processed food, generally sees a similar level of weight loss, but has greater impact on your body’s cardiovascular system. A recent Spanish study found that an energy-unrestricted Mediterranean diet can reduce the risk of a major cardiovascular event by up to 30%. This study focussed specifically on people who lived in Mediterranean countries with an already high cardiovascular risk, so it’s important to understand your own body when comparing weight management approaches. You can find out more about the benefits of weight loss to your cardiovascular system here.
It is important to remember that when it comes to weight loss, changes to your diet are just one part of long-term management. Your healthcare provider will be able to recommend a weight management plan that is best for your lifestyle, as there is no ‘one size fits all’ method when it comes to managing your weight.
3. How does intermittent fasting affect your BMI?
Your Body Mass Index, often referred to as BMI, is a measurement of height compared with weight. It is the most common way to assess for overweight and obesity. For example, a BMI of 25 kg/m2 or ≥ 30 kg/m2, indicates overweight and obesity respectively.
For some people, intermittent fasting can lead to a reduction in BMI, although despite its widespread use in the medical community, BMI alone as an indicator for obesity has limitations that you should be aware of when using the indicator as a measurement of health.
4. Should you restrict your food intake if you are prescribed a weight management medication?
When talking to your healthcare provider about weight, they may prescribe you a weight management medication. There are several types of weight management medication, and they work with the chemistry in your brain that causes weight gain and prevents weight loss. Weight management medications are prescribed by healthcare professionals as a long-term approach to weight loss and can limit weight regain if continuously used.
Medications should always be taken alongside changes in nutrition and physical activity, rather than as an alternative.
As previously mentioned, for some, fasting is a religious practice rather than a tool for weight management. Studies into whether weight management medication is still effective during periods of fasting have so far shown that there is no change in how they work. However, some weight management medications can impact a person’s iron, vitamin D and other nutrient levels, so it is really important to consult your healthcare professional before you embark on periods of fasting when prescribed a weight management medication.
5. Do the outcomes of intermittent fasting differ between males and females?
As a common theme, the research into biological sex differences for intermittent fasting is limited, however there is no significant difference in how women respond to intermittent fasting versus men.
6. Should intermittent fasting be seen as a long-term approach to weight management?
It is important for your doctor to tailor a nutrition plan that meets your personal preferences, and treatment goals. This can take in a variety of factors that ensure safety, nutritionally sufficient, affordable and suitable changes for your lifestyle.For some, intermittent fasting may be appropriate, but there is limited evidence to show it can lead to weight reduction in the long-term.
Continuous calorie restriction may increase the chances of weight gain in the long-run, as this type of restriction can change the way your body signals hunger, satiety and body weight regulation.
In cases where behavioural interventions (diet and exercise) don’t work to manage your weight, psychological therapy, pharmacological therapy, or bariatric surgery can help you lose weight and prevent weight regain. For long-term weight management strategies, it is best to speak to your healthcare provider, who can assess your lifestyle to work out the best approach for you.
The link between obesity and type 2 diabetes is well established, with both conditions listed as comorbidities of the other.
Insulin explained
Insulin is a naturally occurring hormone that regulates blood glucose in the body. Obesity – especially abdominal fat distribution – can lead to insulin resistance, where the body cannot produce enough insulin, or is unable to properly use the insulin it does produce. Insulin resistance can lead to high blood sugar levels, which greatly increases the risk of developing type 2 diabetes.
Insulin is necessary for carbohydrates, fat, and protein to be metabolised. Therefore, with the compromised insulin function that comes with type 2 diabetes, the risk of obesity also increases.
Because of the significant overlap between these two diseases, they share many of the same lifestyle changes – namely nutrition and physical activity – needed to help keep them in check. While lifestyle factors play an important role in treating obesity and diabetes, in some circumstances, other interventions such as pharmacotherapy may be required.
Individual risk of obesity
Obesity is increasingly common, with close to 2 billion people predicted to be living with obesity by 2035. Obesity develops due to excess body fat, taking the form of a chronic disease or long-lasting condition.
Obesity often suffers from the stigma of being considered a lifestyle disease. However, lifestyle is just one part of that equation. Everyone’s own body, metabolism, and genetics form a unique equation. Science has given us a better understanding of how different genetics are naturally predisposed to an increased risk of obesity.
Not only is obesity a major risk factor for type 2 diabetes, but it is also likely to increase the rate at which type 2 diabetes progresses. Therefore, maintaining a healthy body weight and avoiding weight gain is crucial for diabetes management and prevention. Every day that a person lives with excess weight also increases their risk of adverse cardiovascular outcomes such as heart attack and stroke.
Obesity is a complex chronic disease in which abnormal or excess body fat impairs health, increases the risk of long-term medical complications and reduces lifespan. Obesity is defined using the body mass index (BMI; weight/height2). Obesity is defined as a BMI exceeding 30 kg/m2 and is subclassified into class 1 (30–34.9), class 2 (35–39.9) and class 3 (≥ 40). At the population level, health complications from excess body fat increase as BMI increases.
BMI is a tool to estimate body fat and screen for obesity and health risks. It can be calculated with a BMI calculator and classifies people as being underweight, overweight, and obese based on their height and weight. BMI is calculated by dividing weight in kilograms by height in meters and then comparing your result to the BMI classes. Body mass index (BMI) can also be correlated to type 2 diabetes risk.
There are six weight status categories:
What is a healthy BMI?
Overweight
25 – 29.9
Class I
30.0 – 34.9
Class II
35.0 – 39.9
Class III
Above 40
Find your BMI and health risks
Metric /ImperialHeight
cmWeight
kg
Start your change now
People who fall into the overweight category should talk to their doctor about how to slow the progression or potentially prevent obesity. If you are in obesity class I, II or III you should talk to a doctor about managing your obesity and your type 2 diabetes risk.
How to reduce your risk of obesity & type 2 diabetes
Nutrition and physical activity are key recommendations for reducing the risk or slowing the progression of obesity and type 2 diabetes. While weight management and nutrition can often seem straightforward on paper, it’s rarely as simple in practice. What works for one person might not work as effectively for another.
Our genetic variations mean we all store and spend energy differently. Even as we go about improving our health, our bodies and our metabolism react differently to our changing fitness levels, which means our approach – and often our nutrition – may also need to evolve.
Our ability to make healthy choices – such as being able to access and afford healthy food, or having the time and energy to engage in physical activity – is directly linked to our economies, our living situations, and the environments in which we live.
There is no one-size-fits-all solution to health. What is right at the beginning of a journey might not be right down the line. That means you need to find the right solution, or the right level of change for you. Nobody can achieve everything overnight, so start with what’s manageable and work towards realistic improvement goals.
And remember, nobody needs to take that journey alone. Beyond the advice below, your starting point should always be to seek advice from your doctor.Share
DID YOU KNOW…
The chance of inheriting obesity through genetics is estimated between 40-70%
While nutrition is a key driver of health for everybody, regardless of body size, there is no one-sizefits-all healthy eating plan. You should choose an eating plan that supports your best health and that you can maintain long term.
Short-term diets, or severely restricting the amount you eat, can cause metabolic adaptation which may make any weight loss difficult to sustain after the period of dietary restriction.
Talk to your healthcare provider about how a healthy food plan can help you support your health goals. See a registered dietitian for an individualised approach and support.
Physical activity It’s recommended that everyone should exercise moderately for at least 30 minutes per day, five times a week – not only to manage weight and blood sugar, but also to reduce cardiovascular risk. For some people, this could be high-intensity training, for others, it might be light yoga.
Everybody is different, and the level of physical activity you take on needs to be achievable for your existing level of fitness. Taking on too much too soon can lead to injury or exhaustion. Motivation also tends to be more sustainable with incremental progress.
If you haven’t engaged in physical activity in a long time, start with something light, like a daily walk at a nearby park. Increase distance and pace from week to week so that you keep your pulse up and gradually increase your aerobic fitness. The important thing is to maintain progress. As your fitness improves, so too will your metabolism. To keep improving your health, you should gradually increase the intensity of your physical activity.
Regular physical activity supports a wide range of health benefits in adults across all BMI categories, even without weight loss. Aerobic and resistance exercise can favour the maintenance or improvements in cardiorespiratory fitness, mobility, strength, and muscle mass during weight management.
Depression and insomnia can both be linked to weight gain. The health of the body and mind are intrinsically linked – when one starts to falter, it may invariably impact the other.
With mental health, it can also be difficult to pinpoint the exact cause of symptoms or make changes on your own, so it’s advisable to seek guidance from your doctor if problems persist.
Obesity is complex and difficult to manage. Seek the advice of your doctor when considering lifestyle changes and to better understand the support available.
Due to its complex nature many people find weight management a challenge and see their weight fluctuate or yo-yo’ throughout their life.
Weight gain can happen for a variety of reasons and will vary by person, but common factors can include genetics, significant life events, certain medications, and lifestyle changes.
If you have recently tried and failed to lose weight it may seem hard to find the motivation to begin this process again. While it may seem difficult to achieve at first, maintaining behaviour changes over the long term, is vital, as even limited weight loss can have a significant and long- lasting impact on the heart.
The purpose of this article is therefore to address the different stages of weight loss and how they can have a direct impact on heart health.
Why maintaining a healthy weight is so important for your cardiovascular health
Adults with a BMI over 27.5 or 30 kg/m2 (depending on ethnicity) are classified as living with obesity and this is associated with increased cardiovascular risk, and higher chances of a stroke or heart condition.
If you would like to read more about the link between obesity and heart disease, please click here to view our previous feature ‘Does obesity cause heart disease and how can you reduce your risk?’.
Starting your weight loss journey
If you are worried about the impact of your weight on your cardiovascular health, it is vital you speak to a healthcare professional who can work with you to find the most effective and sustainable approach personalised for you.
There is not one diet or exercise programme that works for everyone, and speaking to a doctor or healthcare professional specialised in obesity care significantly improve the likelihood of successful weight loss.
When you lose 1-5% of your body weight you can expect to see benefits to your cardiovascular health. This level of weight loss has been shown after one year to have a significant impact on the heart and is linked with reduced blood pressure and cholesterol.
Further weight loss
For those living with obesity, using weight management medication like pharmacotherapy, or undergoing surgery can increase weight loss to over 10% of your bodyweight, and in some cases up to 40% with bariatric surgery.
If you do manage to lose over 10% of your body weight, there are even larger health benefits. A 10-year study conducted in 2004, found that those living with overweight or obesity who lost 10% of their body weight in the first year, saw a 21% decrease in the chances of a heart attack or a stroke, a reduction that was not seen in those that lost less than this amount. This weight loss also has benefits to cholesterol levels and blood pressure levels mentioned earlier.
Maintaining your weight after a period of weight loss
While losing any amount of weight is a fantastic achievement, sustaining weight loss is also a vital step to a healthier heart.
Studies have shown that up to 80% of people who have lost a significant amount of weight gain almost all of this back within 2 to 5 years. This can be due to lifestyle changes, but also the body metabolism slowing down following any form of diet and entering ‘fasting mode’.
To help keep the weight off long term it is vital to continue to seek support from healthcare professionals who will be able to advise you on how best to keep the weight off and provide a support network.
While it may seem a difficult task at first there are many resources and forms of support to help you lose weight and the benefits to your heart make the fight to control the disease of obesity potentially lifesaving and one worth winning.
ARYAN'S BLOG 
