small cell lung cancer

Extrachromosomal DNA promotes aggressiveness of small cell lung cancer

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Researchers from CCR have discovered that extrachromosomal DNA — small particles of DNA that exist outside of chromosomes — can intensify tumor cell diversity and aggressiveness. The finding, published January 30, 2023, in Cancer Discovery

, helps explain how tumor cells can take on different characteristics, even within the same patient, that make the cancer more difficult to treat.

Typically, two chromosome copies are divided equally into each new cell during cell division, but ecDNA can segregate unequally, explains Anish Thomas, M.D., MBBS, Lasker Clinical Research Scholar in the Developmental Therapeutics Branch. Thus, one daughter cell can get more copies of the ecDNA than the other.

It was this trait that made ecDNAs intriguing to Thomas, whose group studies small cell lung cancer (SCLC), an aggressive form of lung cancer marked by resistance to chemotherapy and poor patient prognosis. Postdoctoral fellow Lorinc S. Pongor, Ph.D., had observed that certain SCLC cells contained abundant copies of a cancer-associated gene called MYC, which acts like a volume control for a broad range of genes that regulate tumor growth.

In collaboration with research biologist Darawalee Wangsa, Ph.D., and Thomas Ried, M.D., Senior Investigator in the Genetics Branch, the team confirmed that the extra copies of MYC in SCLC were housed outside the chromosome in ecDNA. They also found that the most common gene rearrangement in SCLC, called an RLF-MYCL fusion, is housed on ecDNA.

To investigate further, the researchers developed a non-invasive method to identify the presence of ecDNA in the blood plasma of patients with SCLC. They then looked at the number of MYC copies in multiple tumors from a patient with detectable ecDNA shortly after the patient passed away.

The patient’s tumor cells from different metastatic sites varied in their ecDNA content. Importantly, the tumor cells that had evolved into a more aggressive cell type contained ecDNA that allowed for many extra copies of MYC.

The researchers next step is to decipher how these genetic factors work together with the tumor’s environment to influence tumor cell aggressiveness. They also plan to investigate how ecDNAs might actively drive tumor metastasis in SCLC, with a continued focus on the amount of MYC in cells.

Thomashopes that their non-invasive detection of tumor ecDNA can one day be used to identify patients who are more likely to develop aggressive disease. While this is the first study to describe ecDNAs in SCLC, “fundamentally, it provides more insight into how tumors become diverse and aggressive, and how a single treatment might not be effective at hitting all the different types of tumor cells,” Thomas says.

Small-cell lung cancer patients face barriers to receiving standard-of-care treatment

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https://speciality.medicaldialogues.in/small-cell-lung-cancer-patients-face-barriers-to-receiving-standard-of-care-treatment/

2014 Top Stories in Oncology: Non–Small Cell Lung Cancer.

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Year 2014 in lung cancer has seen further development of personalized medicine for the treatment of metastatic or recurrent non–small cell lung cancer (NSCLC).

A new tyrosine kinase inhibitor (TKI) afatinib (Giotrif) was approved for use in patients with EFGR mutations. Afatinib demonstrated an improved response rate and progression-free survival (PFS) compared with chemotherapy both in Caucasian1 and Asian2 patients. In addition, a meta-analysis of the pivotal trials showed for the first time an advantage in overall survival (OS), restricted to patients with exon 19 mutations, that was never demonstrated before with the two other TKIs gefitinib (Iressa) and erlotinib (Tarceva). Moreover, additional third-generation TKIs, such as AZD9291 and CO-1686, are presently being tested in randomized trials for patients with EGFR mutations who progress under a first-generation TKI and who harbor a T790M mutation causing drug resistance; very promising results have been observed in early development trials. EGFR testing in NSCLC patients should now be part of the initial work-up, and the European Medicines Agency recently approved blood–circulating free DNA as a source of material for EGFR testing, making it easier and faster than testing from biopsy material.

Crizotinib (Xalkori), presently used in second-line therapy, may be used to target ALK/EML4 translocation rather than conventional chemotherapy. The recently published PROFILE 1014 established the superiority of crizotinib over chemotherapy in first-line for response rate and PFS; however, OS results are not available and crossover was allowed.3 Based on the data, crizotinib should be approved shortly for first-line therapy. In addition, second-generation ALK TKIs (ceritinib, alectinib) have already been evaluated in crizotinib-resistant ALK-translocated patients and have showed impressive results in that setting, offering an additional targeted treatment choice. ALK/EML4 translocation should be part of the initial work-up of patients with NSCLC.

Immunotherapy in patients with NSCLC has been actively developing in 2014. Disappointing results from vaccine trials have been reported this year, either in the adjuvant setting with the MAGE-A3 vaccine in the MAGRIT trial or in the locally advanced setting with L-BLP25 vaccine in the START trial. Reasons for failure are not clear; however, a better understanding of the antitumor immune mechanisms allows the development of hypotheses considering the power of immune suppression through immune checkpoints that may prevent tumor–cell specific cytotoxic T lymphocytes from being active. More data have been presented in 2014 on immune system manipulations through immune checkpoint blockade by monoclonal antibodies directed at either CTLA4 or PD1 on lymphocytes from the tumor microenvironment and also at PDL-1 as a ligand on cancer cells.4 This immune suppression mechanism seems ubiquitous, and promising results have been obtained in numerous tumor types, including lung cancer. Initial results from phase I trials and expanded cohorts were mostly seen with anti-PD1, anti-PDL-1, and anti-CTLA4 monoclonal antibodies in all tumor types.5 Numerous antibodies from competing pharmaceutical companies are presently tested in randomized trials for metastatic lung cancers in first- and second-lines but also in locally advanced disease where radiation may potentiate their efficacy by favoring antigen release, as well as in resectable NSCLC.6 This new therapeutic approach is associated with potential immune-related toxicity.7

Response criteria are also expected to be better, like in the irRECIST, because initial treatment may induce an increase in tumor size associated with lymphocytic infiltration reflecting the local immune activation. In terms of individual profiles, present (preliminary) data seem to favor patients with a high expression of PDL-1 on their tumor; however, very little is known about the kinetics of PDL-1 expression. Further, PDL-1 has not always been tested on recent biopsy samples but more often from archived tissues, and responses have been documented in patients with low PDL-1 expression as has durable disease control. Smokers in limited series have had a higher response rate as well, possibly associated with a higher incidence of gene mutation. The field of lung cancer immunotherapy is rapidly expanding and will probably see a major breakthrough in the near future.

Dacomitinib as First-Line Treatment in Selected Advanced NSCLC

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TAKE-HOME MESSAGE

  • In this phase II, open-label, multicenter trial, 89 patients with advanced non–small cell lung cancer (NSCLC) were treated with the pan-HER inhibitor dacomitinib. Of the 45 patients with known activating EGFR mutations, the overall response rate was 76%, the median duration of response was 17 months, and the median progression-free survival was 18 months. Activity was limited in patients with wild-type EGFR.
  • A phase III trial is now ongoing to compare dacomitinib with gefitinib as first-line therapy in patients with advanced EGFR-mutant NSCLC.

– Richard Bambury, MD

ABSTRACT

BACKGROUND

Patients with EGFR-mutant non-small-cell lung cancer generally have a progression-free survival of 9—13 months while being treated with the EGFR tyrosine-kinase inhibitors gefitinib or erlotinib. However, resistance inevitably develops, and more effective EGFR inhibitors are needed. Dacomitinib is a covalent pan-HER inhibitor that has shown clinical activity in patients previously treated with gefitinib or erlotinib. We did a trial of dacomitinib as initial systemic therapy in clinically and molecularly selected patients with advanced non-small-cell lung cancer.

METHODS

In this open-label, multicentre, phase 2 trial, we enrolled treatment-naive patients with advanced lung cancer who had clinical (never-smokers [<100 cigarettes per lifetime] or former light smokers [<10 pack-years per lifetime] and ≥15 years since last cigarette) or molecular (EGFR mutation, regardless of smoking status) characteristics associated with response to EGFR inhibitors. We gave dacomitinib orally once daily (45 mg or 30 mg) until progressive disease, unacceptable toxicity, or patient withdrawal. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.0) to investigate the activity of dacomitinib in all patients with a baseline scan and at least one post-treatment scan, with investigator assessment of response and progression. The primary endpoint was progression-free survival at 4 months in the as-enrolled population, with a null hypothesis of progression-free survival at 4 months of 50% or less.

FINDINGS

Between March 11, 2009, and April 1, 2011, we enrolled 89 patients from 25 centres, including 45 (51%) with EGFR-activating mutations in exon 19 (n=25) or exon 21 (n=20). Progression-free survival at 4 months was 76·8% (95% CI 66·4—84·4) in the as-enrolled population, and was 95·5% (95% CI 83·2—98·9) in the EGFR-mutant population. The most common all-grade treatment-related adverse events were diarrhoea in 83 (93%) patients, dermatitis acneiform in 69 (78%) patients, dry skin in 39 (44%) patients, and stomatitis in 36 (40%) patients. Two patients (2%) had grade 4 treatment-related events (one with hypokalaemia and one with dyspnoea). No grade 5 toxicities were recorded.

INTERPRETATION

Dacomitinib had encouraging clinical activity as initial systemic treatment in clinically or molecularly selected patients with advanced non-small-cell lung cancer.