Lumpectomy

Safe to Omit RT After Lumpectomy in Certain Older Breast Cancer Patients

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Radiotherapy reduced local recurrence, but showed no effect on OS, distant recurrencee

A photo of female radiologists preparing a senior woman for radiotherapy.

Radiotherapy after breast-conserving surgery can be safely omitted in certain older women with low-risk, hormone receptor-positive early breast cancer receiving adjuvant endocrine therapy, 10-year results of the PRIME II trial showed.

In the randomized trial, the omission of post-surgery radiotherapy led to higher rates of local recurrence, but did not adversely affect distant recurrence or overall survival (OS), reported Ian Kunkler, MB, BChir, of the University of Edinburgh in Scotland, and colleagues in the New England Journal of Medicineopens in a new tab or window.

Among more than 1,300 women 65 and up with node-negative tumors and clear surgical margins following surgery, the cumulative incidence of local breast cancer recurrence within 10 years was 9.5% for those randomized to no radiotherapy and 0.9% for those assigned to 40-50 Gy whole-breast radiotherapy (HR 10.4, 95% CI 4.1-26.1, P<0.001).

But distant recurrence and OS at 10 years were similar for the no-radiotherapy and radiotherapy groups:

  • Distant recurrence: 1.6% vs 3.0%, respectively
  • OS: 80.8% vs 80.7%

Kunkler’s team called the absolute 8.6-percentage point difference in local recurrence between groups “modest” and noted that the cumulative incidence of local recurrence at 10 years in the patients who did not receive radiotherapy “lies within range from the European Society of Mastology (EUSOMA) guidelines, which cited a maximum rate of locoregional recurrence of 10% at 10 years.”

Current National Comprehensive Cancer Network (NCCN) guidelinesopens in a new tab or window allow for the omission of radiation therapy after breast-conserving surgery in women ages 70 and older with stage I, estrogen receptor (ER)-positive breast cancer.

A post hoc subgroup analysis of PRIME II, based on ER score, showed that cumulative recurrence at 10 years in the no-radiotherapy group was far more common among women with ER-low tumors (19.1% vs 8.6% for ER-high).

Women in the no-radiotherapy arm who discontinued the recommended 5 years of endocrine therapy had a risk of local recurrence that was more than four times greater than those who stayed on therapy (HR 4.66, 95% CI 1.77-12.25).

These findings combined led Kunkler and co-authors to conclude that PRIME II “provides robust evidence” that radiation therapy can be safely omitted following breast-conserving therapy in older women with grade 1-2, ER-high tumors, “provided that they receive 5 years of adjuvant endocrine therapy.”

Writing in an editorial accompanying the studyopens in a new tab or window, Alice Ho, MD, of Duke University School of Medicine in Durham, North Carolina, and Jennifer Bellon, MD, of the Dana-Farber Cancer Institute in Boston, said the “data offer a response to the long-standing problem of overtreatment in older women with low-risk breast cancer.”

Results from PRIME II, as well as from the Cancer and Leukemia Group B (CALGB) 9343 trialopens in a new tab or window, can “put to rest” any doubt that omitting radiotherapy is possible in women 65 years and older with ER-positive, early-stage breast cancer, they added, pointing out that the 10-year follow-up from the trials is “extremely reassuring, given the long natural history of ER-positive breast cancer.”

Ho and Bellon commented that the results of the trial don’t weaken the value of radiotherapy in reinforcing local control, “which is a compelling endpoint in and of itself, particularly now that radiotherapy can be delivered in less burdensome ways.”

“Individualizing the treatment so that it is concordant with the patient’s goals and values is critical,” they wrote. “Taken together, these data will help patients navigate these complex choices so that they can make well-informed and prudent decisions for the management of their breast cancer.”

Women in PRIME II underwent 1:1 randomization from 2003 to 2009. Of the 1,326 patients in the study, the median age at trial entry was 70 years, and 1,263 were recruited from the U.K.

Patients included had hormone receptor-positive, node-negative, T1-2 primary breast tumors (3 cm or smaller) and needed to have clear excision margins following breast-conserving surgery. Five years of adjuvant endocrine therapy was recommended for all participants (20 mg tamoxifen daily), and adherence was between 60% and 70%.

Noting the higher rate of recurrence in the no-radiotherapy group among women who were nonadherent to tamoxifen, the editorialists said this finding “underscores the fact that endocrine therapy can have side effects, leading many to postulate that a short course of radiotherapy could be an alternative to endocrine therapy.” They added that the EUROPA trialopens in a new tab or window is currently testing such a comparison in women 70 and older with early-stage, low-risk hormone receptor-positive disease.

PRIME II’s primary endpoint was local breast cancer recurrence, while other endpoints such as disease-free survival, breast cancer-specific survival, distant recurrence, and OS were also assessed.

At 10 years, disease-free survival rates were 68.9% in the no-radiotherapy group and 76.3% in the radiotherapy group, while breast cancer-specific survival was 97.4% and 97.9%, respectively. No difference was seen in regional recurrence as well.

Can Elderly Patients with ER+ Breast Cancer Omit Radiation After Lumpectomy? 

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For women who have a lumpectomy or breast-conserving surgery, radiation is a standard element in treatment. And we know from classic studies from the National Surgical Adjuvant Breast and Bowel Project (NSABP) and others that women who have a mastectomy actually have the exact same survival as women who have a lumpectomy, provided that the women who have a lumpectomy additionally receive radiation treatment.[1] The question that arises frequently for older women, typically defined as age 65 or 70 or older, is whether it essential to include radiation therapy? And there have been two studies that have looked at the possibility of omitting radiation treatment in older women with estrogen receptor (ER)–positive breast cancer after lumpectomy. 

The first study, from Cancer and Leukemia Group B (CALGB), was led by Kevin Hughes and compared endocrine therapy alone versus endocrine therapy plus radiation treatment.[2,3]It showed that radiation therapy had no impact on long-term survival. However, women who had radiation treatment did have a lower risk of in-breast recurrence. It went to about 2%, with women who did not have radiation having about a 10% or 12% risk of in-breast recurrence. Again, that’s not overall survival, but it does lower the risk of an event within the breast over the next decade. 

The PRIME II study was a European-based study that also asked a question, can women with ER-positive breast cancer omit radiation after lumpectomy if they are older? And fundamentally, the PRIME II study reached the same conclusion, that there was no impact on overall survival amongst older women, but there was a small decrease in the risk of in-breast recurrence.[4]

So what do we actually do in clinic? For many older women, particularly 75 years and older, I think it’s very comfortable to say that they may omit radiation therapy. The risk of in-breast recurrence is generally low, and there will be no impact on survival. For very vigorous women in their late 60s, early 70s, I think you can also point to these data and say that radiation therapy may lower their risk of in-breast recurrence. And since radiation is generally well tolerated, it can be a good option for such women who have a life expectancy well beyond 10 years. Finally, it’s important to remember that these studies assume that the patient will be taking antiestrogen adjuvant therapy. If there is a reason to believe that the patient will not be taking tamoxifen or an aromatase inhibitor or other appropriate endocrine treatment, then you can’t rely on the endocrine therapy to control in-breast recurrence, and those women should receive radiation treatment after lumpectomy.

Gene Test Might Help Some Breast Cancer Patients Skip Radiation After Lumpectomy

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A new genetic test may help determine which people with breast cancer can safely skip radiation after breast-conserving surgery to remove their tumor.
 

Individuals with invasive breast cancer who had low scores on an investigational gene panel were just as likely to experience a recurrence if they received radiation therapy after breast-conserving surgery or not, Swedish researchers report.

As it stands, people with this type of breast cancer typically have surgery to remove the cancer followed by radiation, to reduce the risk that their breast cancer will return in the same spot.

“For the first time, a genetic screening test can predict which patients can omit radiation,” said study author Dr. Per Karlsson. He is a professor of oncology at the Sahlgrenska Comprehensive Cancer Center and the University of Gothenburg in Sweden.

More research is needed before this gene test is ready for prime time, Karlsson said.

“We will confirm the findings in new cohorts, and we will also start prospective trials to be sure that this is correct, but it looks really promising,” he added.

For the study, researchers evaluated the predictive power of POLAR (Profile for the Omission of Local Adjuvant Radiotherapy), a 16-gene panel that was developed based on differences between people with and without local recurrence following breast-conserving surgery.

The study included 623 people from three trials whose cancer had not spread to their lymph nodes. Their breast cancers were also estrogen receptor-positive and HER2-negative. Their tumors were analyzed after surgery to see which genes were expressed.

Each person received a POLAR score based on this analysis, and then the researchers looked at the benefits of radiation therapy among those people with high and low scores.

The main finding? People with a high POLAR score can benefit from radiation therapy, while those with lower scores can likely skip it, the study findings showed.

People with high POLAR scores who received radiation therapy after breast-conserving surgery had a 63% lower risk of local recurrence compared with those who didn’t receive radiation. By contrast, there was no difference in recurrence rates seen among people with low POLAR scores, regardless of whether they received radiation or not. After 10 years, 5% of people with low scores who received radiation had a local recurrence, compared with 7% of those who didn’t, the investigators found.

It’s a win anytime a person can avoid radiation without risking a cancer recurrence, Karlsson said. “There are side effects for a small percentage of people, and if in the future we can omit radiation for some patients, it will be good for the quality of life,” he noted.

Besides being time-consuming, radiation may cause fatigue as well as skin side effects such as rashes, pain, redness and swelling.

The findings were scheduled for presentation Friday at the San Antonio Breast Cancer Symposium. Research presented at medical meetings should be considered preliminary until published in a peer-reviewed journal.

Breast cancer experts who reviewed the new study agreed that doctors are entering a new era in the diagnosis and treatment of breast cancer.

This type of genetic profiling of breast tumors is the future, said Dr. Julia Smith, a medical oncologist at NYU Langone Perlmutter Cancer Center in New York City. “We are trying to minimize the number of treatments that we are giving in certain subgroups based on molecular and genetic profiles of their cancer.”

This study helps define a subgroup of people who may not need radiation, she said.

“People with this type of breast cancer tend to do well to begin with,” Smith noted. “We need a larger group of women who we can follow for a longer time as people with these types of breast cancer usually don’t recur until more than 10 to 15 years later.”

Doctors don’t want to overtreat people, agreed Dr. Katherina Zabicki Calvillo, a breast surgeon and founder of New England Breast and Wellness in Wellesley, Mass. “We are really focusing on getting the best outcomes for patients with minimal toxicity and risk,” she said.

“It can be safe to omit radiation in certain populations. Although well-tolerated, radiation still has untoward side effects and affects the quality of life and return to work,” Calvillo explained. There may also be cost savings, she noted.

Calling the new study “interesting and important,” Dr. Marisa Weiss said the results can help tailor treatment recommendations about radiation. She is the chief medical officer and founder of Breastcancer.org in Ardmore, Pa.

“The POLAR 16-gene genomic test seems very promising in Swedish women,” Weiss said. “It will be important to test its validity in the much more heterogenous population within the U.S. before we can apply it to diverse populations with confidence.”

Comparing Radiation Therapy Regimens for Early-Stage Breast Cancer.

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Name of the Trial
Phase III Randomized Study of Accelerated Hypofractionated Whole-Breast Irradiation and Concurrent Boost versus Standard Whole-Breast Irradiation and Sequential Boost in Patients with Early-Stage Breast Cancer after Lumpectomy (RTOG-1005). See the protocol summary.

Principal Investigator
Dr. Frank Vicini, Radiation Therapy Oncology Group

Why This Trial Is Important
Women treated with a lumpectomy for early-stage breast cancer often receive postsurgical, or adjuvant, radiation therapy to the breast that contained the cancer. Adjuvant whole-breast irradiation (WBI) has been proven to help prevent the recurrence of breast cancer and to reduce the likelihood of death from the disease. Although adjuvant WBI is considered a standard of care, many women in the United States who undergo lumpectomy for early-stage breast cancer do not receive radiation therapy following surgery.

One of the reasons women may forgo adjuvant WBI after breast cancer surgery is the length of time required to complete a standard course of radiation therapy. Typically, a woman would undergo radiation treatment to the whole breast 5 days a week for 5 weeks, followed by radiation focused on the area from which the tumor was removed (known as a sequential boost) for another 7 to 8 days. (The total duration of treatment is 6.5 weeks because radiation therapy is not given on weekends.)

For many women, the time, expense, and logistics of this extended treatment period may be unmanageable. Shortening the duration of post-surgical radiation therapy may allow more women to undergo this vital treatment.

“We want to see if we can deliver the entire course of radiation—meaning the whole breast irradiation and the boost—in 3 weeks using the more advanced radiation therapy technology now available,” said Dr. Vicini.

A number of clinical trials have investigated the use of accelerated WBI using a method called hypofractionation, in which larger individual doses of radiation are given over a 3-week period. These trials have largely confirmed that hypofractionated WBI confers the same benefits as standard WBI. However, the patients in these studies were carefully selected to minimize factors that may affect the outcomes of treatment. Therefore, these patients may not represent the average woman with breast cancer.

This clinical trial is intended to determine whether a 3-week course of accelerated, hypofractionated WBI therapy is as safe and effective, both clinically and cosmetically, as a standard 6.5-week course of post-surgical radiation therapy. In this study, women with early-stage breast cancer will be randomly assigned to a standard 5-week course of WBI with a 7- to 8-day sequential boost course or 3 weeks of hypofractionated WBI with the boost irradiation given daily during the same 3-week period (that is, a concurrent boost).

“There’s already data showing that 3 weeks of radiation is as effective as 5 weeks, but that’s in a more select group of patients,” Dr. Vicini explained. “If hypofractionation with a concurrent boost proves as effective and safe as the standard 6.5-week course of radiation in this study, we will have applied [the therapy] to a group of patients that is more representative of the majority of women we see in the clinic. So, this study really has the potential to change the standard of care for the average woman with breast cancer.”

Source: NCI