Breast-conserving therapy (BCT) may offer a greater survival benefit compared with mastectomy for women with early-stage, hormone-receptor positive disease if breast cancer biology and heterogeneity are taken into account, according to a study reported at the Breast Cancer Symposium (Abstract 60).
The knowledge gained from genomic information has changed the treatment of breast cancer over the last decade, which has helped clinicians to better understand, categorize, and treat the disease, noted Isabelle Bedrosian, MD, the study's lead author, who is Associate Professor in the Department of Surgical Oncology at the University of Texas MD Anderson Cancer Center.
“There have been changes made in medical oncology, but not so much in surgical oncology. We saw a need to go back and reexamine surgical options recognizing the new breast cancer biology. Breast-conserving therapy [BCT] and mastectomy appear to offer women with early-stage breast cancer equal survival benefit, according to randomized clinical studies from the 1980s. However, those findings come from a time when very little was understood about breast cancer biology,” she explained in an interview.
“Forty years ago, very little was known about breast cancer disease biology, such as the subtypes, differences in radio-sensitivities, radio-resistances, local recurrence, and in metastatic potential. Since then, there has been a whole body of biology that has been learned, none of which has been incorporated into patient survival outcomes for women undergoing BCT or mastectomy.”
She explained that she and her colleagues thought it important to re-visit the issue of BCT versus mastectomy using the new information about tumor biology information, hypothesizing that if that was considered, it would be shown that patients' surgical choice would have an impact on survival.
The researchers conducted a retrospective, population-based study, using the National Cancer Data Base, a nationwide outcomes registry of the American College of Surgeons, the American Cancer Society, and the Commission on Cancer. The database captures about 70 percent of newly diagnosed cancer cases in the U.S., said Bedrosian.
A total of 16,646 women were identified for the 2004-2005 period who had Stage I disease and had undergone mastectomy, breast-conserving surgery followed by six weeks of radiation (BCT), or breast-conserving surgery without radiation (BCS). Bedrosian noted that the study focused solely on women with Stage I disease in order to keep the study group homogenous and because few in this cohort would be ineligible for BCT.
Estrogen receptor (ER) and progesterone receptor (PR) data were available, but not HER2 status. “We were limited in our tumor classification with no HER2 data, and therefore we were not able to refine subtypes to the extent of medical oncologists,” she said. “We were able to classify tumors as hormonally sensitive or not, which is the first large division in breast cancer.” The researchers categorized the tumors as ER or PR positive (HR positive), or both ER and PR negative (HR negative).
Patients were rigorously matched using a propensity score for a broad range of variables, including age, whether they had received hormone therapy and/or chemotherapy, comorbidities, and the type of center where they were treated.
Of the 16,646 women, 1,845 (11%) received BCS; 11,214 women (67%) received BCT; and 3,857 women (22%) underwent a mastectomy.
The analysis shows that patients who had BCT had superior survival rates compared with those who had a mastectomy or BCS: The five-year overall survival (OS) rate was 96 percent for BCT patients, 90 percent for mastectomy patients, and 87 percent for BCS patients.
After adjusting for other risk factors, the researchers again found an overall survival benefit for BCT compared with BCS and mastectomy. In a matched cohort of 1,706 patients in each arm, there was still an overall survival benefit with BCT over mastectomy in the HR-positive subset, but not in the HR-negative subset.
‘To Our Surprise’
“To our surprise, we found that patients with HR-positive tumors who underwent BCT had a 25 percent improvement in OS compared with patients who had mastectomy,” Bedrosian said. “In the HR-negative group, it didn't matter if they had received BCT or mastectomy. The survival advantage was limited to the HR-positive subtype. Interestingly, the data seem to suggest that local treatment may matter if you consider the HR status of breast cancer.”
This research complements other recent studies that show that breast-conserving therapy is associated with a survival benefit compared with mastectomy, she added.
The delivery of radiation therapy may be a possible driver of the survival benefit: “We have historically considered surgery and radiation therapy as tools to improve local control. Yet recent studies suggest that there are survival-related benefits to radiation in excess of local control benefits. Therefore, radiation may be doing something beyond just helping with local control.”
HR-positive tumors are much more sensitive to radiation, which could explain the survival benefit in this group of patients, Bedrosian speculated.
As a next step, the researchers hope to mine the randomized controlled trial findings from the 1980s, matching those cohorts to current patients in the National Cancer Data Base to see whether there is a similar survival benefit.
“BCT is clearly a very good option for early-stage, HR positive breast cancer patients,” Bedrosian said. “There is no disadvantage in BCT. For the medical community at large, we need to reconsider paradigms that were predicated on trials in the 1980s. We need to rethink the optimal surgery and radiation treatment for breast cancer patients who are HER2-positive and triple-negative. We can better tailor medical oncology care, providing the type of surgery and extent of radiation based on tumor characteristics.”
‘BCT Use Not Being Maximized’
There is a national trend toward more mastectomies, but even though mastectomy rates are plateauing, “BCT is still not being maximized in the U.S.,” Bedrosian said. “There is room to utilize BCT more effectively.
“Previously, we just presumed that local treatment was local treatment. This data now demonstrates that may not be true. We need to tailor local therapy based on the breast cancer we see. The message is simple, but it is meaningful. We are trying to align local therapy with the new understanding of tumor biology.”
Matching Proper Loco-regional Treatment to the Individual Patient
Asked her opinion for this article, Catheryn Yashar, MD, Associate Professor of Radiation Oncology at the University of California at San Diego Moores Cancer Center, said, “This study suggests, as we would expect, that tumors may behave differently based on tumor heterogeneity or molecular characteristics. This has been demonstrated to be true in regards to overall prognosis with recurrence rates and survival. It has also been proven to be true for systemic therapy, as molecular differences can predict response to chemotherapy and hormonal therapy.
“What is fairly new information is that this study suggests that even local therapy—surgical and radiation—may be affected by heterogeneity or differences in tumor molecular characteristics.”
Yashar added: “Matching the proper loco-regional treatment, both surgery and radiation, to the patient is paramount, even more so when survival may be affected. The literature is vast, and the changing landscape places the burden of education on physicians to guide patients through the process in selecting the appropriate individual therapy. This information is another tool to guide them toward studies that will indicate the most appropriate choice.”
Tailored local therapy based on a breast cancer patient's individual characteristics can be complicated due to many varied surgical and radiation options, she noted. “Balancing all these factors in the best interest of the patient is what makes education, communication, and preferably a team approach—pathologists, radiologists, surgeons, medical oncologists, radiation oncologists, and the patient—so vital.”
Over the last several years, it has become apparent that loco-regional therapy can affect survival in both early-stage and later-stage patients, Yashar continued. “Through academic endeavor, we have learned that radical surgery is not beneficial and surgeries more tailored to presentation are appropriate.
“We have also learned that the risks of chemotherapy are not outweighed by the benefits in many patients, and that hormonal manipulation is the least toxic and most beneficial. New agents, such as Herceptin, have been discovered that have changed the prognosis for a large number of women. Others have been found to benefit from chemotherapy before surgery. We have discovered new ways to deliver radiation that is safer and, at times, normal tissue can be spared unnecessary dose. All of these advances have resulted from continued exploration and we all benefit—most especially the cancer patient—from continued clinical investigation.”
She did caution that a population-based study such as this provides questions that need to be thoughtfully answered in prospective studies—“so a change in practice immediately, based on this study, should not be done. But the question should be studied further so the appropriate treatments can be offered to the appropriate patient population.”