Survival outcomes in breast cancer patients under the age of 35 was not compromised in those who had initial conservation therapy versus those who had mastectomy, according to our retrospective study published recently in the International Journal of Radiation Oncology. (1)
Historically, women with invasive breast cancer under the age of 40 have had a disproportionately worse overall survival (OS) and higher rates of recurrences compared to older patients, (2), (3), (4) which has led to more aggressive treatment approaches, such as mastectomy instead of breast conservation and the addition of adjuvant therapies.
Previous studies have also found that young breast cancer patients have worse outcomes. However, they have used a variety of study intervals and definitions for “young” or “very young” patients and older comparison groups, and some included patients with stage 0 or stage IV disease. As a result, reports have varied regarding the use and outcomes of breast conservation therapy and mastectomy among young patients.
For our present study, we compared outcomes of young patients with invasive breast cancer treated at Memorial Sloan Kettering Cancer Center (MSK) between 1990 and 2010 with older patient cohorts, with a median follow-up of ten years. Our goal was to identify factors that predict mortality, recurrence, and secondary malignancies in the youngest group of patients. (1)
We examined local control, distant control, and overall survival compared outcomes for 529 women under 35 years with 6,246 women aged 36 to 50 years and 7,294 women aged 51 to 70 years. Within the youngest cohort, we also examined disease control rates by surgical strategy — mastectomy or breast conservation — and the risk of secondary malignancy and contralateral breast cancer associated with the use of adjuvant radiation therapy. (1)
While survival and recurrence outcomes were worse for the youngest cancer patients than the two older cohorts, in concordance with previous reports, we found that OS was statistically similar for patients who had breast-conserving therapy or mastectomy. Our novel finding suggests that breast conservation therapy is appropriate for young breast cancer patients, and the concern for secondary malignancies should not influence the known indications for postoperative radiation therapy. (1)
Breast Cancer in Women Under 35
Breast cancer is the most commonly diagnosed nonskin cancer in women under 40, accounting for 30 percent of diagnoses in this group. (5) While women under 40 only make up about six percent of all invasive breast cancer cases in the United States, they experience disproportionately higher rates of recurrences (2), (3), (4) and worse OS compared to older patients. (1), (4), (6)
Two observations underpin these trends. First, women under the age of 40 are not routinely screened with mammography and are more likely to present with more advanced stages of disease. (5), (7) Second, breast cancer in very young women may have distinct tumor biology, independent of known germline drivers, (8) with many tending to have worse histological features, including high histologic grade, presence of lymphovascular invasion, and an absence of hormone receptors. (9), (10), (11) Young age has been independently associated with worse outcomes after adjusting for clinicopathologic features, (12), (13), (14) and recent studies have found higher risks of mortality and recurrence even among those with early-stage disease and favorable subtypes of disease compared with older women. (3), (10), (13), (14), (15), (16)
Collectively, these observations have led to more aggressive treatment approaches for very young women with breast cancer, such as mastectomy instead of breast conservation therapy and the addition of adjuvant therapies, albeit weighed against the potential for long-term treatment-related toxicities.
We examined records from our institutional database for women ≤ 35 diagnosed with invasive breast cancer from 1990 to 2010, a period with sufficient follow-up time to observe recurrence rates, contralateral breast cancers, and secondary malignancies, and identified 529 patients. We also identified two older comparison cohorts: 6,244 patients aged 36 to 50 and 7,292 patients aged 51 to 70, approximating the cut-off for menopause. (1)
Patients who did not undergo surgical intervention or were stage IV at diagnosis were not included. We collected demographics, germline status, surgical pathology, disease stage, treatment details, and follow-up information from the electronic medical records. Final pathologic staging was performed according to the 7th edition of the American Joint Committee on Cancer classification system. (1)
Note that we used the year 2000 as a classification variable since previous work by Frandsen et al. used the variable to approximate improved treatments, including the increasing use of anthracycline-based chemotherapy in patients younger than 70, the combination of hormonal and chemotherapy in patients under 50, and radiation boosts after whole breast irradiation, which led to improvements in relapse-free survival after this date. (17) The year 2000 also marked the widespread adoption of HER-2 testing and the approval of trastuzumab.
Survival Outcomes for Patients 35 and Under Compared with Older Patients
Ten-year OS was 73 percent among patients 35 years of age and under and was worse than the OS observed in both older cohorts as illustrated by Kaplan Meier curves in Figure 1c in the paper. (1)
Within the ≤ 35 cohort, OS was statistically similar for those who received breast conservation therapy and those who had mastectomies. The only exception was inferior outcomes for the group of patients treated with mastectomy plus radiation therapy.
The disease-free survival (DFS) rate at ten years was 48% for patients in the under 35 group. (1)
Freedom from Local and Distant Failure for Patients 35 and Under
The cumulative incidence of locoregional recurrences at ten years was 20 percent, with local failures occurring more frequently in the mastectomy plus radiation therapy group than in the other three surgical groups that received partial mastectomy plus radiation, partial mastectomy, and mastectomy (p = 0.04). (1)
Patients 35 years and under were significantly more likely to experience local failure than patients in the age a36 to 50 group (HR 2.2, 95% CI 1.8–2.6, p < 0.001) and the age 51 to 70 group (HR 3.1, 95% CI 2.45–3.9, p < 0.001). (1)
Rates of Second Malignancy and Contralateral Breast Cancer in Patients 35 and Under
The rate of secondary malignancies at five and ten years were 2.2% and 4.4%, respectively. Alcohol use, family history, and detection of germline mutations were correlated with the risk of secondary malignancies on univariate analysis. However, receipt of radiation was not associated with an elevated risk of secondary malignancies (HR 1.22, 95% CI 0.57–2.59, p = 0.612). (1)
Patients in the ≤ 35 cohort were not more likely than those in older cohorts to experience secondary malignancies. Of the 33 secondary malignancies in the youngest group, 11 were likely related to receipt of radiation, and another were possibly related. (1)
The contralateral breast cancer rate in the youngest patient cohort was 4 percent at five years and 8.9 percent at ten years. Family history and detection of germline mutations were predictive factors on univariate analysis. Notably, the use of any adjuvant radiation was not associated with the risk of contralateral breast cancer (HR 1.26, 95% CI 0.7–2.27, p = 0.4). (1)
Advancing Breast Cancer Care
At MSK, we are currently conducting 69 clinical trials for patients with breast cancer, testing new treatment options such as novel chemotherapies alone or in combination with other agents, advances in radiation therapy alone and in combination with chemotherapies, and immunotherapies. Whenever possible, our goal is to reduce treatment-related toxicities and late effects without compromising outcomes. We also continue to study ways to improve the quality of life of survivors.
Our Evaluating the Causes of Cancer in Young Patients study seeks to identify gene changes in breast and select other cancers in young patients without a parental history of disease. Our goal is to evaluate whether sporadic or inherited gene mutations caused their cancers. Eligible patients with breast cancer include those diagnosed at or before the age of 40, with a living mother or father without cancer who is willing to provide a saliva sample for genetic analysis.
The study was supported by the NIH Cancer Center Support Grant (P30 CA008748). All study authors declare no financial disclosures or conflicts related to the data in the manuscript.