We examined survival up to 12 years after primary breast cancer therapy among women in population-based registries from across the United States using rigorous statistical methods and found that women undergoing BCS with radiation had a greater likelihood of survival than women who underwent mastectomy. Among a subset of women who represent those enrolled in clinical trials, we found no differences in survival, consistent with the evidence from clinical trials.
Our findings are consistent with a recently reported study demonstrating that distant disease-free survival and overall survival for women with one to three positive lymph nodes was better for women who had segmental mastectomy with radiation than for those treated with mastectomy without radiation [59
]. Thus, radiation may have an important role in breast cancer control. The current understanding of breast cancer emphasizes both the importance of local control as well as the possibility of systemic spread [60
]. A 2005 meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group examined 78 randomized clinical trials evaluating the extent of surgery and the use of radiation therapy and demonstrated benefits to radiation therapy beyond reductions in local recurrence [61
]. For every four local recurrences that were prevented at 5 years, there was one fewer breast cancer death at 15 years. These benefits were present regardless of whether the decrease in local recurrence was via more extensive surgery or radiation. Radiation also improved 15-year survival for women undergoing mastectomy, a finding also noted in observational studies of women with high-risk cancers undergoing mastectomy [62
Because results of observational analyses may be influenced by the presence of unobserved confounders, we rigorously tested the robustness of our estimates to a series of potential unobserved confounders. These analyses suggest that there would have to be very large effects of multiple unobserved confounders to explain our findings or demonstrate a benefit of mastectomy over BCS. Thus, although our effect sizes may be increased due to unobserved confounders, we can be comfortable rejecting the possibility that mastectomy is better
than BCS with radiation. This finding is important because recent data suggest trends towards more aggressive surgery [20
], and rates of mastectomy remain quite high in some areas in the United States [15
The survival benefit to BCS with radiation over mastectomy that we and others [59
] have observed has not been observed in clinical trials. One possible explanation for the different findings is that although clinical trials are the gold standard for examining treatment efficacy, only 2.5% of cancer patients enroll in clinical trials [24
], and participants tend to be younger and healthier than other patients and are typically cared for by providers who practice at or are affiliated with cancer centers [25
]. Women in trials of primary breast cancer therapies were predominantly younger than age 70, had few comorbid illnesses, and had stage I tumors. In our analyses, we identified women who were most like those in the trials and found similar long-term survival following BCS with radiation and mastectomy, consistent with results of clinical trials. It may be that the benefits of radiation in addition to BCS are greatest in women with larger tumors or those cared for outside of major cancer centers.
A second possible explanation is that unobserved confounders contributed to our findings [65
]. The patients in our cohorts differed in many ways that could explain longer-term survival (patients undergoing BCS without radiation were older and sicker than other women, patients undergoing mastectomy with or without radiation had more advanced tumors). We used careful propensity score adjustment and tested the sensitivity of our analyses to unobserved confounders. As noted above, although unmeasured confounders could possibly explain the survival advantage we observed, it is unlikely that the ability to adjust for unobserved confounders would lead to a conclusion that mastectomy is better than BCS with radiation.
Given the importance of local tumor control, it is important to note that 10% of women over the age of 65 underwent BCS without radiation. These women tended to be older and sicker than other women, but we observed worse survival even among younger and healthier women, who may be most likely to benefit from the addition to radiation.
Several previous studies have examined breast cancer treatment effectiveness using observational data. Two studies assessed outcomes associated with mastectomy or BCS using instrumental variable analysis [66
]. The first, which examined women diagnosed with stage II breast cancer in Iowa during 1989–1994, suggested that, for patients whose care was influenced by distance to a radiation facility, mastectomy was associated with better survival than BCS with radiation [66
]. The second examined a national sample of Medicare beneficiaries diagnosed with stage I or II disease during 1992–1994. The instrumental variables analysis found no difference in 3-year survival by treatment type, although the estimates were large and unstable, and an ordinary least-squares approach found a survival advantage of BCS with radiation over mastectomy [67
], similar to our findings. These inconsistent findings of these two articles may be because the first study examined only stage II patients in one state, while the second study included all patients with breast cancer undergoing mastectomy or BCS.
Our findings should be viewed in light of several limitations. First, we studied only older women with breast cancer residing in SEER areas, so the generalizability of our findings to other patients requires further study. Second, we had no information about recurrence and limited information about the breast cancer care that women received following their primary therapy. Third, although our propensity score methods allowed adjustment for observed confounders, our measures of comorbidity were based on administrative data only, and we could not account for possible unobserved confounders, such as hormonal therapy. Still, our sensitivity analyses suggest that the effects of one or more confounders would need to be very large to explain our findings. Finally, we used death certificate data to assess cause of death, and misclassification is possible [68
In summary, we found that the type of primary therapy for early-stage breast cancer is related to many patient, tumor, surgeon, and hospital characteristics, and even after careful adjustment for such factors, there is no evidence to suggest benefits to mastectomy over BCS with radiation; rather, women who underwent BCS with radiation had better survival than women who underwent mastectomy. These findings are reassuring in light of recent trends towards more aggressive primary breast cancer therapy.