In this study, we found that, among 1,434 consecutive women with early-stage invasive BC who received BCT, increasing age was associated with decreased risk of LR independent of BC subtype approximation or other prognostic factors. Yet, although younger women demonstrated the highest rate of LR, the 5.0% risk of LR at 5 years we observed among the youngest age quartile was considerably lower than the 10% to 36% risk of LR at similar follow-up reported in prior studies8–10,22–24,43
from earlier treatment periods that focused on recurrence risk among young women.
The low rate of LR after BCT among young women in our series compared with earlier reports may reflect differences in treatment era. Similar to other centers,43,44
we have observed a progressive decline in LR over time. Our series included women treated with BCT from 1997 to 2006; most prior series report outcomes on women treated before 2000. Modern advances include better preoperative breast imaging and postoperative delineation of the lumpectomy cavity for radiation planning, greater attention to obtaining negative surgical margins, incorporation of a radiation boost, and—perhaps most importantly—the prevalent use of adjuvant systemic therapy. Systemic therapy substantially decreases rates of LR after BCT12,45–49
; in this study, 91% of women received hormonal therapy, chemotherapy, or both. This is in contrast to rates of systemic therapy use of 20% to 35% reported for patients treated in the 1970s, 1980s, and 1990s,8,23,24
and to some contemporary series that still report systemic therapy use among less than 60% of patients,50
which may account for some of the differences observed in rates of LR.
In addition to age, we analyzed LR according to BC subtype, and we observed higher rates of LR among HER2 and triple-negative subtypes, with a trend toward higher LR among patients with luminal B subtype. We defined luminal subtypes as luminal A, luminal B, and luminal HER2 by using histologic grade in addition to hormone receptor status on the basis of data that demonstrated distinct outcomes among three luminal subtypes by incorporating tumor proliferation markers (Ki-67)36
that are now being utilized by some groups.50,51
Our results suggest that, among young women, luminal B and HER2 subtypes are associated with higher rates of LR after BCT compared with older women. Similarly, investigators in Milan reported elevated rates of locoregional recurrence for the luminal B subtype among young women after mastectomy or BCT.50
Other than the luminal B subtype, the luminal subtypes were associated with relatively low rates of LR among the youngest patients, demonstrating that many young women with hormone-positive disease have quite favorable outcomes after BCT.
The prognostic importance of age on risk of LR after BCT remains controversial. Young age has been reported as a risk factor for LR after BCT in most investigations8–12,52,53
but not in all.54–56
Younger women are more likely to present with larger, higher-grade, ER negative, LVI positive, lymph node–positive tumors.35,57,58
Thus, it is challenging to separate these clinicopathologic factors that occur more frequently among young women and are themselves prognostic from the impact of age on outcome. The multivariable analysis in this study suggests that, even in the era of BC subtype approximation, increasing age remains independently prognostic for lower risk of LR, consistent with most prior reports. However, the magnitude of increased LR risk in absolute terms among young women appears modest, and the rates of LR after BCT among the youngest age quartile, or made on the basis of age cutoffs of 35 or 40 years, appear reasonably low.
Additional study is required to understand the mechanisms underlying the prognostic value of age in BC. Anders et al35
has shown that, in addition to unfavorable clinicopathologic characteristics, BC in women 45 years of age or younger exhibited significantly lower ERα mRNA, ERβ mRNA, and PR expression but higher HER2 and epidermal growth factor receptor genomic expression, with over 350 relevant gene sets related to multiple oncogenic signaling pathways that distinguished BC in young women. Recent work suggests that, even within subtypes, there is striking heterogeneity among tumors, with transcriptome analyses identifying six subgroups within the triple-negative subtype that have divergent sensitivities to different chemotherapies or targeted inhibitors.59
Given this apparent diversity of subgroups within BC subtypes and different genomic features among young patients, ongoing research is necessary to additionally characterize what appears to be a distinct biologic expression of BC among young patients that might explain the prognostic significance of age. Indeed, another recent study by Anders et al60
evaluated the distribution of molecular BC subtypes by age to assess for potential confounding effects on the distribution of purported age-associated genes. Their work demonstrated that genes associated with intrinsic subtype and grade appeared to strongly influence the biologic differences observed among tumors in young versus older women. This suggests that, as BC continues to be better characterized at the genomic level and as therapies are selected to target molecular subtypes for individual patients, the importance of age on prognosis may eventually disappear.
There are several potential limitations to this study. Classification according to ER, PR, and HER2 status and grade are only approximations of genotype-based molecular BC subtypes, and our conclusions do not necessarily apply to genotype-based subtypes. Although our redefined BC subtypes incorporating histologic grade in addition to hormone receptor status are based on the heterogeneity of classically defined luminal B tumors61
and prognostic information gained by adding tumor proliferation marker data to classic subtypes,36
our findings that are based on these new definitions must be confirmed by other studies. Other possible limitations are the relatively small patient numbers in certain subgroups, such as for the HER2 subtype that contained only 55 patients. Additionally, no patients received trastuzumab in this cohort, but it is now the standard of care for patients with HER2-positive BC40,41
; thus, the LR risk seen in the HER2 subgroup may now be lower than what we observed among women treated until 2006. In the two largest randomized trials, adjuvant trastuzumab decreased the risk of LR among HER2-positive patients by almost 50%, although LR was not a specific end point. Moreover, with a median follow-up of 7.1 years, we have reported cumulative incidence of LR at 5 years, and longer follow-up may be required to determine accurate long-term rates of LR. Finally, dosimetric analyses of whole-breast RT parameters is warranted, given that we found that increasing whole-breast RT dose was associated with reduced LR rates. Because there exists an important interplay between total RT dose, dose per fraction, and dose homogeneity within the breast,62,63
additional investigation of the impact of dosimetry on our results is necessary and has been undertaken.
In conclusion, this study demonstrates that, in an era of routine use of systemic therapy and clinical BC subtype approximation, young age remains an independent risk factor for LR, with variability in LR risk for young patients according to BC subtype. More important, however, is our observation of the low overall risk of LR among the youngest age group in our study. The 5.0% risk of LR at 5 years we found among the youngest age quartile is substantially lower than the risk of LR reported in prior series from earlier treatment periods, and it constitutes an acceptably low risk of LR after BCT among young women in the current era.