The present study has demonstrated reasonably low rates of local recurrence and local–regional recurrence at 10 years from ECOG E2197, which was a randomized clinical trial using doxorubicin-based and in approximately half of the patients, also taxane-based adjuvant systemic chemotherapy. For the overall group of 388 patients, local recurrence was 5.4 % and local–regional recurrence was 6.6 % at 10 years after breast conservation treatment with definitive radiation (; ). These results for local recurrence and local–regional recurrence are consistent with other randomized clinical trials and retrospective clinical studies. Local recurrence and local–regional recurrence were reasonably low for the overall group of patients as well as for all subgroups of patients identified. Therefore, no patient subgroup was identified in the current study for which breast conservation treatment with radiation was contraindicated, including patient subgroups based on biologic subtype or 21-gene recurrence score.
The only subgroups identified in the current study with 10-year rates of local recurrence or local–regional recurrence >10 % were: (1) HR-positive tumors with a high 21-gene recurrence score; (2) HR positive, HER2-negative tumors with a high 21-gene recurrence score; and (3) patients age ≤39 years (, ; ). However, the results in these subgroups are based on relatively small numbers of patients with correspondingly wide 95 % confidence intervals. Relatively few studies have examined the relationship of biologic subtype to local recurrence or local–regional recurrence after breast conservation treatment [4
]. Many studies, including the present study, have approximated biologic subtype through the combination of the three tumor markers of ER status, PR status, and HER2 status [6
]. The use of these three tumor markers to approximate biologic subtype has practical value in that these tumor markers are commonly available from retrospective data and guide the selection of targeted adjuvant systemic therapies (e.g., hormonal therapy, trastuzumab). Some studies have suggested an increased risk of local recurrence or local–regional recurrence after breast conservation treatment associated with the triple negative (basal-like) subtype or associated with tumors that are HER2 positive, although these associations have not been demonstrated uniformly in all studies [4
]. In the present study, no statistically significant differences in the 10-year rates of local recurrence or local– regional recurrence were observed based on biologic subtype (both P
≥ 0.76; ; ).
Mamounas et al. [1
] evaluated the impact of the 21-gene recurrence score on local–regional recurrence from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 and B-20 studies. The patients in this analysis had node negative, ER-positive breast cancer, and some of the patients had received adjuvant systemic therapy consisting of tamoxifen with or without adjuvant systemic chemotherapy. Systemic chemotherapy consisted of either cyclophosphamide, methotrexate, and 5-flourouracil (CMF) or methotrexate and 5-flourouracil (MF) with leucovorin rescue. For the patients treated with chemotherapy (CMF or MF) plus tamoxifen, the 10-year rates of local– regional recurrence for low, intermediate, and high 21-gene recurrence score were 1.6, 2.7, and 7.8 %, respectively (P
= 0.028). For the patients treated with tamoxifen (without chemotherapy) and either by mastectomy or breast conservation treatment, the 21-gene recurrence score was an independent predictor of local–regional recurrence on multivariate analysis (hazard ratio 2.16; P
For the subgroup of 390 patients treated with lumpectomy, breast radiation, and tamoxifen, Mamounas et al. reported an interaction of the 21-gene recurrence score with patient age [1
]. After breast conservation treatment, the 10-year rates of local–regional recurrence for patients age <50 years were 12.5 % for low 21-gene recurrence score, 27.7 % for intermediate recurrence score, and 26.5 % for high recurrence score. However, the 10-year rates of local–regional recurrence for patients age ≥50 years were low regardless of 21-gene recurrence score (3.6, 3.7 and 4.8 %, respectively).
There are currently no data indicating that biologic markers can identify a subgroup of patients for whom breast conservation treatment is not indicated when using contemporary systemic therapies. The present study has therefore analyzed the potential role of the 21-gene recurrence score and biologic subtype in a randomized clinical trial using contemporary systemic chemotherapy and hormonal therapy.
In the present study, the rates of local recurrence and local–regional recurrence were higher with increasing 21-gene recurrence score, although these did not achieve statistical significance on univariate and multivariate analyses (; , ). Similarly, for the subset of patients with HR-positive tumors, a trend was seen for higher 10-year rates of local recurrence and local–regional recurrence with increasing 21-gene recurrence score, although also not statistically significant. For the subset of HR-positive tumors, evaluation of the 21-gene recurrence score as a continuous variable showed a statistically significant hazard ratio for local–regional recurrence (hazard ratio 2.66; P = 0.03).
The results from the present study are consistent with a possible effect of biologic subtype based on 21-gene recurrence score, given that the 21-gene recurrence score was designed and validated in the setting of patients with HR-positive tumors who were treated with hormonal therapy. However, the magnitude of the differences between the recurrence score groups may be reduced in patients receiving contemporary adjuvant systemic treatment, including doxorubicin-based chemotherapy, taxane-based chemotherapy, and for HR-positive tumors, hormonal therapy. In addition, the magnitude of these differences may be further reduced due to a greater sensitivity of tumors with high 21-gene recurrence score to cytotoxic chemotherapy [24
Adjuvant systemic chemotherapy and adjuvant hormonal treatment have both been shown to reduce local recurrence and local–regional recurrence in numerous studies. Retrospective studies have documented improvements in local recurrence and local–regional recurrence associated with improvements in patient selection and treatment techniques over time [26
]. In the study by Mamounas et al. [1
], adjuvant tamoxifen and chemotherapy reduced the risk of local–regional recurrence within each recurrence score subgroup (low, intermediate, and high) in comparison to placebo-treated patients.
The rate of local–regional recurrence was 10.1 % for patients age ≤39 years (). However, patient age did not achieve statistical significance for local recurrence or local–regional recurrence (both P ≥ 0.50). Nonetheless, there is a trend, which is not statistically significant, toward increasing local recurrence and local–regional recurrence in the younger age population, consistent with other studies. The lack of statistical significance may be secondary to the relatively small number of patients in the youngest age group (n = 43 for age ≤39 years).
The factors identified in the present study as statistically significantly associated with local recurrence and local– regional recurrence on both univariate and multivariate analyses were T stage and adjuvant systemic chemotherapy arm (). In the current study, the local recurrence and local–regional recurrence rates were higher for T1 tumors in comparison with T2/T3 tumors, which is in contrast to other reported studies. There is no clear explanation for the finding that the local recurrence and local–regional recurrence rates were higher for T1 tumors in comparison to T2/T3 tumors and for patients treated with AT in comparison to AC. No imbalance or other factors were found to explain these differences. One possible explanation is that these results are false positive findings associated with the play of chance.
There are several limitations of the present study. First, the numbers of patients in some of the subsets were relatively small with correspondingly wide 95 % confidence intervals. Second, the patients treated in the present study predated the era of adjuvant trastuzumab for HER2-positive tumors, although only 15 % of the tumors in the present study were HER2 positive (). The addition of trastuzumab for HER2-positive tumors has been associated with a reduction in local recurrence [28
]. Third, biologic subtype was approximated based on the combination of three tumor markers of ER status, PR status, and HER2 status, although recognizing the limitations of this approximation. Finally, patients in the present study represent a subset of the overall population of patients included in the original E2197 study ().
In summary, the present study has demonstrated reasonably low 10-year rates of local recurrence and local– regional recurrence for patients in a randomized clinical trial using doxorubicin-based and for approximately half of the patients, also taxane-based adjuvant systemic chemotherapy. The current analysis identified no subgroup of patients for which breast conservation treatment was contraindicated, including subgroups based on biologic subtype and the 21-gene recurrence score. On the basis of the current analysis, neither biologic subtype nor the 21-gene recurrence score should preclude breast conservation treatment with radiation.