Although breast cancer outcomes have improved owing to recent advances in adjuvant chemotherapy, it is possible that patients who do not require chemotherapy also receive superfluous treatment. From this perspective, the possibility of separately evaluating the appropriateness of adjuvant chemotherapy for individual patients using multigene assays has garnered attention. The 95GC multigene assay is useful for the prognostic assessment of ER-positive, node-negative breast cancer [12, 13, 15]. However, previous studies regarding the usefulness of 95GC as a prognostic factor have been based only on patients from a single facility or public databases.
In the present investigation, we performed a retrospective study of the usefulness of 95GC in patients from five Japanese facilities with ER-positive, node-negative breast cancer who received endocrine therapy alone as adjuvant therapy. The 10-year relapse-free survival rate for patients diagnosed with 95GC-L was 88.4%, suggesting that favorable outcomes can be expected for these patients even if chemotherapy is omitted and only endocrine therapy is administered.
We examined the relationship between 95GC and intrinsic subtypes. The proportion of luminal A tumors was significantly higher among 95GC-L patients than among 95GC-H patients, whereas that of luminal B tumors was lower. Furthermore, luminal B tumors can be divided based on 95GC, with 95GC-L showing more favorable outcomes than 95GC-H. This finding demonstrates the possibility that patients with tumors classified by PAM50 as luminal B include a few for whom the addition of chemotherapy will have little beneficial effect on the outcome and that unnecessary chemotherapy for such patients may be reduced by combining PAM50 and 95GC results.
With regard to the association with histologic grade, when 95GC was used to divide the patients with grade 2 tumors into two groups (95GC-L and 95GC-H), the 10-year relapse-free survival rate for 95GC-L was 96.3%, which was significantly better than that for 95GC-H, and the relapse rate was extremely low. Therefore, chemotherapy can be considered omissible in patients with a histologic grade of 2 if they are 95GC-L.
By performing a multivariate analysis of 95GC and clinicopathological factors utilized in previous studies to assess breast cancer recurrence risk, such as age, tumor diameter, tumor grade, Ki-67, and PAM50, we were able to confirm that 95GC is a significant independent prognostic factor that influences the recurrence risk. In our cohort we did not include patients that have received neoadjuvant therapy. Because neoadjuvant chemotherapy is often added in tumors ≥3 cm, the T2 cohort included only cases with a size close to T1 stage, and as a result, there was no difference in prognosis between T1 and T2 stages.
The 95GC assay could provide extremely useful information for the selection of therapeutic strategies, such as adjuvant chemotherapy. The 95GC-L group had a better prognosis in response to adjuvant endocrine therapy than the 95GC-H group. Further prospective studies are needed to evaluate whether 95GC assays could be used to determine the necessity of chemotherapy in patients with ER-positive, node-negative breast cancer.
The Oncotype DX®, a breast cancer multigene assay, analyzes 21 genes using reverse transcription polymerase chain reaction, and classifies patients by recurrence score (RS) (0–100) into low-, mid-, and high-RS groups. It is a useful prognostic factor in hormone receptor-positive, HER2-negative, node-negative breast cancer and a factor for predicting the effectiveness of adjuvant chemotherapy in the high-RS group [5, 6]. Naoi et al. reported that in an indirect comparison with Oncotype DX® using Recurrence Online, 95GC could be used to classify 81 patients as having a mid-range risk (95GC-L group of 38 patients and 95GC-H group of 43 patients), with a significantly better recurrence-free survival rate in the 95GC-L group than in the 95GC-H group .
In everyday clinical practice, if a multigene assay is not available, Ki-67 is often used as a prognostic factor for ER-positive, HER2-negative breast cancer. In our study, Ki-67 measurement was performed through a central pathology review, but it was not a significant prognostic factor. It is difficult to establish a standardized method for evaluating Ki-67; therefore, it is difficult to accurately assess recurrence risk based on this factor. In the future, multigene assays for breast cancer should be incorporated more widely in everyday clinical practice.
With regard to the usefulness of 95GC as a predictive factor for the effectiveness of chemotherapy, Tsunashima et al. examined 72 patients from their facility and 287 public database patients who underwent neoadjuvant chemotherapy. They reported a significantly greater tumor-shrinking effect in the 95GC-H group than in the 95GC-L group . Even though further prospective studies are needed, in the future, 95GC might be used not only as a prognostic factor but also as a predictive factor for the effectiveness of chemotherapy.
The main limitation of this study was its small sample size. Additionally, the retrospective nature of the study resulted in a selection bias. Moreover, because of the archived samples, the quality of which was not controlled owing to the surgical practices used in the earlier days, 26.5% (27/102) of the samples had poor RNA quality. However, in recent times, the strict rules enforced for the handling of post-extraction specimens have helped to preserve RNA quality and, thus, guarantee a high rate of sample recuperation in everyday clinical practice. Finally, all study participants were Japanese, and the performance when targeting other races in other countries is unknown. However, a recently published study evaluated the recurrence stratification of patients from both Japan and the US, with comparable results between populations .
Currently, 95GC has been available in Japan since 2013 for research purposes. Hence, further validation of the benefits of 95GC through a prospective study using a larger sample size is warranted to confirm the validity of incorporating 95GC in everyday clinical practice in Japan.