Key points

Introduction

Luminal breast cancers are traditionally the most frequent subtypes of breast cancer, representing a heterogeneous group of tumors with a large variation in clinical presentation. Selection of patients who might forego chemotherapy within these subgroups represents a major question.

Controversies concern groups with bulky tumors and/or positive nodes who present with favorable biology (ideally luminal A) versus patients with small and node-negative tumors but with an unfavorable biology (ideally biologically aggressive luminal B). Among smaller tumors traditionally judged as low risk and not requiring chemotherapy, there is a not negligible subgroup with adverse tumor biology that should be considered for a combined chemoendocrine therapeutic approach. Within this subgroup, the cross talk with other pathways should be also considered and new strategies to escape multipathway drivers of tumor growth and progression should be implemented. Novel agents to be added to endocrine therapy are under investigation to shut down bypass signaling pathways that drive tumor growth.

Similarly, among subsets defined by high levels of expression of ER along with low proliferation, commonly cured with endocrine therapy alone, there is a subgroup presenting with very large tumor burden and a related dismal prognosis that might require the addition of chemotherapy.

Care for patients through a personalized approach remains a central issue, and clinicians are currently more likely to give selective interventions to minimize acute and late toxicity without compromising efficacy. In particular, for the subgroup of patients with ER-positive disease, appropriate adjuvant systemic therapy involves choosing treatments tailored to individual patients according to biologic features and assessments of patient risk but also according to comorbidities, desire to preserve fertility, and patient preference.

Recommendations from the St. Gallen consensus panel suggested the use of standard pathology reports based on IHC measurements of ER, PgR, Ki67, and HER2 as a surrogate molecular classification to identify subgroup of patients who might avoid/receive chemotherapy. Common features that might indicate increased response to endocrine therapy include high expression of ER and PgR. Conversely, the presence of high proliferation index and/or lower expression of steroid hormone receptors might identify a subgroup of patients with luminal disease at higher probability of response to chemotherapy.

This clinicopathologic classification requires the availability of reliable measurements of its individual components, therefore guidelines have been published for ER and PgR determination and for the proper evaluation of Ki67.

In parallel with clinicopathologic classification, a great advance was reached in the development of multigene prognostic signatures for gene expression patterns to identify a subset of patients with luminal breast cancers who benefit from adding chemotherapy to endocrine therapy.

In particular, the fine tuning for prediction of which groups may benefit from endocrine therapy alone has been possible with the advent of multigene assays, such as the 21-gene recurrence score (RS) and 70-gene assays, because the findings from the retrospective analysis of 2 large trials (SWOG S8814 and NSABP [National Surgical Adjuvant Breast and Bowel Project] B-20) have shown that patients with low RS may be sufficiently treated with endocrine therapy alone. A popular method for assessing the magnitude of benefit of endocrine therapy and chemotherapy in luminal breast cancer is Adjuvant! Online ( Fig. 1 ). The algorithm used, however, is based on historical trials with biologic features evaluated in an older fashion, in which the comparator groups may not have received adequate endocrine therapy.

Decision recommendation for adjuvant chemotherapy in early-stage breast cancer patients.

( From Jacot W, Gutowski M, Azria D, et al. Adjuvant early breast cancer systemic therapies according to daily used technologies. Crit Rev Oncol Hematol 2012;82(3):361–9; with permission.)

Prospective validation of these multigene signatures is under way. Specifically, the Trial Assigning Individualized Options for treatment (Rx) (TAILORx) (ClinicalTrials.gov identifier NCT00310180 ) is studying the utility of the Oncotype DX score to predict chemotherapy benefit in the intermediate score subgroup.

The Microarray in Node-negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy Trial (MINDACT) (ClinicalTrials.gov identifier NCT00433589 ) is studying the outcomes of patients with discordant risk assessments using the 70-gene expression signature of MammaPrint compared with clinicopathologic features with the Adjuvant! Online program. The RxPONDER ([Rx for Positive Node, Endocrine Responsive Breast Cancer] ClinicalTrials.gov identifier NCT01272037 ) is a large prospective trial designed to determine the benefit of chemotherapy among women with hormone receptor–positive breast cancer, 1 to 3 positive nodes, and an RS less than or equal to 25, as determined by Oncotype DX testing. The results from these large, prospective studies are eagerly awaited and will hopefully shed light on the best strategies to personalize adjuvant treatment in patients with luminal breast cancer.

This article discusses the evolving knowledge of adjuvant treatments in order to define reasonable but also novel treatment strategies in patients with ER-positive/HER2-negative (luminal A and luminal B) breast cancer.

Introduction

Luminal breast cancers are traditionally the most frequent subtypes of breast cancer, representing a heterogeneous group of tumors with a large variation in clinical presentation. Selection of patients who might forego chemotherapy within these subgroups represents a major question.

Controversies concern groups with bulky tumors and/or positive nodes who present with favorable biology (ideally luminal A) versus patients with small and node-negative tumors but with an unfavorable biology (ideally biologically aggressive luminal B). Among smaller tumors traditionally judged as low risk and not requiring chemotherapy, there is a not negligible subgroup with adverse tumor biology that should be considered for a combined chemoendocrine therapeutic approach. Within this subgroup, the cross talk with other pathways should be also considered and new strategies to escape multipathway drivers of tumor growth and progression should be implemented. Novel agents to be added to endocrine therapy are under investigation to shut down bypass signaling pathways that drive tumor growth.

Similarly, among subsets defined by high levels of expression of ER along with low proliferation, commonly cured with endocrine therapy alone, there is a subgroup presenting with very large tumor burden and a related dismal prognosis that might require the addition of chemotherapy.

Care for patients through a personalized approach remains a central issue, and clinicians are currently more likely to give selective interventions to minimize acute and late toxicity without compromising efficacy. In particular, for the subgroup of patients with ER-positive disease, appropriate adjuvant systemic therapy involves choosing treatments tailored to individual patients according to biologic features and assessments of patient risk but also according to comorbidities, desire to preserve fertility, and patient preference.

Recommendations from the St. Gallen consensus panel suggested the use of standard pathology reports based on IHC measurements of ER, PgR, Ki67, and HER2 as a surrogate molecular classification to identify subgroup of patients who might avoid/receive chemotherapy. Common features that might indicate increased response to endocrine therapy include high expression of ER and PgR. Conversely, the presence of high proliferation index and/or lower expression of steroid hormone receptors might identify a subgroup of patients with luminal disease at higher probability of response to chemotherapy.

This clinicopathologic classification requires the availability of reliable measurements of its individual components, therefore guidelines have been published for ER and PgR determination and for the proper evaluation of Ki67.

In parallel with clinicopathologic classification, a great advance was reached in the development of multigene prognostic signatures for gene expression patterns to identify a subset of patients with luminal breast cancers who benefit from adding chemotherapy to endocrine therapy.

In particular, the fine tuning for prediction of which groups may benefit from endocrine therapy alone has been possible with the advent of multigene assays, such as the 21-gene recurrence score (RS) and 70-gene assays, because the findings from the retrospective analysis of 2 large trials (SWOG S8814 and NSABP [National Surgical Adjuvant Breast and Bowel Project] B-20) have shown that patients with low RS may be sufficiently treated with endocrine therapy alone. A popular method for assessing the magnitude of benefit of endocrine therapy and chemotherapy in luminal breast cancer is Adjuvant! Online ( Fig. 1 ). The algorithm used, however, is based on historical trials with biologic features evaluated in an older fashion, in which the comparator groups may not have received adequate endocrine therapy.

Decision recommendation for adjuvant chemotherapy in early-stage breast cancer patients.

( From Jacot W, Gutowski M, Azria D, et al. Adjuvant early breast cancer systemic therapies according to daily used technologies. Crit Rev Oncol Hematol 2012;82(3):361–9; with permission.)

Prospective validation of these multigene signatures is under way. Specifically, the Trial Assigning Individualized Options for treatment (Rx) (TAILORx) (ClinicalTrials.gov identifier NCT00310180 ) is studying the utility of the Oncotype DX score to predict chemotherapy benefit in the intermediate score subgroup.

The Microarray in Node-negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy Trial (MINDACT) (ClinicalTrials.gov identifier NCT00433589 ) is studying the outcomes of patients with discordant risk assessments using the 70-gene expression signature of MammaPrint compared with clinicopathologic features with the Adjuvant! Online program. The RxPONDER ([Rx for Positive Node, Endocrine Responsive Breast Cancer] ClinicalTrials.gov identifier NCT01272037 ) is a large prospective trial designed to determine the benefit of chemotherapy among women with hormone receptor–positive breast cancer, 1 to 3 positive nodes, and an RS less than or equal to 25, as determined by Oncotype DX testing. The results from these large, prospective studies are eagerly awaited and will hopefully shed light on the best strategies to personalize adjuvant treatment in patients with luminal breast cancer.

This article discusses the evolving knowledge of adjuvant treatments in order to define reasonable but also novel treatment strategies in patients with ER-positive/HER2-negative (luminal A and luminal B) breast cancer.

Specific consideration for adjuvant treatment choice in luminal A tumors

Based on retrospective analysis of past trials, prospectively stratified for the degree of ER expression, the effect of chemoendocrine therapy on luminal A patients compared with endocrine therapy alone is unclear. The evidence in node-negative disease comes from the International Breast Cancer Study Group (IBCSG) trial IX for postmenopausal women and from IBCSG trial VIII for premenopausal patients.

The trials compared 3 or 6 courses of adjuvant classical cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without endocrine therapy versus endocrine therapy alone. No clear chemotherapy benefit was observed in ER-positive/HER2-negative disease (hazard ratio [HR] 0.90; 95% CI, 0.74–1.11). Moreover, these 2 trials showed no benefit of chemotherapy in the subset of ER positive, HER2 negative, and low Ki67, corresponding to the surrogate definition of luminal A disease.

In a retrospective analysis of the NSABP B-20 trial, the Oncotype Dx RS was used to predict CMF chemotherapy benefit. It was demonstrated that patients with ER-positive/node-negative breast cancer treated with tamoxifen and with a low RS did not benefit from the addition of chemotherapy. Analogous findings were reported by Albain and colleagues, in a retrospective analysis of the SWOG 8814 trial, where patients with ER-positive/node-positive disease had no benefit from adding cyclophosphamide, doxorubicin, and fluorouracil regimen to tamoxifen if low to intermediate RS was demonstrated. Clinicians in favor of the inclusion of chemotherapy might argue, however, against these conclusions, considering the retrospective nature of the studies, the small number of cases that were available for inclusion, and the lack of a taxane in the delivered chemotherapy.

According to the recent St Gallen consensus conferences, the intrinsic luminal A subtype corresponds to the clinicopathologic surrogate definition as luminal A–like. These luminal A tumors are characterized by high expression of steroid hormone receptors and are HER2 negative and Ki67 low. The optimal cutpoint between high and low values for Ki67 has not been established, given the potential variability of assessment among different laboratories.

A level of Ki67 less than 14% best correlated with gene array definition of luminal A, based on results in a single reference laboratory. Recent data support a threshold of 20% or higher as potentially indicative of high Ki67 status.

Literature data recently also sustain the introduction of PgR to optimally distinguish between luminal A and luminal B tumors. The value of PgR suggested for categorizing luminal A and luminal B subtypes is proposed as more than 20%, according to a recent report, where the fine tuning was done by comparing the multigene expression–based assays across 5 independent cohorts and the IHC-based definition of luminal A and luminal B.

In conclusion, the threshold for the definition of luminal disease remains a matter of debate.