Introduction

•Women with early-stage breast cancer are often treated with adjuvant systemic therapy consisting of chemotherapy, endocrine therapy, agents against human epidermal growth factor receptor 2 (HER2), alone or combinations of these

•Treatment decisions are based on a number of factors including tumor characteristics (hormonal receptor and HER2 status, tumor grade and size, and lymph node status)  and patient characteristics (age, menopausal status, and performance status)

•Tools that incorporate these features and help in decision making include Adjuvant! Online and PREDICT Plus

•However, algorithms such as those listed above do not take into consideration individual biologic characteristics of the patient’s tumor

•Given that a substantial number of patients with breast cancer are overtreated and thus are being exposed to the risk of toxic treatments without deriving benefit, several genomic tests have been developed to help better predict clinical outcome and to determine whether the addition of adjuvant chemotherapy to endocrine therapy is worthwhile

•One genomic test is the 70-gene signature (MammaPrint), which classifies tumors into groups that are associated with a good prognosis or a poor prognosis on the basis of the risk of distant recurrence at 5 years and at 10 years

•The authors sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical–pathological criteria in selecting patients for adjuvant chemotherapy


Findings

•From 2007 through 2011,  patients were enrolled at 112 institutions in nine European countries. Patients had histologically confirmed primary invasive breast cancer (stage T1 or T2 or operable T3)

•The authors used the 70-gene signature to determine genomic risk and Adjuvant! Online (version 8.0 with HER2 status) (www.adjuvantonline.com) to determine clinical risk

•Patients with low-risk disease according to both clinical and genomic results were advised not to receive adjuvant chemotherapy, whereas patients who were categorized as having high-risk disease by both tests were advised to receive chemotherapy

•Patients with discordant results (i.e., either high clinical risk and low genomic risk or low clinical risk and high genomic risk) were randomly assigned to the chemotherapy group or the no-chemotherapy group on the basis of either the clinical result or the genomic result

•A 5 year median follow-up time was used (which the authors cite is supported by studies that have recognized adjuvant chemotherapy exerts most of its beneficial effects early in the course of the disease (i.e., during the first 5 years), thus justifying their primary end point)

•6693 patients were enrolled in the study and divided into four categories according to their clinical and genomic risk: low clinical risk and low genomic risk (2745 patients (41.0%)); low clinical risk and high genomic risk (592 patients (8.8%)); high clinical risk and low genomic risk (1550 patients (23.2%)); and high clinical risk and high genomic risk (1806 patients (27.0%)) [Table 1 shows the characteristics of the patients and tumors according to risk group]

•They found the following:

•Among these patients at high clinical risk and low genomic risk, 48% had node-positive disease, 93% had grade 2 or 3 disease, and 34% were 50 years of age or younger — all features that usually indicate high risk.

•At 5 years, patients who were at high clinical risk and low genomic risk who did not receive adjuvant chemotherapy (primary-test population) had a rate of survival without distant metastasis of 94.7% (95% confidence interval [CI], 92.5 to 96.2)

•Those with high clinical risk and ow genomic risk who received chemotherapy (intention to treat population) had a 5-year rate of survival without distant metastasis of 95.9% (95% CI, 94.0 to 97.2), while those who underwent randomization on the basis of genomic risk and therefore received no chemotherapy had a rate of 94.4%

•Those with low clinical risk and high genomic risk who underwent randomization based on genomic risk and therefore received chemotherapy had a 5-year rate of survival without distant metastasis of 95.8%, as compared with a rate of 95.0% among those who underwent randomization on the basis of clinical risk (and therefore received no chemotherapy)

•The 70-gene signature was significantly associated with survival without distant metastasis after adjustment for chemotherapy use, clinical risk, and patient and tumor characteristics in a multivariate analysis


Conclusions

•At a median follow-up of 5 years, patients who were classified as high risk according to clinical-pathological factors and who therefore would have been usual candidates for adjuvant chemotherapy were able to forgo chemotherapy on the basis of a low genomic risk, which resulted in a rate of survival without distant metastasis that was an average of 1.5 percentage points lower, a rate of disease-free survival that was 2.8 percentage points lower, and a rate of overall survival that was 1.4 percentage points higher than the rate among those who received chemotherapy

•The authors thus conclude that in a large group of patients at high clinical risk for breast-cancer recurrence, the addition of the 70-gene signature to the traditional clinical and pathological factors provided valuable information for considering which patients might benefit from adjuvant chemotherapy

•Follow-up is ongoing to determine whether these conclusions remain valid for longer-term outcome

Introduction

•Biomarkers (genetic or protein markers that reflect cellular biology) are increasingly used to prognosticate recurrence risks and to guide therapeutic decisions

•Breast cancer can be classified into intrinsic biological subtypes, which can be approximated with IHC for ER, PR, and HER2:

•Luminal A - overexpress estrogen pathway genes; nonproliferative; ER+ or PR+/ HER 2- / grade 1-2

•Luminal B - overexpress estrogen pathway genes and proliferation genes; ER+ or PR+ / HER 2- / grade 3

•Human epidermal growth factor receptor 2 (HER 2)-enriched: Luminal HER 2 (ER+ or PR+ / HER 2+) and HER 2 (ER- / PR - / HER 2 +)

•Basal or triple-negative (TNBC)- estrogen receptor negative, highly proliferative, express genes with stemlike multipotential phenotype; ER- / PR - / HER 2 -

•The role of adjuvant radiation therapy (RT) in women with node-negative breast cancer treated with modified radical mastectomy is controversial, and questions are increasingly raised regarding whether subtype information may be used in combination with traditional clinicopathologic factors to improve locoregional recurrence risk prognostication and to assist locoregional treatment decisions

•The purpose of this study was to examine locoregional and distant recurrence (LRR and DR) in women with pT1-2N0 breast cancer according to approximated subtype and clinicopathologic characteristics

 

Findings

•This was a multi-institutional study that pooled data of women with newly diagnosed pathologic T1-2, N0,M0 breast cancer treated with mastectomy without PMRT. It included 1994 patients

•The patients were classified into 1 of 5 subtypes:  Luminal A (n=1202, 61%), Luminal B (n=294, 15%), Luminal HER 2 (n=221, 11%), HER 2 (n=105, 5%), and triple-negative breast cancer (n=172, 9%)

•The prognostic variables examined were age at diagnosis, histology, tumor size, grade, lymphovascular invasion (LVI), margin status (positive = tumor touching ink, close <2 mm, negative 2/= mm), number of excised nodes, and adjuvant systemic therapy (chemotherapy, hormone therapy, both, or none)

•Comparisons of clinicopathologic and treatment characteristics by subtype are summarized in Table 2

•No difference in LRR-free survival was observed among the 5 subtypes (P=0.81) (Fig. 1). The 5-year KM LRR rates were 1.8% in luminal A, 3.1% in luminal B, 1.7% in luminal HER 2, 1.9% in HER 2, and 1.9% in TNBC cohorts

•Women with TNBC had the highest DR risk compared with other subtypes. The 5-year KM DR were 1.8% in luminal A, 5.0% in luminal B, 2.4% in luminal HER 2, 1.1% in HER 2, and 9.6% in TNBC cohorts (P<.001)

•Overall survival outcomes were similar among the 5 subgroups (P=0.18)

•Comparisons of 5-year KM LRR by subtypes and other clinicopathologic characteristics are summarized in Table 3

•Factors associated with increased LRR were tumor size >2 cm, lobular histology, and close/positive surgical margins. Institution, age at diagnosis, grade, LVI, number of excised nodes, and subtype were not significantly associated with LRR (Table 4)

 

Conclusions

•This study found that the 5-year risk of locoregional recurrence in women with pT1-2N0 breast cancer treated with mastectomy was low overall

•There was no significant differences in LRR observed between approximated biologic subtypes of breast cancer

•They study found that that women with TNBC had higher rates of distant relapse relative to other subtypes

•The findings of this study suggest that although subtype alone cannot be used as the sole criterion to offer postmastectomy radiation therapy, it may reasonably be considered in conjunction with other clinicopathologic factors including tumor size, histology, and margin status

•Larger cohorts and longer follow-up times are needed to define which women with node-negative breast cancer have high postmastectomy LRR risks in contemporary practice