The Triple Negative Paradox: Primary Tumor Chemosensitivity of Breast Cancer Subtypes

Abstract

Purpose: Gene expression analysis identifies several breast cancer subtypes. We examined the relationship of neoadjuvant chemotherapy response to outcome among these breast cancer subtypes. Experimental Design: We used immunohistochemical profiles [human epidermal growth factor receptor 2^positive (HER2+)/hormone receptor^negative for HER2+/estrogen receptorn egative (ERÀ), hormone receptor and HER2À for basal-like, hormone receptor^positive for luminal] to subtype a prospectively maintained data set of patients with breast cancer treated with neoadjuvant anthracycline-based (doxorubicin plus cyclophosphamide, AC) chemotherapy. We analyzed each subtype for clinical and pathologic response to neoadjuvant chemotherapy and examined the relationship of response to distant disease^free survival and overall survival. Results: Of the 107 patients tested, 34 (32%) were basal-like, 11 (10%) were HER2+/ERÀ, and 62 (58%) were luminal. After neoadjuvant AC, 75% received subsequent chemotherapy and all received endocrine therapy if hormone receptor^positive. The chemotherapy regimen and pretreatment stage did not differ by subtype. Clinical response to AC was higher among the HER2+/ERÀ (70 %) and basal-like (85 %) than the luminal subtypes (47 %; P < 0.0001).Pathologic complete response occurred in 36% of HER2+/ERÀ, 27% of basal-like, and 7% of luminal subtypes (P = 0.01). Despite initial chemosensitivity, patients with the basal-like and HER2+/ERÀ subtypes had worse distant disease^free survival (P = 0.04) and overall survival (P = 0.02) than those with the luminal subtypes. Regardless of subtype, only 2 of 17 patients with pathologic complete response relapsed. The worse outcome among basal-like and HER+/ ERÀ subtypes was due to higher relapse among those with residual disease (P = 0.003). Conclusions: Basal-like and HER2+/ERÀ subtypes are more sensitive to anthracycline-based neoadjuvant chemotherapy than luminal breast cancers. Patients that had pathologic complete response to chemotherapy had a good prognosis regardless of subtype. The poorer prognosis of basal-like and HER2+/ERÀ breast cancers could be explained by a higher likelihood of relapse in those patients in whom pathologic complete response was not achieved.Gene expression studies have identified three major subtypes of breast cancer (basal-like, HER2+/ERÀ, and luminal; ref. 1) that have differing prognoses (2). A particularly poor outcome is seen among the two hormone receptor -negative subtypes (i.e., basal-like and HER2+/ERÀ), compared with the hormone receptor -high luminal group (2, 3). Evidence suggests that the effect of improved adjuvant chemotherapy is greater among hormone receptor -negative breast cancer (4). A recent report revealed significantly higher pathologic complete response to neoadjuvant chemotherapy among basal-like and HER2+/ERÀ subtypes compared with luminal subtypes (5). If so, this raises the question of whether the traditional perspective of pathologic complete response as a proxy for relapse and survival holds true across e...

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

“…17,18 Immunohistochemical marker panels that have been proposed to define basal-like breast cancers include: (1) lack of ER, PR, and HER2 expression ('triple-negative' immunophenotype); (2) expression of one or more high-molecular-weight/ basal cytokeratins (CK5/6, CK14, and CK17); (3) lack of expression of ER and HER2 in conjunction with expression of CK5/6 and/or epidermal growth factor receptor (EGFR); 17 and (4) lack of expression of ER, PR, and HER2 in conjunction with expression of CK5/6 and/or EGFR. 19 Despite the different definitions for basal-like breast cancers, it has been demonstrated that these tumors have distinctive clinical presentations, 20 histological features, 18,21 response to chemotherapy, [22][23][24][25][26][27][28] sites of distant relapse, and outcome. 7,9,[29][30][31] In brief, basal-like tumors comprise a heterogeneous group that accounts for up to 15% of all breast cancers, affect younger patients, are more prevalent in African-American women, and often present as interval cancers.…”

“…24,28,59,[61][62][63] This aggressiveness is best exemplified by the fact that the peak risk of recurrence is between the first and third years and the majority of deaths occur in the first 5 years following therapy. 59,61 Patients with triple-negative cancers, 59,63 similar to those with basal-like cancers, 42 have a significantly shorter survival following the first metastatic event when compared with those with non-basal-like/non-triple-negative controls.…”

“…As to treatment response, 17-58% of patients with triple-negative breast cancers have been shown to have a pathological complete response after anthracycline-or anthracycline þ taxane-based neoadjuvant chemotherapy 25,28,122,123 and 17% of triplenegative cancers have been shown to have a pathological complete response after neoadjuvant platinum-based chemotherapy. 124 However, those who fail to achieve pathological complete response have a dismal outcome.…”

“…124 However, those who fail to achieve pathological complete response have a dismal outcome. 25,28 It should be noted, however, that markers for the identification of patients with triple-negative and basal-like cancers that benefit most from chemotherapy remain to be defined. Recently, several groups have identified a subgroup of good prognosis ERÀ cancers, encompassing a subgroup of triple-negative and basal-like tumors, which is characterized by the expression of an immune response module.…”

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

“…Most women with triple negative tumors will respond to chemotherapy to some extent, but many will experience recurrence or metastatic disease. 122 Responses in this subset are heterogeneous, and further stratification and development of new targeted therapies are needed.…”