The Role of Immunohistochemistry in Breast Cancer Patients Treated With Neoadjuvant Chemotherapy: An Old Tool With an Enduring Prognostic Value

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Abstract

Pathologic complete response (pCR) to neoadjuvant chemotherapy is a potential surrogate for survival. We defined molecular subtypes determined by hormonal receptors (HR) and human epidermal growth factor receptor 2 (HER2) status. pCR was significantly higher in patients with HR−/HER2− and in HR−/HER2+ breast cancer treated with dose-dense neoadjuvant chemotherapy. Molecular subtypes, pCR, and the Ki-67 proliferative marker were independent prognostic factors for disease-free survival and overall survival.

Background:

To assess the molecular subtypes determined by hormonal receptors (HR) and human epidermal growth factor receptor 2 (HER2) status and the role of proliferation measured by the Ki-67 marker as predictive and prognostic factors in breast cancer patients treated with neoadjuvant chemotherapy.

Methods:

A total of 127 breast cancer patients were treated with neoadjuvant chemotherapy every 2 weeks as part of 2 studies. Study A consisted of the administration of Adriamycin (40 mg/m2) on day 1 plus paclitaxel (150 mg/m2) and gemcitabine 2000 mg/m2) on day 2 for 6 cycles (n = 54). Study B consisted of the administration of epirubicin (90 mg/m2), cyclophosphamide (600 mg/m2) on day 1 for 3 cycles, followed by the administration of paclitaxel (150 mg/m2) and gemcitabine 2500 (mg/m2) on day 1 with or without trastuzumab according to HER2 status (n = 73). In study A, patients did not receive trastuzumab regardless of HER2 status. The molecular subtypes of the patients with breast cancer were classified as 49% HR+/HER2−, 17.5% HR+/HER2+, 13.5% HR−/HER2+, and 20% HR−/HER2−.

Results:

Pathologic complete response (pCR), defined as the absence of invasive cells in the breast and the lymph nodes, was achieved in 35 (28%) patients. The pCR rate was significantly different between the molecular subtypes of breast cancer, with 9% in HR+/HER2−, 23% in HR+/HER2+, 50% in HR−/HER2+, and 56% in HR−/HER2− tumors (P < .001). The pCR rate was significantly higher in tumors that had high Ki-67 (≥20%) expression and were HR−. HER2+ was associated with a higher trend of pCR but did not reach statistical significance. The median follow-up was 81 months (r = 15-150 months). Patients who achieved a pCR had a significantly lower recurrence (P = .01) and higher overall survival (P = .02) compared with those who did not achieve pCR. A multivariate analysis revealed that pCR (hazard ratio 0.24 [95% CI, 0.07-0.7]; P = .019), the molecular subtype (hazard ratio 0.3 [95% CI, 0.1-0.8]; P = .02), and the Ki-67 index (hazard ratio 3.2 [95% CI, 1.4-7.1]; P = .004) were significant independent predictors of disease-free survival. Similar results were obtained for overall survival, in which the pCR rate (hazard ratio 0.119 [95% CI, 0.028-0.5]; P = .004), the molecular subtype (hazard ratio 0.17 [95% CI, 0.03-0.86]; P = .02), and the Ki-67 index (hazard ratio 3.6 [95% CI, 1.3-9.7]; P = .01) also displayed a significant influence on survival.

Conclusions:

Molecular subtypes and Ki-67 index were independent prognostic factors for disease-free survival and overall survival in breast cancer patients treated with neoadjuvant chemotherapy. A high rate of Ki-67 and HR− expression were predictors of pCR.

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