Women with large (≥3 cm) and locally advanced breast cancers (T3, 4, N1, 2, M0) receiving neoadjuvant chemotherapy (NAC: cyclophosphamide, doxorubicin, docetaxel): addition of capecitabine improves 4-year disease-free survival

Abstract

PurposeTo determine whether capecitabine (X), combined with docetaxel (T) following doxorubicin (A) and cyclophosphamide (C), enhanced the pathological complete response (pCR) in the breast and axillary lymph nodes (ALNs) of women with large or locally advanced breast cancers (LLABCs) improving outcome, and the effect on quality of life (QoL).Patients and methods117 women were enrolled, 112 randomised to 2 cycles of AC (60 mg/m2, 600 mg/m2) given 3 weekly. Tumour responses were assessed by magnetic resonance mammography. Responders (n = 77) received 2 further cycles of AC and were randomised to 4 cycles of T (100 mg/m2) (Group A) or T (75 mg/m2) and X (2000 mg/m2/day), day one to 14 of each 3 weekly cycle (Group B). Non-responders (n = 35) were randomised to 6 cycles of T (Group C) or T + X (Group D). QoL questionnaires were completed at each chemotherapy visit. Pathological responses were evaluated using established criteria.ResultsThe groups were comparable in patient and tumour characteristics (79.5% T2, 85.7% ductal, 73.2% ER +ve, 22.3% HER2 +ve, 42% involved ALNs). Overall breast pCR was 27.1%, Groups A + C versus B + D (p = 0.446). ALN +ve pCR was 41.9%, Groups A + C versus B + D (p = 0.231). 4-year disease-free survival (DFS) was significantly improved with X (p = 0.016) but not overall survival (p = 0.056). Triple -ve and HER2 +ve tumours, and persistent ALN disease were risk factors for metastases. X increased severe nail changes (p = 0.0002) and hand-foot syndrome (p = 0.014) without affecting QoL.ConclusionNAC-X did not increase breast and ALN pCR but improved 4-year DFS, without detriment to QoL.

The Differential Contribution of the Innate Immune System to a Good Pathological Response in the Breast and Axillary Lymph Nodes Induced by Neoadjuvant Chemotherapy in Women with Large and Locally Advanced Breast Cancers

“…A pCR following NAC in breast cancer has been shown in some studies to be a surrogate marker for a good prognosis and survival [ 46 , 66 ]. Cortazar et al described a correlation between favourable outcome and pCR in breast cancer [ 67 ].…”

“…In our study, there was a significant association between TIMs and tumour ER status and grade and between pCR and tumour ER status and grade. Highly proliferative, triple-negative breast cancers are significantly associated with high rates of pCR but have a poor DFS and OS [ 9 , 46 , 68 ]. Esserman et al showed by studying breast cancer subsets that a pCR was a better predictor for a DFS [ 69 ].…”

“…NAC, in particular anthracyclines and taxanes, is known to disrupt tumour cells, exposing expression of calreticulin and release of tumour-associated antigens (TAAs) [ 78 , 79 ]. This drug combination was used in our NAC study [ 46 ].…”

“…Paraffin-embedded sections of breast tumours and tumour-draining ALNs from 33 women with large (L: ≥3 cm) and locally advanced breast cancers (LABCs: T3, 4; N1, 2; M0), enrolled in a study of NAC (108 patients enrolled between 2008 and 2011), were studied [ 46 ]. Histological diagnosis was established from ultrasound-guided core biopsies.…”

Crucial Contributions by T Lymphocytes (Effector, Regulatory, and Checkpoint Inhibitor) and Cytokines (TH1, TH2, and TH17) to a Pathological Complete Response Induced by Neoadjuvant Chemotherapy in Women with Breast Cancer

“…We carried out an immunohistochemical analysis of various lymphocytic immune cells and humoral factors infiltrating LLABCs. We documented the pathological impact of NAC on the tumour microenvironment and the possible contribution of different host immune cells and humoral factors to an immune-mediated tumour cell death and pCR to NAC, a recognised surrogate marker of a beneficial long-term clinical response in breast cancer [ 23 , 24 ].…”