BACKGROUND:In this study, the authors evaluated whether a pathologic complete response (pCR) or a clinical complete response (cCR) to neoadjuvant treatment in patients with locally advanced breast cancer differed among the 3 subtypes of breast cancer: triple-negative breast cancer (TNBC), human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and hormone receptor-positive/HER2-negative breast cancer. Whether a cCR or a pCR was correlated with fewer recurrences and better survival also was investigated. METHODS: Patients with stage II/III breast cancer received 4 cycles of neoadjuvant docetaxel and carboplatin (TC) every 3 weeks. Patients with HER2-positive tumors were randomized to receive either additional weekly trastuzumab preoperatively or TC alone. Postoperatively, all patients received 4 cycles of TC, and all HER2-positive patients received a total of 52 weeks of trastuzumab. The recurrence-free survival (RFS) and overall survival (OS) rates at 2 years were reported. RESULTS: Seventy-four patients were enrolled, including 11 patients with TNBC, 30 patients with HER2-positive tumors, and 33 patients with hormone receptor-positive/HER2-negative tumor. The cCR rates were 45.4%, 50% and 40.6% in TNBC, HER2-positive, and hormone receptor-positive/HER2-negative groups, respectively. The pCR rate for the entire group was 26.8%, and patients with TNBC had the best response (54.6%) followed by patients with HER2-positive tumors (24.1%) and patients with hormone receptor-positive/HER2-negative tumors (19.4%; P ¼ .0126). The pCR rate for patients with HER2-positive tumors improved from 7% to 40% if trastuzumab was added (P ¼ .08). Infiltrating ductal cancer, TNBC, negative estrogen receptor and/or progesterone receptor status, tumor classification predicted a pCR (P .05). Multivariate analysis using a logistic regression test indicated that tumor type was an independent predictor. The RFS rate for patients who did versus patients who did not achieve a pCR was 93.8% versus 78.4% at 2 years, respectively, and 83.3% versus 58% at 3 years, respectively (P ¼ .1227); whereas, for patients who did versus patients who did not achieve a cCR, the RFS rate was 80.9% versus 83.9%, respectively, at 2 years and 65% versus 64.3%, respectively, at 3 years (P ¼ .999). CONCLUSIONS: The current results indicated that the TC combination is promising for the treatment of TNBC. The addition of trastuzumab to TC improved the pCR rate significantly in patients with HER2-positive breast cancer.
Breast cancer (BC) is a leading cause of cancer-related death in women. Adjuvant systemic chemotherapies are effective in reducing risks of recurrence and have contributed to reduced BC mortality. Although targeted adjuvant treatments determined by biomarkers for endocrine and HER2-directed therapies are largely successful, predicting clinical benefit from chemotherapy is more challenging. Drug resistance is a major reason for treatment failures. Efforts are ongoing to find biomarkers to select patients most likely to benefit from chemotherapy. Importantly, cell surface biomarkers CD44+/CD24− are linked to drug resistance in some reports, yet underlying mechanisms are largely unknown. This study focused on the potential role of CD24 expression in resistance to either docetaxel or doxorubicin in part by the use of triple-negative BC (TNBC) tissue microarrays. In vitro assays were also done to assess changes in CD24 expression and differential drug susceptibility after chemotherapy. Further, mouse tumor xenograft studies were done to confirm in vitro findings. Overall, the results show that patients with CD24-positive TNBC had significantly worse overall survival and disease-free survival after taxane-based treatment. Also, in vitro cell studies show that CD44+/CD24+/high cells are more resistant to docetaxel, while CD44+/CD24−/low cells are resistant to doxorubicin. Both in vitro and in vivo studies show that cells with CD24-knockdown are more sensitive to docetaxel, while CD24-overexpressing cells are more sensitive to doxorubicin. Further, mechanistic studies indicate that Bcl-2 and TGF-βR1 signaling via ATM-NDRG2 pathways regulate CD24. Hence, CD24 may be a biomarker to select chemotherapeutics and a target to overcome TNBC drug resistance.
Notorious for its poor prognosis and aggressive nature, triple-negative breast cancer (TNBC) is a heterogeneous disease entity. The nature of its biological specificity, which is similar to basal-like cancers, tumors arising in BRCA1 mutation carriers, and claudin-low cancers, is currently being explored in hopes of finding the targets for novel biologics and chemotherapeutic agents. In this review, we aim to give a broad overview of the disease’s nomenclature and epidemiology, as well as the basic mechanisms of emerging targeted therapies and their performance in clinical trials to date.
Protein-based markers that classify tumor subtypes and predict therapeutic response would be clinically useful in guiding patient treatment. We investigated the LC-MS/MS-identified protein biosignatures in 39 baseline breast cancer specimens including 28 HER2-positive and 11 triple-negative (TNBC) tumors. Twenty proteins were found to correctly classify all HER2 positive and 7 of the 11 TNBC tumors. Among them, galectin-3-binding protein and ALDH1A1 were found preferentially elevated in TNBC, whereas CK19, transferrin, transketolase, and thymosin β4 and β10 were elevated in HER2-positive cancers. In addition, several proteins such as enolase, vimentin, peroxiredoxin 5, Hsp 70, periostin precursor, RhoA, cathepsin D preproprotein, and annexin 1 were found to be associated with the tumor responses to treatment within each subtype. The MS-based proteomic findings appear promising in guiding tumor classification and predicting response. When sufficiently validated, some of these candidate protein markers could have great potential in improving breast cancer treatment.
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