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Small (T1a, b), lymph node negative breast tumors represent an entity diagnosed with increasing frequency due to the implementation of wide-scale screening programs. Patients bearing such tumors usually exhibit favorable long-term outcomes, with low breast cancer mortality rates at 10 years, even in the absence of adjuvant chemotherapy. However, most available data derive from retrospective studies. Additionally, a subset of patients with these tumors experience recurrence of the disease, indicating that early tumor stage itself is not a sufficient prognosticator. It is of paramount importance to refine the prognosis of this population, identifying patients with high risk of recurrence, for whom adjuvant treatment is needed. The underlying biology of the disease provides relevant information, such as grade and status of hormone receptors and HER-2 (human epidermal growth factor receptor 2), with high grade, triple negative and HER-2-positive tumors having worse prognosis. Additionally, multigene signatures may improve further the prognostication of patients with small, node negative breast cancers. Further research for this increasingly frequent group of patients is urgently needed, so that better informed clinical decision making, in particular regarding adjuvant chemotherapy, can occur. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To assess the efficacy and toxicity of docetaxel (D) plus epirubicin (E) in combination with bevacizumab (B) [DEB regimen] as front-line treatment in patients with metastatic breast cancer (MBC). Patients and methods: Women with previously untreated HER2-negative MBC received B (15 mg/kg), E (75 mg/m2) and D (75 mg/m2) with prophylactic G-CSF support every 3 weeks (q3w) for up to 9 cycles followed by B (15 mg/kg q3w) until disease progression. Primary endpoint was the overall response rate (ORR). Circulating tumor cells (CTCs) were evaluated using the CellSearch system at different time points during therapy. Results: Eighty-three women were enrolled with median age 62 years, performance status 0–1 in 93%, triple negative disease in 12% and liver metastases in 47%. In an intention to treat analysis, complete response was achieved in 13 (15.7%) and partial response in 42 (50.6%) (overall response rate 66.3%; 95% CI 56.09–76.44%). The median time to progression was 20.1 months and the 1-year overall survival rate 82.3%. Grade 3–4 neutropenia occurred in 37%, febrile neutropenia in 10%, anemia in 4%, thrombocytopenia in 2% and diarrhea in 2% of patients. There were two deaths possibly related to study treatment (sigmoid perforation n = 1; sudden death n = 1). Moreover, one patient developed pulmonary embolism and another one myocardial infarction while on treatment. Although DEB administration significantly reduced the proportion of patients presenting CTCs, the detection of ≥5 or ≥1 CTCs before treatment initiation was significantly associated with worse progression-free survival (p = 0.001 and p = 0.004) and overall survival (p = 0.001 and p = 0.027), respectively. Conclusions: The DEB regimen is a very active but also potentially toxic combination in MBC. Detection of CTCs before treatment is associated with worse outcome. Clinicaltrials.gov: NCT00705315 [Copyright &y& Elsevier]

KEYNOTE-522 demonstrated statistically significant improvements in pathological complete response (pCR) with neoadjuvant pembrolizumab plus chemotherapy and event-free survival (EFS) with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in patients with high-risk, early-stage triple-negative breast cancer (TNBC). Prior studies have shown the prognostic value of the residual cancer burden (RCB) index to quantify the extent of residual disease after neoadjuvant chemotherapy. In this preplanned exploratory analysis, we assessed RCB distribution and EFS within RCB categories by treatment group. A total of 1174 patients with stage T1c/N1-2 or T2-4/N0-2 TNBC were randomized 2 : 1 to pembrolizumab 200 mg or placebo every 3 weeks given with four cycles of paclitaxel + carboplatin, followed by four cycles of doxorubicin or epirubicin + cyclophosphamide. After surgery, patients received pembrolizumab or placebo for nine cycles or until recurrence or unacceptable toxicity. Primary endpoints are pCR and EFS. RCB is a prespecified exploratory endpoint. The association between EFS and RCB was assessed using a Cox regression model. Pembrolizumab shifted patients into lower RCB categories across the entire spectrum compared with placebo. There were more patients in the pembrolizumab group with RCB-0 (pCR), and fewer patients in the pembrolizumab group with RCB-1, RCB-2, and RCB-3. The corresponding hazard ratios (95% confidence intervals) for EFS were 0.70 (0.38-1.31), 0.92 (0.39-2.20), 0.52 (0.32-0.82), and 1.24 (0.69-2.23). The most common first EFS events were distant recurrences, with fewer in the pembrolizumab group across all RCB categories. Among patients with RCB-0/1, more than half [21/38 (55.3%)] of all events were central nervous system recurrences, with 13/22 (59.1%) in the pembrolizumab group and 8/16 (50.0%) in the placebo group. Addition of pembrolizumab to chemotherapy resulted in fewer EFS events in the RCB-0, RCB-1, and RCB-2 categories, with the greatest benefit in RCB-2. These findings demonstrate that pembrolizumab not only increased pCR rates, but also improved EFS among most patients who do not have a pCR. • KEYNOTE-522 evaluated neoadjuvant pembrolizumab + chemotherapy/adjuvant pembrolizumab versus neoadjuvant chemotherapy alone in early TNBC. • Neoadjuvant pembrolizumab + chemotherapy/adjuvant pembrolizumab significantly improved pCR/EFS versus neoadjuvant chemotherapy alone. • We explored the effect of adding pembrolizumab to chemotherapy on outcomes by RCB category. • Pembrolizumab not only increased pCR rates, but also improved EFS among many patients who do not have a pCR. • Findings support neoadjuvant pembrolizumab + chemotherapy/adjuvant pembrolizumab as a standard of care treatment in early TNBC. [ABSTRACT FROM AUTHOR]

The phase Ib KEYNOTE-173 study was conducted to assess the safety and preliminary antitumor activity of neoadjuvant chemotherapy plus pembrolizumab in high-risk, early-stage, non-metastatic triple-negative breast cancer (TNBC). Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A–F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), then eight cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks, and then doxorubicin and cyclophosphamide for an additional 12 weeks before surgery. Primary end points were safety and recommended phase II dose (RP2D); secondary end points were pathological complete response (pCR) rate, objective response rate, and event-free and overall survival. Exploratory end points were the relationship between outcome and potential biomarkers, such as tumor programmed death ligand 1 (PD-L1) expression (combined positive score) and stromal tumor-infiltrating lymphocyte levels (sTILs). Sixty patients were enrolled between 18 February 2016, and 28 February 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n = 10 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold; two cohorts did (A, E). The most common grade ≥3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%) and were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range 49%–71%). Twelve-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 combined positive score, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively). Combination neoadjuvant chemotherapy and pembrolizumab for high-risk, early-stage TNBC showed manageable toxicity and promising antitumor activity. In an exploratory analysis, the pCR rate showed a positive correlation with tumor PD-L1 expression and sTIL levels. ClinicalTrials.gov identifier: NCT02622074. • Neoadjuvant pembrolizumab + chemotherapy showed no unexpected safety findings in patients with high-risk, early-stage TNBC. • Two chemotherapy regimens met the RP2D threshold: nab-paclitaxel 125 mg/m2 qw; paclitaxel 80 mg/m2 qw + carboplatin AUC5 q3w. • pCR rate (ypT0/Tis ypN0) across all cohorts was 60% and 12-month EFS and OS rates ranged from 80% to 100% across cohorts. • pCR rate showed positive correlation with tumor PD-L1 expression and stromal tumor-infiltrating lymphocyte levels. [ABSTRACT FROM AUTHOR]

Background In multifocal breast cancer, guidelines recommend basing adjuvant systemic treatment decisions on characteristics of the largest lesion, disregarding multifocality as an independent prognosticator. We assessed the association between multifocal disease and both the 70-gene signature (70-GS), and distant metastasis-free survival (DMFS) in clinical low-risk breast cancer patients enrolled in the European Organisation for Research and Treatment of Cancer 10041/BIG 03-04 Microarray In Node-negative and 1 to 3 positive lymph node Disease may Avoid ChemoTherapy (MINDACT) trial. Patients and methods The analysed population consisted of enrolled patients in the MINDACT trial with clinical low-risk disease, defined by a modified Adjuvant! Online cut-off for the 10-year risk of recurrent disease or death. Eligibility criteria of MINDACT dictate that patients with multifocal disease could be included if the different lesions had similar pathological characteristics. The presence of multifocal disease was deducted from the case report form (CRF)-question for sum of diameter for all invasive tumour foci. Clinicopathological characteristics and gene expression of patients with unifocal and multifocal (largest lesion) disease were compared. Subsequently, the association between multifocal disease and the 70-GS was evaluated as well as the association between multifocality and 5-year DMFS. Results The study included 3090 clinical low-risk patients with unifocal and 238 patients with multifocal disease. Apart from a higher prevalence of lobular tumours (21.8% versus 10.8%, by local pathology), we did not observe differences in baseline characteristics between multifocal and unifocal tumours. Patients with multifocal tumours were more likely to be at high genomic risk as compared to patients with unifocal tumours (22.7% versus 17.3%, odds ratio [OR] 1.45, 95% confidence interval [CI] 1.02–2.07, P = 0.038). We did not find a significant association between tumour focality and DMFS (97.1% for unifocal versus 96.9% for multifocal, hazard ratio [HR] = 1.55, 95% CI 0.68–3.46, P = 0.172), nor a signal for a potential interaction between the prognostic effect of the 70-GS and focality of the tumour regarding DMFS. Conclusion In the group of clinical low-risk MINDACT patients, multifocal tumours were more likely to have a high-risk 70-GS profile compared to unifocal tumours. We did not observe a significant interaction between multifocality and the 70-GS with respect to survival without distant metastasis in these patients. [ABSTRACT FROM AUTHOR]

Background Reproductive and lifestyle factors influence both breast cancer risk and prognosis; this might be through breast cancer subtype. Subtypes defined by immunohistochemical hormone receptor markers and gene expression signatures are used to predict prognosis of breast cancer patients based on their tumour biology. We investigated the association between established breast cancer risk factors and the 70-gene prognostication signature in breast cancer patients. Patients and methods Standardised questionnaires were used to obtain information on established risk factors of breast cancer from the Dutch patients of the MINDACT trial. Clinical-pathological and genomic information were obtained from the trial database. Logistic regression analyses were used to estimate the associations between lifestyle risk factors and tumour prognostic subtypes, measured by the 70-gene MammaPrint ® signature (i.e. low-risk or high-risk tumours). Results Of the 1555 breast cancer patients included, 910 had low-risk and 645 had high-risk tumours. Current body mass index (BMI), age at menarche, age at first birth, age at menopause, hormonal contraceptive use and hormone replacement therapy use were not associated with MammaPrint ® . In parous women, higher parity was associated with a lower risk (OR: 0.75, [95% confidence interval {CI}: 0.59–0.95] P = 0.018) and longer breastfeeding duration with a higher risk (OR: 1.03, [95% CI: 1.01–1.05] P = 0.005) of developing high-risk tumours; risk estimates were similar within oestrogen receptor–positive disease. After stratifying by menopausal status, the associations remained present in post-menopausal women. Conclusion Using prognostic gene expression profiles, we have indications that specific reproductive factors may be associated with prognostic tumour subtypes beyond hormone receptor status. [ABSTRACT FROM AUTHOR]