Prediction of benefit from adjuvant chemotherapy following resection of early breast cancer and, as a result, proper selection of candidates remains an elusive goal since the relative magnitude of ...benefit is the same regardless of the presence of clinicopathologic factors. Multiple studies, including randomized trials, establish the role of certain gene expression signatures in node-negative disease since they predict the risk of breast cancer relapse being so low that adjuvant chemotherapy can be omitted. In contrast, more limited data are available in higher risk, node-positive breast cancer patients, making the exclusion of adjuvant chemotherapy potentially hazardous. ‘Prospective–retrospective’ studies and limited prospective data show that several signatures, namely Oncotype Dx, MammaPrint, Prosigna, EndoPredict and Breast Cancer Index, select with different levels of success node-positive patients at very low risk for distant recurrence despite not receiving chemotherapy, although the long-term follow-up is still awaited. Pending, however the publication of the results from ongoing randomized studies which enroll patients with node-positive disease, major caution is warranted. Improper use and misinterpretation of these transcriptomic profiles can lead to undertreatment and exposure of patients to unnecessary risks resulting in increased breast cancer mortality for patients with axillary node-positive disease. With this review we critically discuss the available data on gene expression signatures that are used in clinical practice and offer practical recommendations regarding the management of patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive breast cancer.
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.
The past 30 years have seen the introduction of a number of cancer therapies with the aim of restricting the growth and spread of primary and metastatic tumours. A shared commonality among these ...therapies is their targeting of various aspects of the cancer hallmarks, that is traits that are essential to successful tumour propagation and dissemination. The evolution of molecular‐scale technology has been central to the identification of new cancer targets, and it is not a coincidence that improved therapies have emerged at the same time as gene expression arrays and DNA sequencing have enhanced our understanding of cancer genetics. Modern tumour pathology is now viewed at the molecular level ranging from IHC biomarkers, to gene signature classifiers and gene mutations, all of which provide crucial information about which patients will respond to targeted therapy regimens. In this review, we briefly discuss the general types of targeted therapies used in a clinical setting and provide a short background on immunohistochemical, gene expression and DNA sequencing technologies, before focusing on three tumour types: breast, lung and colorectal cancers. For each of these cancer types, we provide a background to the disease along with an overview of the current standard therapies and then focus on the relevant targeted therapies and the pathways they inhibit. Finally, we highlight several strategies that are pivotal to the successful development of targeted anti‐cancer drugs.
Staging of the axilla is not routine in ductal cancer in situ (DCIS) although invasive cancer is observed in 20-25 per cent of patients at final pathology. Upfront sentinel lymph node dissection ...(SLND) is advocated in clinical practice guidelines in certain situations. These include expected challenges in subsequent SLN detection and when the risk for invasion is high. Clinical practice guidelines are, however, inconsistent and lead to considerable practice variability.
Clinical practice guidelines for upfront SLND in DCIS were identified and applied to patients included in the prospective SentiNot study. These patients were evaluated by six independent, blinded raters. Agreement statistics were performed to assess agreement and concordance. Receiver operating characteristic curves were constructed, to assess guideline accuracy in identifying patients with underlying invasion.
Eight guidelines with relevant recommendations were identified. Interobserver agreement varied greatly (kappa: 0.23-0.9) and the interpretation as to whether SLND should be performed ranged from 40-90 per cent and with varying concordance (32-88 per cent). The diagnostic accuracy was low with area under the curve ranging from 0.45 to 0.55. Fifty to 90 per cent of patients with pure DCIS would undergo unnecessary SLNB, whereas 10-50 per cent of patients with invasion were not identified as 'high risk'. Agreement across guidelines was low (kappa = 0.24), meaning that different patients had a similar risk of being treated inaccurately.
Available guidelines are inaccurate in identifying patients with DCIS who would benefit from upfront SLNB. Guideline refinement with detailed preoperative work-up and novel techniques for SLND identification could address this challenge and avoid overtreatment.
The decision whether to operate on the axilla in women with a diagnosis of ductal cancer in situ (DCIS) is based on the risk of an undiagnosed underlying invasive cancer and on the concern that resection of the breast will not allow for accurate axillary mapping afterwards. Guidelines stem from older knowledge and are heterogeneous. In this study, different breast cancer guidelines were tested in a patient cohort from the SentiNot prospective trial for uniformity of interpretation and diagnostic accuracy. Results show that guidelines did not allow for easy and uniform interpretation and had the predictive ability of the toss of a coin. This suggests that guidelines regarding the need of axillary evaluation in patients operated for DCIS need to be revised and that techniques that will address the conundrum should be developed.
Metastatic breast cancer is a severe condition without curative treatment. How relative and absolute risk of distant metastasis varies over time since diagnosis, as a function of treatment, age and ...tumour characteristics, has not been studied in detail.
A total of 9514 women under the age of 75 when diagnosed with breast cancer in Stockholm and Gotland regions during 1990-2006 were followed up for metastasis (mean follow-up=5.7 years). Time-dependent development of distant metastasis was analysed using flexible parametric survival models and presented as hazard ratio (HR) and cumulative risk.
A total of 995 (10.4%) patients developed distant metastasis; the most common sites were skeleton (32.5%) and multiple sites (28.3%). Women younger than 50 years at diagnosis, with lymph node-positive, oestrogen receptor (ER)-negative, >20 mm tumours and treated only locally, had the highest risk of distant metastasis (0-5 years' cumulative risk =0.55; 95% confidence interval (CI): 0.47-0.64). Women older than 50 years at diagnosis, with ER-positive, lymph node-negative and ≤20-mm tumours, had the same and lowest cumulative risk of developing metastasis 0-5 and 5-10 years (cumulative risk=0.03; 95% CI: 0.02-0.04). In the period of 5-10 years after diagnosis, women with ER-positive, lymph node-positive and >20-mm tumours were at highest risk of distant recurrence. Women with ER-negative tumours showed a decline in risk during this period.
Our data show no support for discontinuation at 5 years of clinical follow-up in breast cancer patients and suggest further investigation on differential clinical follow-up for different subgroups of patients.
Traditionally, estrogen receptor (ER)-positive breast cancer has been defined as tumors with ≥1% positive for ER. The updated American Society of Clinical Oncology/College of American Pathologists ...(ASCO/CAP) guidelines recommend that tumors with ER expression of 1%-10% should be classified as ER-low-positive, recognizing the limited clinical evidence on the prognostic and predictive role of low ER expression. We aimed to investigate the predictive role of ER-low expression to neoadjuvant chemotherapy (NeoCT) and the prognostic significance of ER-low expressing breast tumors compared with ER-positive or ER-negative breast tumors.
A meta-analysis was conducted using the Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines and eligible articles were identified on PubMed and ISI Web of Science databases. The primary outcome was pathologic complete response and secondary outcomes were disease-free survival (DFS) and overall survival (OS). Twelve retrospective cohort studies were included in the meta-analysis. NeoCT resulted in higher pathologic complete response among patients with ER-low expression compared with ER-positive and comparable to ER-negative. Patients with ER-low breast cancer had a statistically significant worse DFS and OS compared with patients with ER-positive breast cancer, whereas no difference in DFS or OS was observed between ER-low and ER-negative subgroups.
The current evidence suggests that ER-low breast cancer has a more similar outcome to ER-negative than to ER-positive breast cancer in terms of DFS and OS. ER-low expression seems also to have a predictive role regarding NeoCT. Considering the certainty of current evidence categorized as low to moderate, our results urge the need for well-designed prospective studies investigating the molecular background and the most appropriate treatment strategy for ER-low expressing breast cancer.
•The predictive and prognostic roles of estrogen receptor (ER)-low breast cancer have been studied in this meta-analysis.•ER-low expression was associated with higher pathologic complete response after NeoCT compared with ER-positive.•Both disease-free and overall survival were comparable between ER-low breast cancer and ER-negative breast cancer.
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