Biological changes that occur during metastatic progression of breast cancer are still incompletely characterized. In this study, we compared intrinsic molecular subtypes and gene expression in 123 paired primary and metastatic tissues from breast cancer patients. Intrinsic subtype was identified using a PAM50 classifier and χ2 tests determined the differences in variable distribution. The rate of subtype conversion was 0% in basal-like tumors, 23.1% in HER2-enriched (HER2-E) tumors, 30.0% in luminal B tumors, and 55.3% in luminal A tumors. In 40.2% of cases, luminal A tumors converted to luminal B tumors, whereas in 14.3% of cases luminal A and B tumors converted to HER2-E tumors. We identified 47 genes that were expressed differentially in metastatic versus primary disease. Metastatic tumors were enriched for proliferation-related and migration-related genes and diminished for luminal-related genes. Expression of proliferation-related genes were better at predicting overall survival in metastatic disease (OSmet) when analyzed in metastatic tissue rather than primary tissue. In contrast, a basal-like gene expression signature was better at predicting OSmet in primary disease compared with metastatic tissue. We observed correlations between time to tumor relapse and the magnitude of changes of proliferation, luminal B, or HER2-E signatures in metastatic versus primary disease. Although the intrinsic subtype was largely maintained during metastatic progression, luminal/HER2-negative tumors acquired a luminal B or HER2-E profile during metastatic progression, likely reflecting tumor evolution or acquisition of estrogen independence. Overall, our analysis revealed the value of stratifying gene expression by both cancer subtype and tissue type, providing clinicians more refined tools to evaluate prognosis and treatment.

BackgroundPredicting treatment benefit and/or outcome before any therapeutic intervention has taken place would be clinically very useful. Herein, we evaluate the ability of the intrinsic subtypes and the risk of relapse score at diagnosis to predict survival and response following neoadjuvant chemotherapy. In addition, we evaluated the ability of the Claudin-low and 7-TNBCtype classifications to predict response within triple-negative breast cancer (TNBC).MethodsGene expression and clinical-pathological data were evaluated in a combined dataset of 957 breast cancer patients, including 350 with TNBC, treated with sequential anthracycline and anti-microtubule-based neoadjuvant regimens. Intrinsic subtype, risk of relapse score based on subtype and proliferation (ROR-P), the Claudin-low subtype and the 7-TNBCtype subtype classification were evaluated. Logistic regression models for pathological complete response (pCR) and Cox models for distant relapse-free survival (DRFS) were used.ResultsBasal-like, Luminal A, Luminal B, and HER2-enriched subtypes represented 32.7 %, 30.6 %, 18.2 %, and 10.3 % of cases, respectively. Intrinsic subtype was independently associated with pCR in all patients, in hormone receptor-positive/HER2-negative disease, in HER2-positive disease, and in TNBC. The pCR rate of Basal-like disease was >35 % across all clinical cohorts. Neither the Claudin-low nor the 7-TNBCtype subtype classifications predicted pCR within TNBCs after accounting for intrinsic subtype. Finally, intrinsic subtype and ROR-P provided independent prognostic information beyond clinicopathological variables and type of pathological response. A 5-year DRFS of 97.5 % (92.8–100.0 %) was observed in these neoadjuvant-treated and clinically node-negative patients predicted to be low risk by ROR-P (i.e. 57.4 % of Luminal A tumors with clinically node-negative disease).ConclusionsIntrinsic subtyping at diagnosis provides prognostic and predictive information for patients receiving neoadjuvant chemotherapy. Although we could not exclude a survival benefit of neoadjuvant chemotherapy in patients with early breast cancer with clinically node-negative and ROR-low disease at diagnosis, the absolute benefit of cytotoxic therapy in this group might be rather small (if any).Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0540-z) contains supplementary material, which is available to authorized users.

Background: Breast cancer (BC) subtypes have different survival and response to therapy. We studied predictors of central nervous system metastases (CNS-M) and outcome after CNS-M diagnosis according to tumor subtype.

Background. Human epidermal growth factor receptor (HER)-2 testing in patients with operable breast cancer is aimed at identifying candidates for adjuvant anti-HER-2 treatment. However, commonly defined "HER-2 ؊ " tumors express variable levels of the HER-2 protein, which can influence prognosis. We compared the clinical outcomes of operable breast cancer patients stratified according to a common HER-2 testing algorithm.Methods. We studied 1,150 women (median age, 58 years; range, 22-94 years) undergoing surgery for early breast cancer at our institution. HER-2 status was determined using the HercepTest™ (Dako, Glostrup, Denmark) and, when needed, by fluorescence in situ hybridization (FISH). Patients receiving adjuvant trastuzumab were excluded. The impact of HER-2 status on the disease-free survival (DFS) time was studied using multivariate Cox proportional regression analysis.

Importance: The patient's perspective on chemotherapy-related side effects is becoming increasingly acknowledged both in experimental clinical trials and in the clinical practice.Objective: To evaluate how breast cancer patients receiving standard adjuvant chemotherapy report and grade side effects using a ten-item, paper questionnaire derived from the US National Cancer Institute's (NCIs) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 and to compare patient with doctor reports.Design, setting and participants: The questionnaire was administered to 604 patients at 11 sites after the first and third cycle of adjuvant chemotherapy between January 2011 and October 2013. CTCAE v4.0 definitions of grade of severity for nausea, vomiting, constipation, anorexia, dysgeusia, diarrhea, fatigue, pain, paresthesia, and dyspnea were translated into Italian and rephrased. Side effect information was also extracted from the medical charts to compare to patient-reported data. Main outcomes and measures:Differences in side effects reporting between paired questionnaires were studied by the McNemar Test and the Wilcoxon signed rank test.Agreement between patient and doctor side effect reporting (grade 0 vs. grade ≥1) was studied using Cohen's kappa statistic. The effect of the number of patients enrolled at each Institution on the magnitude of discrepancy in side effect reporting between patients and doctors was studied by linear regression.Results: 596 and 581 questionnaires were collected after cycles 1 and 3, respectively. A median of 82% of fields were filled in. A corresponding doctor questionnaire completed from chart data was available for 594 and 573 patient questionnaires. The frequency and severity of chemotherapy-related side effects were consistently greater in patient-reported than doctor-reported data. As a result, inter-rater agreement was low for most side effects, 3 ranging from 0.10 for anorexia to 0.51 for vomiting (Cohen's kappa statistic). There was a strong and significant positive correlation between the magnitude of the discrepancy in the frequency of reporting side effects and the number of patients enrolled at each site. Conclusions and relevance:Adherence to reporting adjuvant chemotherapy-related side effects using the CTCAE system is high in women undergoing adjuvant chemotherapy for breast cancer. Workload may contribute to agreement discrepancies by limiting the doctorpatient relationship.

BACKGROUND:The relationship between quantitative immunohistochemical hormone receptor expression and response to the combination of trastuzumab with chemotherapy in HER2-positive advanced breast cancer is currently unknown. METHODS: Estrogen receptor (ER) and progesterone receptor expression was studied both as a dichotomous variable (positivity set at !1% of positive cells) and as a continuous variable. The effect of hormone receptor expression on overall response rate and progression-free survival in patients receiving trastuzumab-based treatment was studied by univariate and multivariate analysis. RESULTS: One hundred eleven of 227 consecutive advanced breast cancer patients treated at 2 Institutions had hormone receptor-positive tumors (49%). High expression of ER (!30% of tumor cells) predicted reduced probability of tumor response to trastuzumab plus chemotherapy (multivariate odds ratio, 0.422; 95% confidence interval [CI], 0.222-0.803; P ¼ .009). In patients with hormone receptor-positive tumors (!1% of tumor cells), maintenance endocrine therapy added to trastuzumab upon the completion of chemotherapy was associated with a significant progression-free survival benefit (hazard ratio, 0.521; 95% CI, 0.3325-0.836; P ¼ .007). CONCLUSIONS: Our results suggest a predictive role of hormone receptor expression in HER2-positive tumors. Further investigation in this patient subset is warranted to optimize the use of HER2-targeting agents, chemotherapy, and endocrine therapy. Cancer 2012;118:17-

Overall, buparlisib is a safe and tolerable drug and, despite its peculiar toxicity profile, it is suitable for studies in combination with other anticancer agents in BC. Early-phase clinical trials in BC have provided evidence of antitumor activity. Several trials are being conducted in all the biological subsets of BC, including combinations with endocrine therapy, anti-HER2 agents, PARP-inhibitors and chemotherapy. While clinical results are eagerly awaited, biological material suitable for both genomic and non-genomic analyses is being collected. The authors expect an intense investigation of the potential biomarkers that explain response or resistance to buparlisib and inspire strategies to rationally explore the therapeutic potential of this drug.

BackgroundWe recently reported that self‐evaluation of the incidence and severity of treatment‐related side effects (TSEs) using a National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0‐based questionnaire was feasible and more informative than doctor reports in patients undergoing standard adjuvant chemotherapy for operable breast cancer. Here, we compare self‐ and doctor‐evaluated day of onset and duration of TSEs in the same population.Patients and methodsSix hundred and four patients were enrolled at 11 sites in Italy. CTCAE v4.0 definitions of grade of severity of nausea, vomiting, constipation, anorexia, dysgeusia, diarrhea, fatigue, pain, paresthesia, and dyspnea were translated into Italian and rephrased. Questionnaires were administered after the first and third chemotherapy cycles. At each time‐point, information on TSEs was extracted from the medical charts and compared to patient questionnaires.ResultsA total of 594 and 573 paired patient and doctor questionnaires were collected after cycles one and three, respectively. TSE duration was significantly longer when reported by patients compared to doctors for six and seven of ten items after cycles one and three, respectively. Due to the combined effect of doctor underreporting of TSE incidence and duration, the mean percentages of cycle days with TSEs were significantly higher for all ten items when based on patient reports. Day of onset could not be evaluated because of insufficient numbers of complete records.ConclusionsSelf‐reporting TSE duration is feasible using a CTCAE‐derived questionnaire. As doctors tend to underestimate TSE incidence and duration, patient‐reported outcomes should be incorporated into clinical practice, perhaps using eHealth technologies, to harness their potential to better estimate total TSE burden.