Prognostic and predictive impact of gene expression in node-positive early breast cancer patients receiving dose-dense versus standard-dose adjuvant chemotherapy

Adjuvant chemotherapy; Early breast cancer; Lymph node-positiveQuimioterapia adyuvante; Cáncer de mama temprano; Ganglio linfático positivoQuimioteràpia adjuvant; Càncer de mama precoç; Gangli limfàtic positiuThe utility of multigene expression assays in advanced (≥ 4 positive lymph nodes) early breast cancer (EBC) is limited. We conducted exploratory transcriptomic analysis of 758 genes (Breast Cancer 360 panel, nCounter® platform; NanoString) in primary tumor samples collected during a phase 3 trial comparing adjuvant taxane-containing dose-dense chemotherapy (ddCTX) versus standard-dosed chemotherapy (stCTX) in resected EBC with ≥ 4 positive lymph nodes. Prognostic and predictive associations with disease-free survival (DFS) and overall survival (OS) were evaluated by Cox regression with false discovery rate (FDR) adjustment. Data were available from tumor samples of 141/226 patients (median follow-up: 14 years). Several genes/signatures, including immune markers, showed prognostic relevance in unadjusted analyses. Of these, two remained significant after multiplicity adjustment: a positive effect on DFS of programmed cell death 1 ligand-2 (PD-L2) in the ddCTX arm (univariate HR: 0.53, FDR-adjusted P = 0.036) and a negative effect on OS of HER2-enriched (HER2-E) signature in the stCTX arm (univariate HR: 5.40, FDR-adjusted P = 0.036). Predictive analyses showed greater DFS benefit of ddCTX in tumors with high antigen processing machinery (APM) expression (multivariate interaction P = 0.024). Multigene expression assays have a prognostic and predictive potential in advanced EBC, and further investigation is warranted in order to identify candidates for de-escalated treatment. In addition, intrinsic subtype and immune gene expression have predictive potential

Genomic Profiling in Luminal Breast Cancer

The developments in gene expression analysis have made it possible tosub-classify hormone receptor-positive (luminal) breast cancer indifferent prognostic subgroups. This sub-classification is currentlyused in clinical routine as prognostic signature (e. g. 21-gene OnoctypeDX (R), 70-gene Mammaprint (R)). As yet, the optimal method forsub-classification has not been defined. Moreover, there is no evidencefrom prospective trials. This review explores widely used genomicsignatures in luminal breast cancer, making a critical appraisal ofevidence from retrospective/prospective trials. It is based onsystematic literature search performed using Medline (accessed September2013) and abstracts presented at the Annual Meeting of American Societyof Clinical Oncology and San Antonio Breast Cancer Symposium

Gene signatures in patients with early breast cancer and relapse despite pathologic complete response

Prognostic markers; Tumour biomarkersMarcadores pronósticos; Biomarcadores tumoralesMarcadors pronòstics; Biomarcadors tumoralsA substantial minority of early breast cancer (EBC) patients relapse despite their tumors achieving pathologic complete response (pCR) after neoadjuvant therapy. We compared gene expression (BC360; nCounter® platform; NanoString) between primary tumors of patients with post-pCR relapse (N = 14) with: (i) matched recurrent tumors from same patient (intraindividual analysis); and (ii) primary tumors from matched controls with pCR and no relapse (N = 41; interindividual analysis). Intraindividual analysis showed lower estrogen receptor signaling signature expression in recurrent tumors versus primaries (logFC = −0.595; P = 0.022). Recurrent tumors in patients with distant metastases also exhibited reduced expression of immune-related expression parameters. In interindividual analyses, primary tumor major histocompatibility complex class II expression was lower versus controls in patients with any relapse (logFC = −0.819; P = 0.030) or distant relapse (logFC = −1.151; P = 0.013). Primaries with later distant relapse also had greater homologous recombination deficiency than controls (logFC = 0.649; P = 0.026). Although no associations remained statistically significant following adjustment for false discovery rate, our results show that transcriptomic analyses have potential for prognostic value and may help in selecting optimal treatment regimens for EBC at risk of relapse and warrant further investigation

WSG ADAPT - adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early breast cancer: study protocol for a prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III trial

Background: Adjuvant treatment decision-making based on conventional clinical/pathological and prognostic single molecular markers or genomic signatures is a therapeutic area in which over-/under-treatment are still key clinical problems even though substantial and continuous improvement of outcome has been achieved over the past decades. Response to therapy is currently not considered in the decision-making procedure. ADAPT is one of the first new generation (neo) adjuvant trials dealing with individualization of (neo) adjuvant decision-making in early breast cancer and aims to establish early predictive surrogate markers, e. g., Ki-67, for therapy response under a short induction treatment in order to maximally individualize therapy and avoid unnecessary toxicity by ineffective treatment. Methods/design: The prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III ADAPT trial has an innovative ``umbrella{''} protocol design. The ``umbrella{''} is common for all patients, consisting of dynamic testing of early therapy response. ADAPT will recruit 4,936 patients according to their respective breast cancer subtype in four distinct sub-trials at 80 trial sites in Germany; 4,000 patients with hormone receptor positive (HR+) and HER2 negative disease will be included in the ADAPT HR+/HER2-sub-trial, where treatment decision is based on risk assessment and therapy response to induction therapy, and 380 patients will be included in ADAPT HER2+/HR+. A further 220 patients will be included in ADAPT HER2+/HR- and 336 patients will be recruited for ADAPT Triple Negative. These three sub-trials focus on identification of early surrogate markers for therapy success in the neoadjuvant setting. Patients will be allocated to the respective sub-trial according to the result of their diagnostic core biopsy, as reported by local/central pathology for HR and HER2 status. Discussion: Recent trials, such as the GeparTrio, have shown that response-guided therapy using clinical response may improve outcome. For chemotherapy or HER2-targeted treatment, pathologic complete response in a neoadjuvant setting is an excellent predictor of outcome. For endocrine therapy, response to short induction treatment - as defined by decrease in tumor cell proliferation - strongly correlates with outcome. ADAPT now aims to combine static prognostic and dynamic predictive markers, focusing not just on single therapeutic targets, but also on general markers of proliferation and cell death. Biomarker analysis will help to optimize selection of subtype-specific treatment. Trial registration: ClinicalTrials.gov: ADAPT Umbrella: NCT01781338; ADAPT HR+/HER2-: NCT01779206; ADAPT HER2+/HR+: NCT01745965; ADAPT HER2+/HR-: NCT01817452; ADAPT TN: NCT01815242

Genomic Profiling in Luminal Breast Cancer

The developments in gene expression analysis have made it possible tosub-classify hormone receptor-positive (luminal) breast cancer indifferent prognostic subgroups. This sub-classification is currentlyused in clinical routine as prognostic signature (e. g. 21-gene OnoctypeDX (R), 70-gene Mammaprint (R)). As yet, the optimal method forsub-classification has not been defined. Moreover, there is no evidencefrom prospective trials. This review explores widely used genomicsignatures in luminal breast cancer, making a critical appraisal ofevidence from retrospective/prospective trials. It is based onsystematic literature search performed using Medline (accessed September2013) and abstracts presented at the Annual Meeting of American Societyof Clinical Oncology and San Antonio Breast Cancer Symposium

Immune Markers and Tumor-Related Processes Predict Neoadjuvant Therapy Response in the WSG-ADAPT HER2-Positive/Hormone Receptor-Positive Trial in Early Breast Cancer

Prognostic or predictive biomarkers in HER2-positive early breast cancer (EBC) may inform treatment optimization. The ADAPT HER2-positive/hormone receptor-positive phase II trial (NCT01779206) demonstrated pathological complete response (pCR) rates of ~40% following de-escalated treatment with 12 weeks neoadjuvant ado-trastuzumab emtansine (T-DM1) ± endocrine therapy. In this exploratory analysis, we evaluated potential early predictors of response to neoadjuvant therapy. The effects of PIK3CA mutations and immune (CD8 and PD-L1) and apoptotic markers (BCL2 and MCL1) on pCR rates were assessed, along with intrinsic BC subtypes. Immune response and pCR were lower in PIK3CA-mutated tumors compared with wildtype. Increased BCL2 at baseline in all patients and at Cycle 2 in the T-DM1 arms was associated with lower pCR. In the T-DM1 arms only, the HER2-enriched subtype was associated with increased pCR rate (54% vs. 28%). These findings support further prospective pCR-driven de-escalation studies in patients with HER2-positive EBC

Evidence-based guidelines for managing patients with primary ER+ HER2− breast cancer deferred from surgery due to the COVID-19 pandemic

Many patients with ER+ HER2- primary breast cancer are being deferred from surgery to neoadjuvant endocrine therapy (NeoET) during the COVID-19 pandemic. We have collated data from multiple international trials of presurgical endocrine therapy in order to provide guidance on the identification of patients who may have insufficiently endocrine-sensitive tumors and should be prioritised for early surgery or neoadjuvant chemotherapy rather than NeoET during or in the aftermath of the COVID-19 pandemic for safety or when surgical activity needs to be prioritized. For postmenopausal patients, our data provide strong support for the use of ER and PgR status at diagnosis for triaging of patients into three groups in which (taking into account clinical factors): (i) NeoET is likely to be inappropriate (Allred ER 10%) indicates a higher priority for early surgery. Too few data were available for premenopausal patients to provide a similar treatment algorithm. These guidelines should be helpful for managing patients with early ER+ HER2- breast cancer during and in the aftermath of the COVID-19 crisis

ERBB2mRNA expression and response to Ado-Trastuzumab Emtansine (T-DM1) in HER2-positive breast cancer

Trastuzumab emtansine (T-DM1) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (BC) and for residual disease after neoadjuvant therapy; however, not all patients benefit. Here, we hypothesized that the heterogeneity in the response seen in patients is partly explained by the levels of human epidermal growth factor receptor 2 gene (ERBB2) mRNA.We analyzed ERBB2 expression using a clinically applicable assay in formalin-fixed para n-embedded (FFPE) tumors (primary or metastatic) from a retrospective series of 77 patients with advanced HER2+ BC treated with T-DM1. The association of ERBB2 levels and response was further validated in 161 baseline tumors from the West German Study (WGS) Group ADAPT phase II trial exploring neoadjuvant T-DM1 and 9 in vitro BC cell lines. Finally

Arbeitsgemeinschaft Gynäkologische Onkologie Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2023

Background: Each year the interdisciplinary Arbeitsgemeinschaft Gynäkologische Onkologie (AGO), German Gynecological Oncology Group Breast Committee on Diagnosis and Treatment of Breast Cancer provides updated state-of-the-art recommendations for early and metastatic breast cancer. Summary: The updated evidence-based treatment recommendation for early and metastatic breast cancer has been released in March 2023. Key Messages: This paper concisely captures the updated recommendations for early breast cancer chapter by chapter

The impact of anthracyclines in intermediate and high-risk HER2-negative early breast cancer—a pooled analysis of the randomised clinical trials PlanB and SUCCESS C

Background Anthracycline/cyclophosphamide-taxane-containing chemotherapy (AC-T) is the standard of care in the adjuvant treatment of HER2-negative early breast cancer (EBC), but recent studies suggest omission of anthracyclines for reduced toxicity without compromising efficacy. Methods Based on individual patient data ( n  = 5924) pooled from the randomised Phase III trials PlanB and SUCCESS C, we compared disease-free survival (DFS) and overall survival (OS) between intermediate to high-risk HER2-negative EBC-patients treated with either six cycles of docetaxel/cyclophosphamide (TC6) or an AC-T regime using univariable and adjusted multivariable Cox regression models. Results AC-T conferred no significant DFS or OS advantage in univariable (DFS: hazard ratio (HR) for TC vs. AT 1.05, 95% confidence interval (CI): 0.89–1.24, P  = 0.57; OS: HR 1.00, 95% CI: 0.80–1.26, P  = 1.00) and adjusted multivariable analysis (DFS: HR 1.01, 95% CI: 0.86–1.19, P  = 0.91; OS: HR 0.97, 95% CI: 0.77–1.22, P  = 0.79). Patients receiving TC6 had significantly fewer grade 3–4 adverse events. Exploratory subgroup analysis showed that AC-T was associated with significantly better DFS and OS in pN2/3 patients, specifically in those with lobular histology. Conclusion For most patients with HER2-negative EBC, AC-T is not associated with a survival benefit compared to TC6. However, patients with lobular pN2/pN3 tumours seem to benefit from anthracycline-containing chemotherapy.None declared for the pooled analysis presented in this manuscript. However, the PlanB-study was supported by Genomic Health, Amgen and Sanofi-Aventis, the Success C-study by Sanofi-Aventis, Chugai, Pfizer, GlaxoSmithKline and Janssen Diagnostics