Patritumab deruxtecan in HER2-negative breast cancer: part B results of the window-of-opportunity SOLTI-1805 TOT-HER3 trial and biological determinants of early response.

Patritumab deruxtecan (HER3-DXd) exhibits promising efficacy in breast cancer, with its activity not directly correlated to baseline ERBB3/HER3 levels. This research investigates the genetic factors affecting HER3-DXd's response in women with early-stage hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer. In the SOLTI-1805 TOT-HER3 trial, a single HER3-DXd dose was administered to 98 patients across two parts: 78 patients received 6.4 mg/kg (Part A), and 44 received a lower 5.6 mg/kg dose (Part B). The CelTIL score, measuring tumor cellularity and infiltrating lymphocytes from baseline to day 21, was used to assess drug activity. Part A demonstrated increased CelTIL score after one dose of HER3-DXd. Here we report CelTIL score and safety for Part B. In addition, the exploratory analyses of part A involve a comprehensive study of gene expression, somatic mutations, copy-number segments, and DNA-based subtypes, while Part B focuses on validating gene expression. RNA analyses show significant correlations between CelTIL responses, high proliferation genes (e.g., CCNE1, MKI67), and low expression of luminal genes (e.g., NAT1, SLC39A6). DNA findings indicate that CelTIL response is significantly associated with TP53 mutations, proliferation, non-luminal signatures, and a distinct DNA-based subtype (DNADX cluster-3). Critically, low HER2DX ERBB2 mRNA, correlates with increased HER3-DXd activity, which is validated through in vivo patient-derived xenograft  models. This study proposes chemosensitivity determinants, DNA-based subtype classification, and low ERBB2 expression as potential markers for HER3-DXd activity in HER2-negative breast cancer.

A 14-gene B-cell immune signature in early-stage triple-negative breast cancer (TNBC): a pooled analysis of seven studies.

BACKGROUND: Early-stage triple-negative breast cancer (TNBC) displays clinical and biological diversity. From a biological standpoint, immune infiltration plays a crucial role in TNBC prognosis. Currently, there is a lack of genomic tools aiding in treatment decisions for TNBC. This study aims to assess the effectiveness of a B-cell/immunoglobulin signature (IGG) alone, or in combination with tumor burden, in predicting prognosis and treatment response in patients with TNBC. METHODS: Genomic and clinical data were retrieved from 7 cohorts: SCAN-B (N = 874), BrighTNess (n = 482), CALGB-40603 (n = 389), METABRIC (n = 267), TCGA (n = 118), GSE58812 (n = 107), GSE21653 (n = 67). IGG and a risk score integrating IGG with tumor/nodal staging (IGG-Clin) were assessed for event-free survival (EFS) and overall survival (OS) in each cohort. Random effects model was used to derive pooled effect sizes. Association of IGG with pathological complete response (pCR) was assessed in CALGB-40603 and BrighTNess. Immune significance of IGG was estimated through CIBERSORTx and EcoTyper. FINDINGS: IGG was associated with improved EFS (pooled HR = 0.77, [95% CI = 0.70-0.85], I2 = 18%) and OS (pooled HR = 0.79, [0.73-0.85], I2 = 0%) across cohorts, and was predictive of pCR in CALGB-40603 (OR 1.25, [1.10-1.50]) and BrighTNess (OR 1.57 [1.25-1.98]). IGG-Clin was predictive of recurrence (pooled HR = 2.11, [1.75-2.55], I2 = 0%) and death (pooled HR = 1.99, 95% [0.84-4.73], I2 = 79%) across cohorts. IGG was associated with adaptive immune response at CIBERSORTx and EcoTyper analysis. INTERPRETATION: IGG is linked to improved prognosis and pCR in early-stage TNBC. The integration of IGG alongside tumor and nodal staging holds promise as an approach to identify patients benefitting from intensified or de-intensified treatments. FUNDING: This study received funding from: Associació Beca Marta Santamaria, European Union's Horizon 2020 research and innovation and Marie Sklodowska-Curie Actions programs, Fundación FERO, Fundación CRIS contra el cáncer, Agència de Gestó d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, Fundación Contigo, Asociación Cáncer de Mama Metastásico IV, Breast Cancer Research Foundation, RESCUER, Fundación científica AECC and FSEOM.

Clinical implications of the intrinsic molecular subtypes in hormone receptor-positive and HER2-negative metastatic breast cancer.

Traditionally, the classification of breast cancer relies on the expression of immunohistochemical (IHC) biomarkers readily available in clinical practice. Using highly standardized and reproducible assays across patient cohorts, intrinsic molecular subtypes of breast cancer - also called "intrinsic subtypes" (IS) - have been identified based on the expression of 50 genes. Although IHC-based subgroups and IS moderately correlate to each other, they are not superimposable. In fact, non-luminal biology has been detected in a substantial proportion (5-20%) of hormone receptor-positive (HoR+) tumors, has prognostic value, and identifies reduced and increased sensitivity to endocrine therapy and chemotherapy, respectively. During tumor progression, a shift toward a non-luminal estrogen-independent and more aggressive phenotype has been demonstrated. Intrinsic genomic instability and cell plasticity, alone or combined with external constraints deriving from treatment selective pressure or interplay with the tumor microenvironment, may represent the determinants of such biological diversity between primary and metastatic disease, and during metastatic tumor evolution. In this review, we describe the distribution and the clinical behavior of IS as the disease progresses, focusing on HoR+/HER2-negative advanced breast cancer. In addition, we provide an overview of the ongoing clinical trials aiming to validate the predictive and prognostic value of IS towards their incorporation into routine care.

Pre-operative ribociclib plus letrozole versus chemotherapy: Health-related quality of life outcomes from the SOLTI CORALLEEN trial.

INTRODUCTION: In the phase II CORALLEEN trial, patients with PAM50 luminal B early breast cancer (EBC) were randomised to neoadjuvant ribociclib plus letrozole (R + L) or chemotherapy based on anthracyclines and taxanes. Results from the primary efficacy analysis showed a similar proportion of patients with response at surgery in both groups. How health-related quality of life (HRQoL) outcomes with R + L compare with chemotherapy in EBC setting is still unknown. Here, we report the results of the HRQoL analysis from the CORALLEEN study. METHODS: A total of 106 women were randomised 1:1 to receive neoadjuvant R + L (n = 52) or chemotherapy (n = 54). Patient-reported outcomes were assessed using two questionnaires: EORTC QLQ-C30 and EORTC QLQ-BR23. Change from baseline in the global health status, functional, and symptom scales was analysed using linear mixed-effect models, and between-treatment differences were estimated along with 95% confidence interval (95% CI). RESULTS: At baseline, the overall questionnaire available rate was 94.3%, and patient-reported outcomes were similar between treatment groups. At the end of the study treatment (24 weeks), patients receiving R + L showed better global health status scores with a between-treatment difference of 17.7 points (95% CI 9.2-26.2; p-value <0.001). The R + L group also presented numerically better outcomes in all functional and symptom scales. The larger between-treatment differences in symptom severity were found in fatigue (-28.9; 95% CI -38.5 to -19.3), appetite loss (-23; 95% CI -34.9 to -11.2) and systematic therapy side-effects (-11.4; 95% CI -18.3 to -4.6). CONCLUSIONS: Neoadjuvant R + L was associated with better HRQoL outcomes compared with chemotherapy in patients with luminal B EBC. REGISTRATION IDENTIFICATION: ClinicalTrials.gov Identifier: NCT03248427.

Oncolytic viruses: A new immunotherapeutic approach for breast cancer treatment?

Immunotherapy has revolutionized the oncology field during the last years, mainly with the introduction of immune checkpoint inhibitors in the clinical routine. Despite the recent approval of these drugs for the treatment of triple-negative breast cancer, most breast cancer patients cannot benefit from immunotherapy as most tumors are not considered immunoreactive. Therefore, new strategies must be developed to bring immunotherapy closer to breast cancer patients. The introduction of oncolytic viruses in the immuno-oncology field has shown promising results in cancer treatment, including breast cancer. However, a better understanding of their mechanisms of action, increase evidence of safety and efficacy, and the implications of its use as a systemic therapy must be examined in more depth. This review provides a summary of oncolytic virotherapy in the context of breast cancer, both in the pre-clinical and clinical setting.

Minimally important differences for the EORTC QLQ-C30 in prostate cancer clinical trials.

BACKGROUND: The aim of the study was to estimate the minimally important difference (MID) for interpreting group-level change over time, both within a group and between groups, for the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) scores in patients with prostate cancer. METHODS: We used data from two published EORTC trials. Clinical anchors were selected by strength of correlations with QLQ-C30 scales. In addition, clinicians' input was obtained with regard to plausibility of the selected anchors. The mean change method was applied for interpreting change over time within a group of patients and linear regression models were fitted to estimate MIDs for between-group differences in change over time. Distribution-based estimates were also evaluated. RESULTS: Two clinical anchors were eligible for MID estimation; performance status and the CTCAE diarrhoea domain. MIDs were developed for 7 scales (physical functioning, role functioning, social functioning, pain, fatigue, global quality of life, diarrhoea) and varied by scale and direction (improvement vs deterioration). Within-group MIDs ranged from 4 to 14 points for improvement and - 13 to - 5 points for deterioration and MIDs for between-group differences in change scores ranged from 3 to 13 for improvement and - 10 to - 5 for deterioration. CONCLUSIONS: Our findings aid the meaningful interpretation of changes on a set of EORTC QLQ-C30 scale scores over time, both within and between groups, and for performing more accurate sample size calculations for clinical trials in prostate cancer.

Prognosis in patients diagnosed with loco-regional failure of breast cancer: 34 years longitudinal data from the Stockholm-Gotland cancer registry.

RATIONALE: Survival after loco-regional failure (LRF) of breast cancer was investigated at the population level. METHODS: Using the Stockholm cancer registry, 2698 patients diagnosed with LRF between 1980 and 2014 were identified and divided into three cohorts by year of LRF diagnosis. Post-relapse event-free survival (EFS) and overall survival (OS) were analyzed separately in local and loco-regional relapses and compared across the cohorts by Kaplan-Meier method. Relative survival was estimated and Poisson regression models, adjusted for clinically relevant prognostic factors, were fitted for excess mortality ratio calculation. Age-related survival trends were also explored. RESULTS: Among 1922 patients diagnosed with local relapse, 1032 (54%) EFS events and 931 (48%) deaths were registered. A significant improvement in EFS (p < 0.001) and OS (p < 0.001) was demonstrated in tumors that recurred locally in the years 1990-1999 and 2000-2014 compared with 1980-1989, regardless of age at relapse (≤ 60 years; > 60 years). In women with loco-regional relapse, 557 out of 776 (72%) experienced a post-relapse event and 522 (67%) died. Significantly longer EFS and OS were seen over time in the whole group (p < 0.001 and p = 0.003, respectively) and in younger (p < 0.001; p < 0.001) but not in older women (p = 0.55; p = 0.80). Relative survival was consistent with OS and a statistically significant decrease in mortality after loco-regional recurrence over time was seen only in women aged ≤ 60 years. CONCLUSIONS: Survival after loco-regional failure of breast cancer has improved over time, especially in younger women.

Gene Expression Signatures and Immunohistochemical Subtypes Add Prognostic Value to Each Other in Breast Cancer Cohorts.

Purpose: Gene signatures and Ki67 stratify the same breast tumor into opposing good/poor prognosis groups in approximately 20% of patients. Given this discrepancy, we hypothesized that the combination of a clinically relevant signature and IHC markers may provide more prognostic information than either classifier alone.Experimental Design: We assessed Ki67 alone or combined with ER, PR and HER2 (forming IHC subtypes), and the research versions of the Genomic Grade Index, 70-gene, cell-cycle score, recurrence score (RS), and PAM50 signatures on matching TMA/whole tumor sections and microarray data in two Swedish breast cancer cohorts of 379 and 209 patients, with median follow-up of 12.4 and 12.5 years, respectively. First, we fit Cox proportional hazards models and used the change in likelihood ratio (Δ LR) to determine the additional prognostic information provided by signatures beyond that of (i) Ki67 and (ii) IHC subtypes. Second and uniquely, we then assessed whether signatures could compete well with pathology-based IHC classifiers by calculating the additional prognostic information of Ki67/IHC subtypes beyond signatures.Results: In cohort 1, only RS and PAM50 provided additional prognostic information beyond Ki67 and IHC subtypes (Δ LR-χ2 Ki67: RS = 12.8, PAM50 = 20.7, IHC subtypes: RS = 12.9, PAM50 = 11.7). Conversely, IHC subtypes added prognostic information beyond all signatures except PAM50. Similar results were observed in cohort 2.Conclusions: RS and PAM50 provided more prognostic information than the IHC subtypes in all breast cancer patients; however, the IHC subtypes did not add any prognostic information to PAM50. Clin Cancer Res; 23(24); 7512-20. ©2017 AACR.

Intrinsic subtypes and genomic signatures of primary breast cancer and prognosis after systemic relapse.

Molecular subtypes and gene expression signatures are widely used in early breast cancer but their role in metastatic disease is less explored. Two hundred-twenty patients diagnosed with primary breast cancer and subsequent relapse in Stockholm, Sweden between 1997 and 2006 were identified and their primary tumor was assessed for immunohistochemistry (IHC)- and PAM50-based subtypes, risk of recurrence (ROR-S) score, 21-gene and 70-gene signatures using research-based microarray expression profiles. Clinical and pathological data were retrospectively collected. Post-relapse survival within intrinsic subtypes and genomic signatures was investigated by Kaplan-Meier and Cox regression methods. ROR weighted for proliferation index (ROR-P) was explored and the prognostic contribution provided when combined to a clinical model estimated as change in LR- χ(2). IHC classified 27%, 24%, 36% and 13% of the tumors as luminal A, luminal B, HER2+ and triple negative, respectively. PAM50 categorized 22%, 24%, 26%, 22%, 6% of the tumors as luminal A, luminal B, HER2-enriched, basal-like and normal-like. Triple negative and basal tumors had a significantly shorter median post-relapse survival in comparison with luminal. Overall, neither IHC nor PAM50 subtypes, 21- and 70- gene profiles were prognostic in multivariable models. Low and medium ROR-S had a longer survival compared with the high-risk group (23 vs 10 months; p = 0.04). ROR-P independently correlated with post-relapse survival (p = 0.002) and provided the most significant prognostic information when added to a clinical model. ROR score from primary tumor represents an independent prognostic factor of post-relapse survival beyond classical clinical and pathological variables.

A retrospective safety and efficacy analysis of the first patients treated with eribulin for metastatic breast cancer in Stockholm, Sweden.

BACKGROUNDS: Eribulin is a non-taxane, microtubule dynamics inhibitor approved for the treatment of patients with metastatic breast cancer (MBC) in Europe in March 2011. MATERIAL AND METHODS: For the purpose of an internal quality control, all patients with MBC treated with eribulin at Karolinska University Hospital were registered in a database. Clinical data were collected retrospectively for patients that were registered by August 2012 and safety and efficacy of eribulin were evaluated. Treatment toxicity including fatigue, neurotoxicity and infection was graded according to CTCAE v4.0. Objective response to treatment was investigated using routinely performed radiological assessments. When only clinical assessments were made, the evaluation of the treating physician was used. Furthermore, the efficacy of eribulin was investigated in different tumor subtypes. RESULTS: Forty-eight patients who received at least one cycle of eribulin were identified. Most patients were heavily pretreated with a median of 3 (range 1-7) previous chemotherapy lines prior to eribulin. Median patient age was 56 years (range 35-74). At the end of the analysis, 23 patients were alive and two were still treated with eribulin. No hypersensitivity reactions and no toxic deaths were seen. Fatigue grade 3-4 was observed in three patients (6.3%). One patient experienced grade 4 neurotoxicity. Grade 3-4 neutropenia was documented in 18.8%, and three patients were treated for a grade 3 infection. Interestingly, three individuals developed Herpes zoster reactivation. One patient responded to treatment with complete remission, while 33.3% had a partial response. 48% of all patients had a clinical benefit (objective response or stable disease for more than six months). CONCLUSIONS: Eribulin administered outside of a clinical trial in patients with advanced breast cancer was safe and well tolerated. A clinical benefit was seen in half of the cases. No statistically significant differences in objective response or survival were observed between histopathological subgroups.

Ki67 measured in metastatic tissue and prognosis in patients with advanced breast cancer.

The purpose of this study is to determine the prognostic role of Ki67 evaluated in relapse biopsies from patients with metastatic breast cancer (MBC). Two hundred and ten patients diagnosed with MBC in Stockholm, Sweden between 1998 and 2009 and with Ki67 assessed at time of first systemic relapse (mKi67) were retrospectively identified and divided into two groups according to mKi67 fraction (low ≤20 %, high >20 %). Post-relapse survival was compared between the groups using Kaplan-Meier and Cox regression methods. Death rate as function of continuous mKi67 was also evaluated. Furthermore, the prognostic role of intra-individual change in Ki67 between primary tumor and matched metastasis was explored by Kaplan-Meier plots. One hundred and twenty-five patients had low and 85 had high mKi67. Median survival was 25 and 17 months in low- and high-mKi67 group, respectively [hazard ratio (HR) 0.69, 95 % confidence intervals (CI) 0.51-0.92, P = 0.01]. In a multivariate model adjusted for prognostic confounders, low-mKi67 showed a non-significant trend toward better survival (HR 0.85, 95 %CI 0.62-1.16, P = 0.30). Nevertheless, mKi67 independently correlated with survival when compared with primary tumor proliferation (HR 0.56, 95 %CI 0.38-0.81, P = 0.002). The 2-year death rate steeply increased as mKi67 increased. Moreover, the change from high in primary tumor to low in metastasis significantly correlated with longer survival when compared with stable Ki67 levels (HR 0.48, 95 %CI 0.31-0.76, P = 0.002). In this cohort of MBC patients, mKi67 inversely but not independently correlated with survival. However, a significant association between mKi67 and survival was shown regardless of primary tumor proliferation.

Molecular mechanism and clinical implications of endocrine therapy resistance in breast cancer.

Endocrine therapy, the first targeted therapy in oncology, is the most successful systemic therapy in the management of estrogen receptor (ER)-positive breast cancer. Approximately 50% of patients with advanced disease do not respond to first-line treatment with tamoxifen, and many women who receive tamoxifen as adjuvant therapy experience tumor relapse and die from their disease. Aromatase inhibitors are proving superior to tamoxifen, at least in certain patient subsets. However, the response rate to these compounds is only slightly higher than that to tamoxifen in patients with advanced breast cancer, and both de novo or acquired resistance also occur, limiting the efficacy of the treatment. Advanced studies of ER biology have highlighted the role of an intimate cross talk between the ER and HER2/growth factor signaling pathways as a fundamental contributor to the development of resistance to hormone therapies. The aim of this review article is to summarize the current knowledge on mechanisms of resistance of breast cancer cells to endocrine therapies due to the cross talk between the ER and growth factor signaling pathways, and to explore newly available therapeutic strategies that could prolong duration of response and circumvent endocrine-resistant tumor growth.