Genomic signature to guide adjuvant chemotherapy treatment decisions for early breast cancer patients in France: a cost-effectiveness analysis

IntroductionChemotherapy (CT) is commonly used as an adjuvant treatment for women with early breast cancer (BC). However, not all patients benefit from CT, while all are exposed to its short- and long-term toxicity. The Oncotype DX® test assesses cancer-related gene expression to estimate the risk of BC recurrence and predict the benefit of chemotherapy. The aim of this study was to estimate, from the French National Health Insurance (NHI) perspective, the cost-effectiveness of the Oncotype DX® test compared to standard of care (SoC; involving clinicopathological risk assessment only) among women with early, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC considered at high clinicopathological risk of recurrence.MethodsClinical outcomes and costs were estimated over a lifetime horizon based on a two-component model that comprised a short-term decision tree representing the adjuvant treatment choice guided by the therapeutic decision support strategy (Oncotype DX® test or SoC) and a Markov model to capture long-term outcomes.ResultsIn the base case, the Oncotype DX® test reduced CT use by 55.2% and resulted in 0.337 incremental quality-adjusted life-years gained and cost savings of €3,412 per patient, compared with SoC. Being more effective and less costly than SoC, Oncotype DX® testing was the dominant strategy.DiscussionWidespread implementation of Oncotype DX® testing would improve patient care, provide equitable access to more personalized medicine, and bring cost savings to the health system

EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand

Background: The randomized phase II INTELLANCE-2/EORTC_1410 trial on EGFR-amplified recurrent glioblastomas showed a trend towards improved overall survival when patients were treated with depatux-m plus temozolomide compared with the control arm of alkylating chemotherapy only. We here performed translational research on material derived from this clinical trial to identify patients that benefit from this treatment.Methods: Targeted DNA-sequencing and whole transcriptome analysis was performed on clinical trial samples. High-throughput, high-content imaging analysis was done to understand the molecular mechanism underlying the survival benefit.Results: We first define the tumor genomic landscape in this well-annotated patient population. We find that tumors harboring EGFR single-nucleotide variations (SNVs) have improved outcome in the depatux-m + TMZ combination arm. Such SNVs are common to the extracellular domain of the receptor and functionally result in a receptor that is hypersensitive to low-affinity EGFR ligands. These hypersensitizing SNVs and the ligand-independent EGFRvIII variant are inversely correlated, indicating two distinct modes of evolution to increase EGFR signaling in glioblastomas. Ligand hypersensitivity can explain the therapeutic efficacy of depatux-m as increased ligand-induced activation will result in increased exposure of the epitope to the antibody-drug conjugate. We also identified tumors harboring mutations sensitive to "classical" EGFR tyrosine-kinase inhibitors, providing a potential alternative treatment strategy.Conclusions: These data can help guide treatment for recurrent glioblastoma patients and increase our understanding into the molecular mechanisms underlying EGFR signaling in these tumors.</p

The EGFRvIII transcriptome in glioblastoma, a meta-omics analysis.

BACKGROUND: EGFR is among the genes most frequently altered in glioblastoma, with exons 2-7 deletions (EGFRvIII) being amongst its most common genomic mutations. There are conflicting reports about its prognostic role and it remains unclear whether and how it differs in signalling compared with wildtype EGFR. METHODS: To better understand the oncogenic role of EGFRvIII, we leveraged four large datasets into one large glioblastoma transcriptome dataset (n=741) alongside 81 whole-genome samples from two datasets. RESULTS: The EGFRvIII/EGFR expression ratios differ strongly between tumours and ranges from 1% to 95%. Interestingly, the slope of relative EGFRvIII expression is near-linear, which argues against a more positive selection pressure than EGFR wildtype. An absence of selection pressure is also suggested by the similar survival between EGFRvIII positive and negative glioblastoma patients. EGFRvIII levels are inversely correlated with pan-EGFR (all wildtype and mutant variants) expression, which indicates that EGFRvIII has a higher potency in downstream pathway activation. EGFRvIII-positive glioblastomas have a lower CDK4 or MDM2 amplification incidence than EGFRvIII-negative (p=0.007), which may point towards crosstalk between these pathways. EGFRvIII-expressing tumours have an upregulation of 'classical' subtype genes compared to those with EGFR-amplification only (p=3.873e-6). Genomic breakpoints of the EGFRvIII deletions have a preference towards the 3' end of the large intron-1. These preferred breakpoints preserve a cryptic exon resulting in a novel EGFRvIII variant and preserve an intronic enhancer. CONCLUSIONS: These data provide deeper insights into the complex EGFRvIII biology and provide new insights for targeting EGFRvIII mutated tumours

The predictive value of patient-reported outcomes on the impact of breast cancer treatment-related quality of life

International audiencePurpose Patient-reported outcomes (PROs) have been widely used to measure breast cancer (BC) treatment outcomes. However, evidence is still limited on using routinely PROs to personalize treatment decision-making, including or not chemotherapy, targeted therapy, and radiotherapy. Using patient baseline PRO scores, we aimed to use PROs before treatment initiation to predict improvement or decline in health-related quality of life (HRQoL) due to treatment that they receive.Methods In two French cancer sites, women with non-metastatic BC completed the EORTC QLQ-C30 and QLQ-BR23 and BREAST-Q questionnaires to assess their PROs at baseline and again at 6 months. The outcome measured was post-operative change in PROs with minimal important difference for QLQ-C30 domains. We performed multivariate ordinal logistic regression to estimate the incremental probability of post-operative PRO improvements and deteriorations depending upon treatment options and baseline HRQoL.Results One hundred twenty-seven women completed questionnaires. Chemotherapy had significant negative impacts on Global health status (GHS) and on physical and social functioning. Chemotherapy and radiotherapy increased patient fatigue scores after adjusting for clinical factors (p&lt; 0.01 and p&lt; 0.05, respectively). The incremental probability of GHS deteriorations for chemotherapy was +0.3, +0.5, and +0.34 for patients with baseline GHS scores of 40, 70, and 100, respectively. This showed that different pre-treatment PROs might predict differential effects of chemotherapy on women change in HRQoL.Conclusion Patients with different baseline PRO scores may experience dissimilar impacts from BC treatments on post-operative PROs in terms of improvements and deteriorations. Oncologists might decide to adapt the treatment option based on a given level of the negative impact. Future studies should concentrate on incorporating this information into routine clinical decision-making strategies to optimize the treatment benefit for patients

A pharmacokinetic evaluation of alpelisib for the treatment of HR+, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer

International audienceIntroduction: In most cases, metastatic breast cancer remains an incurable disease. A PIK3CA mutation is detected in 30-40% of all hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancers. PIK3CA activating mutations have been linked to endocrine resistance. PI3K inhibitors therefore offer promising new therapeutic options for this disease. Areas covered: This review discusses the pharmacologic properties, preclinical development, clinical efficacy, and safety profile of alpelisib, a PI3K inhibitor indicated in HR+/HER2 - PIK3CA-mutated advanced breast cancer, describing current therapeutic indication and open questions. Expert opinion: Following results of the SOLAR-1 trial, alpelisib became the first PI3K inhibitor approved by the U.S. Food and Drug Administration, in combination with fulvestrant, for postmenopausal women and men with HR+/HER2 - PIK3CA-mutated advanced breast cancer following progression on or after an endocrine-based regimen. This trial showed a substantial improvement in progression-free survival. However, given the side effects of alpelisib, the treatment decision should follow a thorough benefit-risk assessment. The BYLieve trial suggests alpelisib-fulvestrant benefit after progression on CDK 4/6 inhibitors. The identification of patients that are likely to benefit the most from PI3K inhibitors is still eagerly sought

Functional pre-therapeutic evaluation by genome editing of variants of uncertain significance of essential tumor suppressor genes

International audienceBackground: Targeted therapies in oncology are promising but variants of uncertain significance (VUS) limit their use for clinical management and necessitate functional testing in vitro. Using BRCA1 and BRCA2 variants, which have consequences on PARP inhibitor sensitivity, and POLE variants, potential biomarkers of immunotherapy response, we developed a rapid functional assay based on CRISPR-Cas9 genome editing to determine the functional consequences of these variants having potentially direct implications on patients' access to targeted therapies.Methods: We first evaluated the functional impact of 26 BRCA1 and 7 BRCA2 variants by editing and comparing NGS results between the variant of interest and a silent control variant. Ten of these variants had already been classified as benign or pathogenic and were used as controls. Finally, we extended this method to the characterization of POLE VUS.Results: For the 23 variants that were unclassified or for which conflicting interpretations had been reported, 15 were classified as functionally normal and 6 as functionally abnormal. Another two variants were found to have intermediate consequences, both with potential impacts on splicing. We then compared these scores to the patients' responses to PARP inhibitors when possible. Finally, to prove the application of our method to the classification of variants from other tumor suppressor genes, we exemplified with three POLE VUS. Among them, two were classified with an intermediate functional impact and one was functionally abnormal. Eventually, four POLE variants previously classified in databases were also evaluated. However, we found evidence of a discordance with the classification, variant p.Leu424Val being found here functionally normal.Conclusions: Our new rapid functional assay can be used to characterize the functional implication of BRCA1 and BRCA2 variants, giving patients whose variants were evaluated as functionally abnormal access to PARP inhibitor treatment. Retrospective analysis of patients' responses to PARP inhibitors, where accessible, was consistent with our functional score evaluation and confirmed the accuracy of our protocol. This method could potentially be extended to the classification of VUS from all essential tumor suppressor genes and can be performed within a timeframe compatible with clinical applications, thereby having a direct theranostic impact

The acquired resistance of mammary cancer cells to CDK4/6 inhibitors drives a DNA methylation reprogramming of genes encoding for BCL2 family members that confers a phenotype of high apopto-sensitivity induced by a BH3-mimetic drug

International audienceIntroduction. Due to the aberrant deregulation of the CDK4/6-INK4-RB pathway in breast cancer, CDK4/6 inhibitors are now a cornerstone of first line treatment of metastatic breast cancer showing an increase of progression free survival and overall survival. However, resistance to treatment eventually occur. We aimed at deciphering the molecular mechanisms of resistance to CDK4-6 inhibitors and at evaluating associations of therapies that could restore the sensitivity to the treatment. Methods. To identify potential DNA methylation signatures associated with the acquired resistance to CDK4/6 inhibitors, we established a MCF7 model, resistant to CDK4/6 inhibitors that we also used in Swiss nude mice via xenograft experiments. qMSRE were used to analyze the methylation status of genes encoding for BCL2 family members in cells, but also on circulating tumor DNA (ctDNA) in our in vivo model. Results. Using acquired resistant MCF7 cells to CDK4/6 inhibitors, our work demonstrate that these cells harbor a phenotype of high apopto-sensitivity induced by a BH3-mimetic drug. We next discern that DNMT3A and TET2 are the molecular determinants of this phenomenon via the epigenetic modulation of DNA methylation profile of genes encoding for BCL2 family. Using in vivo model, we noted that the ctDNA dynamic of the DNA methylation level of genes encoding for BCL2 family members is associated with the emergence of the resistance to CDK4/6 inhibitor demonstrated by the absence of tumor growth inhibition. Our experiments also indicated that the administration of a BH3-minetic drug at this time point restores the inhibition of tumor growth. Conclusion. This work provides the evidence that epigenetic modulation (methylation level) of key genes detected in ctDNA is associated with resistance to CDK4-6 inhibitors. The BH3-mimetic drugs are seem really appealing in that context

Impact of HER2 Status on Pathological Response after Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer

Purpose: Investigates the link between HER2 status and histological response after neoadjuvant chemotherapy in patients with early TNBC. Methods: We retrieved clinical and anatomopathological data retrospectively from 449 patients treated for the first time with standard neoadjuvant chemotherapy for early unilateral BC between 2005 and 2020. The primary endpoint was pathological complete response (pCR, i.e., ypT0 ypN0), according to HER2 status. Secondary endpoints included invasive disease-free survival (I-DFS) and overall survival (OS). Results: 437 patients were included, and 121 (27.7%) patients had HER2-low tumours. The pCR rate was not significantly different between the HER2-low group vs. the HER2-0 group (35.7% versus 41.8%, p = 0.284) in either univariate analysis or multivariate analysis adjusted for TNM classification and grade (odds ratio [OR] = 0.70, confidence interval [CI] 95% 0.45–1.08). With a median follow-up of 72.9 months, no significant survival differences were observed between patients with HER2-low tumours vs. patients with HER2-0 tumours in terms of I-DFS (p = 0.487) and OS (p = 0.329). Conclusions: In our cohort, HER2 status was not significantly associated with pCR in a manner consistent with data published recently on TNBC. However, the prognostic impact of HER2-low expression among TNBC patients warrants further evaluation

Hormonoresistance in advanced breast cancer: a new revolution in endocrine therapy

Endocrine therapy is the mainstay of treatment of estrogen-receptor-positive (ER+) breast cancer with an overall survival benefit. However, some adaptive mechanisms in the tumor emerge leading to the development of a resistance to this therapy. A better characterization of this process is needed to overcome this resistance and to develop new tailored therapies. Mechanisms of resistance to hormone therapy result in activation of transduction signal pathways, including the cell cycle regulation with cyclin D/CDK4/6/Rb pathway. The strategy of combined hormone therapy with targeted agents has shown an improvement of progression-free survival (PFS) in several phase II or III trials, including three different classes of drugs: mTOR inhibitors, PI3K and CDK4/6 inhibitors. A recent phase III trial has shown that fulvestrant combined with a CDK 4/6 inhibitor doubles PFS in aromatase inhibitor-pretreated postmenopausal ER+ breast cancer. Other combinations are ongoing to disrupt the interaction between PI3K/AKT/mTOR and cyclin D/CDK4/6/Rb pathways. Despite these successful strategies, reliable and reproducible biomarkers are needed. Tumor genomics are dynamic over time, and blood-based biomarkers such as circulating tumor DNA represent a major hope to elucidate the adaptive mechanisms of endocrine resistance. The optimal combinations and biomarkers to guide this strategy need to be determined