Isabel Echavarria

Neratinib for the treatment of HER2-positive early stage breast cancer

ABSTRACT Introduction: Despite the advances in the treatment of HER2-positive breast cancer, resistance to actual chemotherapeutic regimens eventually occurs. Neratinib, an orally available pan-inhibitor of the ERBB family, represents an interesting new option for early-stage HER2-positive breast cancer. Areas covered: In this article, the development of neratinib, with a special focus on its potential value in the treatment of early-stage HER2-positive breast cancer, has been reviewed. For this purpose, a literature search was conducted, including preclinical studies, early-phase trials in advanced cancer with neratinib in monotherapy and in combination, and phase II and large phase III trials in the early setting. Management of neratinib-induced toxicity, future perspectives for the drug, and ongoing trials are also discussed in this review. Expert commentary: Neratinib is emerging as a promising oral drug for the treatment of HER2-positive breast cancer. Although FDA and EMA approval is derived from the extended adjuvant treatment, this setting may not be the ideal scenario to obtain the beneficial effects of neratinib. Confirmatory data in the neoadjuvant setting and subgroup analysis from the ExTENET trial might bring some light into the best setting for neratinib therapy. Data from confirmatory trials in the metastatic setting are also required.

Cyclin Kinase Inhibitors in Breast Cancer: From Bench to Bedside

A precise knowledge of cell-cycle machinery and its effect on tumorigenesis has led to the development of a large number of anticancer drugs targeting this pathway. In breast cancer research, the promising results of recent clinical trials of novel selective CDK-inhibitors, for example palbociclib, have generated high expectations for this field. This review gathers the results of the most recent clinical trials of CDK inhibitors for breast cancer, and outlines their potential as anticancer therapy.

Pathological Response in a Triple-Negative Breast Cancer Cohort Treated with Neoadjuvant Carboplatin and Docetaxel According to Lehmann's Refined Classification

Purpose: Triple-negative breast cancer (TNBC) requires the iden- tification of reliable predictors of response to neoadjuvant chemotherapy (NACT). For this purpose, we aimed to evaluate the performance of the TNBCtype-4 classifier in a cohort of patients with TNBC treated with neoadjuvant carboplatin and docetaxel (TCb). Methods: Patients with TNBC were accrued in a nonrandomized trial of neoadjuvant carboplatin AUC 6 and docetaxel 75 mg/m2 for six cycles. Response was evaluated in terms of pathologic complete response (pCR, ypT0/is ypN0) and residual cancer burden by Symmans and colleagues. Lehmanns subtyping was performed using the TNBCtype online tool from RNAseq data, and germline sequencing of a panel of seven DNA damage repair genes was conducted. Results: Ninety-four out of the 121 patients enrolled in the trial had RNAseq available. The overall pCR rate was 44.7%. Lehmann subtype distribution was 34.0% BL1, 20.2% BL2, 23.4% M, 14.9% LAR, and 7.4% were classified as ER+. Response to NACT with TCb was significantly associated with Lehmann subtype (P = 0.027), even in multivariate analysis including tumor size and nodal involvement, with BL1 patients achieving the highest pCR rate (65.6%), followed by BL2 (47.4%), M (36.4%), and LAR (21.4%). BL1 was associated with a significant younger age at diagnosis and higher ki67 values. Among our 10 germline mutation carriers, 30% were BL1, 40% were BL2, and 30% were M. Conclusions: TNBCtype-4 is associated with significantly different pCR rates for the different subtypes, with BL1 and LAR displaying the best and worse responses to NACT, respectively. Clin Cancer Res; 24(8); 1845–52. ©2018 AACR.

Ribociclib for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer

CDK4/6 inhibitors are a promising new class of drugs for hormone-receptor-positive breast cancer and have been shown to overcome and delay hormone resistance in advanced breast cancer. Ribociclib, a selective oral inhibitor of CDK4/6, was approved by the US FDA for first-line treatment of hormone-receptor-positive/HER2-negative metastatic breast cancer. This review summarizes the clinical evidence available for ribociclib, from preclinical data to the pivotal studies, with a special focus on toxicity and its management. In addition, this article reviews potential new combinations under study, as well as ongoing clinical trials both in the metastatic and early setting. Finally, this review compares ribociclib activity and toxicity with those of the drugs of the same class (palbociclib and abemaciclib).

Incorporating CDK4/6 Inhibitors in the Treatment of Advanced Luminal Breast Cancer

After optimizing endocrine monotherapy modalities in the setting of advanced luminal breast cancer (BC), dual endocrine/targeted therapy combinations have been tested with positive results, and are transforming this BC subtype treatment landscape. Cell cycle deregulation is a hallmark of cancer that has become a key druggable target in hormone receptor (HR)-positive BC due to its role in endocrine resistance mechanisms. Cyclin dependent kinase (CDK)4/6 inhibitors have experienced a fast development in combination with endocrine therapy and have already been commercialized in some countries. In this review, we will summarize the development of these CDK4/6 inhibitors in luminal BC, from the preclinical data to the pivotal phase III trials that led to their approval, focusing on the efficacy and safety data for each of the treatment settings. Moreover, we will consider the challenges CDK4/6 inhibitors face in their positioning in the algorithm of treatment for advanced luminal BC and the considerations physicians should take into account when selecting these therapies for their patients. However, we are still in need of reliable predictive biomarkers in order to identify patients who will derive the greatest benefit from these drug combinations that are not exempt from toxicity.

Evaluation of Breast Cancer Patients with Genetic Risk in a University Hospital: Before and After the Implementation of a Heredofamilial Cancer Unit

The identification of patients at risk for breast cancer by genetic testing has proven to reduce breast cancer mortality. In 2010, due to a lack of systematization in hereditary cancer assistance in our center, we implemented a multidisciplinary Heredofamilial Cancer Unit (HFCU). We analyze if the HFCU improved the rates of referrals and preventive management of breast cancer patients with genetic risk. We retrospectively compared family history records, referrals of high-risk patients to genetic counseling, and detection and management of patients with BRCA1/2 mutations in two cohorts of breast cancer patients diagnosed before (first period: 2007–2010) and after the creation of the HFCU (second period: 2010–2013). In the first period, 893 patients were included, and 902 were included in the second. Due to the inability to establish their genetic risk, 142 patients (15.9%) vs. 70 (7.8%) were excluded from analysis (p < 0.001). Among the evaluable patients, 194 (25.8%) vs. 223 (26.8%) fulfilled one or more risk criteria (p = 0.65). Family history documentation in patient’s medical records (92.4 vs. 97.8%, p < 0.001) and referral rate (26.3 vs. 52%, p < 0.0001) significantly increased in the second period. Eight BRCA1/2 mutations were detected among patients referred in the first period and 17 among those referred to the HFCU. The rate of preventive surgeries in patients with BRCA mutations significantly increased in the second period (25 vs. 76.5%, p = 0.03). In conclusion, there was a clear improvement in family history records, referrals, and preventive surgeries in breast cancer patients with genetic risk after the implementation of the HFCU.

Abstract P4-20-01: Implications of financial modeling in breast cancer clinical research from 1990 to 2010

SUMMARY : Over the past two decades significant progress has been made in breast cancer treatment resulting in a substantial improvement in patients9 outcome. But we have to think about who promotes all this research and the consequences of the type of fundingThis project aims to evaluate the implication of finance in clinical research and the variance according to the type of funding. OBJETIVES : To evaluate the financial evolvement of breast cancer clinical trials in the past two decades, regarding the phase of development design of the studies, the collaboration between Academy (Acad) and Industry (Ind), the sample size, the study results and the statistical analyses conducted. METHODS: A systematic review was performed using MEDLINE to identify breast cancer randomized clinical trials published between January1990 and December2010. Studies that involved chemotherapy, endocrine and/or targeted therapies, wherethe primary endpoint was considered adequate to support a drug approval in oncology according to the FDA and EMA (U.S. Food and Drug Administration and European Medicines Agency, respectively), were included. RESULTS: Data were evaluated 2,211 and 472 met selection criteria comprised in the methodology During the first decade the Acad was the main breast cancer research promoter being replaced by the Inv. throughout the second decade (p CONCLUSIONS: There is a significant tendency towards the promotion of research by the pharmaceutical industries during the last two decades, leading a change in the clinical trials design and the endpoints. Citation Format: Jerez Y, Lopez-Tarruella S, Marquez-Rodas I, Perez S, Ocana A, Echavarria I, Lobo M, Gallego I, Torres G, Ortega L, Garcia G, Palomero I, Gonzalez Del Val R, Massarrah T, Esteban M, Del Monte-Millan M, Martin M. Implications of financial modeling in breast cancer clinical research from 1990 to 2010 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-20-01.