Rossella Martinello

Hormone-receptor expression and activity of trastuzumab with chemotherapy in HER2-positive advanced breast cancer patients

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.

Metastatic breast cancer subtypes and central nervous system metastases

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. PATIENTS AND METHODS 488 patients with diagnosis of metastatic BC were retrospectively evaluated. According to the combination of hormone receptors (HR) and HER2 status, tumors were grouped in: Luminal (Lum), Luminal/HER2+, pure HER2-positive (pHER2+) and triple negative (TN). Time to CNS progression, CNS-M free interval and Overall Survival (OS) after CNS-M occurrence were compared by the log-rank test. Cox-proportional hazard models were used to study predictor factors associated with CNS progression, including tumor subtype and all potentially clinical relevant variables. RESULTS 115 patients (pts) developed CNS-M with a median time to CNS progression of 31 months. The rate of CNS-M by subtype was: Lum 14%, Lum/HER2+ 35%, pHER2+ 49%, TN 22% (p < 0.001). Compared with Lum tumors, Lum/HER2+ (HR 2.514, p < 0.001), pHER2+ (HR 6.799, p < 0.0001) and TN (HR = 3.179, p < 0.001) subtypes were at higher risk of CNS-M. Median OS in months after CNS-M was: Lum 7.4, Lum/HER2+ 19.2, pHER2+ 7, TN 4.9 (p < 0.002). Belonging to the Lum/HER2+ subtype (HR 0.48, p < 0.037) and having isolated CNS (HR 0.37, p < 0.004) predicted significantly reduced risk of death. CONCLUSIONS After CNS-M, the Lum/HER2+ subtype appears associated with the longest OS. Prospective clinical trials would be required for evaluating the potential role of screening for asymptomatic CNS lesions and of more aggressive CNS-M treatment in Lum/HER2+ subtype.

Self-evaluation of Adjuvant Chemotherapy-Related Adverse Effects by Patients With Breast Cancer

IMPORTANCE Patient perspective on chemotherapy-related adverse effects is being increasingly acknowledged both in experimental clinical trials and in clinical practice. OBJECTIVE To evaluate a 10-item, paper questionnaire derived from the US National Cancer Institutes Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 for patient-reported chemotherapy-related adverse effects. DESIGN, SETTING, AND PARTICIPANTS Prospective, single-arm study of 604 women with breast cancer receiving standard adjuvant chemotherapy conducted at 11 outpatient oncology clinics at academic and nonacademic Italian hospitals between January 2011 and October 2013. The CTCAE version 4.0 definitions of grade of severity for 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 cycle of chemotherapy. Adverse effect information was also extracted from the medical records to compare with patient-reported data. MAIN OUTCOMES AND MEASURES Differences in adverse effect-reporting between paired questionnaires and agreement between patient and physician adverse effect-reporting (grade 0 vs grade ≥1) were studied. Linear regression was used to study the effect of the number of patients enrolled at each institution on the magnitude of discrepancy in adverse effect-reporting between patients and physicians. RESULTS A total of 604 women (median age, 53.4 years; interquartile range, 45.0-62.7 years) were enrolled. The number of patients enrolled at each site varied between 6 and 236. Three patients withdrew consent prior to starting the first cycle of adjuvant chemotherapy. After cycle 1 of adjuvant chemotherapy, 596 patient questionnaires were collected, and 581 patient questionnaires were collected after cycle 3. Of the questionnaires collected, 594 and 573 had corresponding questionnaire results extracted from medical records at the same time point. The median (interquartile range) percentage of completed questionnaire fields was 82% (80%-88%) for both the first and third cycle questionnaires, and the results of the 2 patient questionnaires showed a reduction in vomiting (severity), diarrhea (both incidence and severity), and pain (both incidence and severity), as well as a statistically significant increase in dysgeusia (both incidence and severity) and dyspnea (both incidence and severity) in the second patient-completed questionnaire. The frequency and severity of chemotherapy-related adverse effects were consistently greater in patient-reported data than physician-reported data. As a result, interrater agreement was low for most adverse effects, ranging from 0.10 for anorexia to 0.54 for vomiting (Cohen κ statistic). There was a strong and significant positive correlation between the magnitude of the discrepancy in the frequency of reporting adverse effects and the number of patients enrolled at each site. CONCLUSIONS AND RELEVANCE Adherence to reporting adjuvant chemotherapy-related adverse effects using the CTCAE system is high in women undergoing adjuvant chemotherapy for breast cancer. Workload may contribute to agreement discrepancies by limiting the physician-patient relationship.

Buparlisib , an oral pan-PI3K inhibitor for the treatment of breast cancer

Introduction: Deregulation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) intracellular signaling pathway is common in breast cancer (BC) and has been found to be potentially implicated in resistance to endocrine and anti-HER2 therapies. Targeting the PI3K/Akt/mTOR pathway may remove this inhibition and restore sensitivity to these compounds. Buparlisib (BKM120) is a potent oral pan-class I PI3K inhibitor that is being extensively evaluated in multiple tumor types. Areas covered: This review briefly summarizes the pharmacodynamics and pharmacokinetics of buparlisib, focusing on preclinical and clinical data in BC and on ongoing randomized trials. Expert opinion: 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.

Trastuzumab with either docetaxel or vinorelbine as first-line treatment for patients with HER2-positive advanced breast cancer: a retrospective comparison.

BackgroundCombinations of trastuzumab with either docetaxel or vinorelbine are considered valuable treatment options for HER2-positive metastatic breast cancer patients. We performed a retrospective comparison of the clinical outcomes associated with either one of these combinations.MethodsFrom a multi-institutional database we retrieved 179 patients treated with either docetaxel or vinorelbine plus trastuzumab as first-line therapy for HER2-positive advanced breast cancer.ResultsDocetaxel-trastuzumab was superior to vinorelbine-trastuzumab in terms of response rate (RR: 77 vs 57%, p = 0.01) and median overall survival (OS: 35 vs 23 months, p = 0.04), but not in median time to progression (TTP: 12 vs 10 months, p = 0.53). At multivariate analysis, type of treatment was not associated with TTP but was an independent predictor of OS, with a significant reduction in the risk of death in favor of docetaxel-trastuzumab (HR 0.474, 95% IC 0,303-0.742, p < 0.01).ConclusionDocetaxel or vinorelbine, when combined with trastuzumab, provide excellent rates of tumor control in patients with previously untreated HER2-positive advanced breast cancer. Docetaxel may offer some advantage in terms of response rate and resulted in a significantly prolonged overall survival, which, because of the retrospective design of our study, deserves further investigation in prospective trials.

Clinical utility of exemestane in the treatment of breast cancer.

Breast cancer is the most prevalent cancer in women, causing a significant mortality worldwide. Different endocrine strategies are available for the treatment of hormone-sensitive breast cancer, including antiestrogen tamoxifen and fulvestrant, as well as third-generation aromatase inhibitors (AIs), such as letrozole, anastrozole, and exemestane. In this review, we will focus on exemestane, its clinical use, and its side effects. Exemestane is a steroidal third-generation AI now used in all treatment settings for breast cancer. In the metastatic disease, it has been extensively investigated as the first-, second-, and further-line treatment and it is now registered for the treatment of postmenopausal women with advanced estrogen-receptor-positive breast cancer whose disease has progressed following antiestrogen therapy. A potential lack of cross-resistance with nonsteroidal AIs has been described, giving additional therapeutic opportunities in sequences of endocrine agents. Exemestane is also approved for the adjuvant treatment of postmenopausal early breast cancer, either as upfront monotherapy for 5 years, as a switch following 2–3 years of tamoxifen, or as extended therapy beyond 5 years of adjuvant treatment. New promising data also showed a beneficial effect in young premenopausal early breast cancer patients, when administered together with ovarian suppression. Interesting results have also emerged when exemestane has been investigated as neodjuvant treatment as well as preventive agent in healthy women at high risk for breast cancer. Exemestane is generally well tolerated, with a side effect profile similar to that of other AIs, including menopausal symptoms, arthralgia, and bone loss. In conclusion, exemestane can be considered an effective and well-tolerated endocrine treatment option for all stages of breast cancer.

Current status and future perspectives in the endocrine treatment of postmenopausal, hormone receptor-positive metastatic breast cancer.

Introduction: Endocrine therapy is a fundamental component of the therapeutic repertoire for treatment of metastatic, hormone receptor-positive breast cancer. Inevitably, however, tumors develop resistance to these compounds, and overcoming this phenomenon is a key motivator of research in this field. Areas covered: This review summarizes the current status of endocrine therapy for the treatment of metastatic disease, with a main focus on postmenopausal patients. Furthermore, strategies that could potentially sustain endocrine resistance and future perspectives in this direction are also to be described. Relevant references were identified by PubMed searches and from the abstract books of the annual meetings of The European Society of Clinical Oncology (ESMO), The American Society of Clinical Oncology (ASCO) and from the San Antonio Breast Cancer Symposia. Expert opinion: Combinations of endocrine therapy with HER2 targeting agents, as well as with compounds that can interfere with PI3K/Akt/mTOR signaling, are two promising strategies for delaying or overcoming endocrine resistance, mediated by these relevant biological pathways. Due to increased costs and the burden of toxicity associated with these combination therapies, compared to endocrine therapy alone, it is imperative to concentrate efforts on establishing biomarkers that can predict efficacy.

Underuse of Anthracyclines in Women with HER-2+ Advanced Breast Cancer

This article examines how discouraging the use of anthracyclines in combination with trastuzumab in patients with human epidermal growth factor receptor 2 positive metastatic breast cancer because of fears of cardiotoxicity has influenced the use of these agents in this patient setting.

New and developing chemical pharmacotherapy for treating hormone receptor-positive/HER2-negative breast cancer

ABSTRACT Introduction: Endocrine therapy is the mainstay of treatment for a substantial proportion of hormone receptor positive (HR+) breast cancer (BC). Indeed, patients with metastatic disease not immediately life threatening may experience long disease control across several lines of endocrine therapy. The major limitation of this therapeutic approach is primary or acquired resistance. A better understanding of endocrine resistance has resulted in newer targeted agents to be added to endocrine therapy. Areas covered: This review highlights new findings in the treatment of HR+/HER2- BC, with a particular focus on new drugs from phase 3 development onwards. Expert opinion: Combining endocrine therapy with agents targeting putative mechanisms of endocrine resistance is a newer treatment paradigm in HR+ BC. Adding a biologically targeted agent to endocrine therapy results in improved response rate, and clinical benefit rate, and prolonged progression-free survival. A clear advantage in overall survival has not yet been reported. Combination therapy allows to delay chemotherapy but increases toxicities and costs, which are critical factors in decision making in the clinical practice. Moreover, identification and validation of biomarkers of response are needed. Ongoing and future trials should elucidate the role of these compounds in the treatment of HR+/HER2- BC.

Linifanib: current status and future potential in cancer therapy.

Angiogenesis is one of the major mechanisms controlling tumor proliferation and metastatic spreading. Targeting of pro-angiogenic factors and their downstream effectors represents an appealing therapeutic option in the treatment of different cancer types. Linifanib (ABT-869) is a novel tyrosine-kinase inhibitor (TKI) inhibitor and its anti-angiogenic activity has been explored in numerous clinical trials. Here, we review preclinical development of linifanib focusing on its pharmacodynamic and pharmacokinetic characteristics and briefly summarize its evaluation in clinical trials. Linifanib selectively targets VEGFR and PDGFR and has low off-target inhibitory activity. Preclinical and early-phase trials have been showing promising efficacy results However, although signals of anti-tumor activity have been proven in some malignancies, linifanib late-phase development has been facing some challenges due to limited efficacy and increased toxicities. New strategies aimed at finding biomarkers of response and minimizing toxicities are needed to allow the further development of a promising compound.