Joyce O'Shaughnessy M.D.

Martin, M., A. Chan, L. Dirix, J. O’Shaughnessy, R. Hegg, A. Manikhas, M. Shtivelband, P. Krivorotko, N. Batista Lopez, M. Campone, M. Ruiz Borrego, Q. J. Khan, J. T. Beck, M. Ramos Vazquez, P. Urban, S. Goteti, E. Di Tomaso, C. Massacesi and S. Delaloge (2016). “A randomized adaptive phase ii/iii study of buparlisib, a pan-class i pi3k inhibitor, combined with paclitaxel for the treatment of her2- advanced breast cancer (belle-4).” Ann Oncol: 2016 Nov [Epub ahead of print].

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BACKGROUND: Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models. PATIENTS AND METHODS: BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after >/=125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility. RESULTS: As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 vs 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 vs 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (>/=40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia. CONCLUSIONS: Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II.

Habib, J. G. and J. A. O’Shaughnessy (2016). “The hedgehog pathway in triple-negative breast cancer.” Cancer Med: 2016 Aug [Epub ahead of print].

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Treatment of triple-negative breast cancer (TNBC) remains challenging due to the underlying heterogeneity of this disease coupled with the lack of predictive biomarkers and effective targeted therapies. Intratumoral heterogeneity, particularly enrichment for breast cancer stem cell-like subpopulations, has emerged as a leading hypothesis for systemic therapy resistance and clinically aggressive course of poor prognosis TNBC. A growing body of literature supports the role of the stem cell renewal Hedgehog (Hh) pathway in breast cancer. Emerging preclinical data also implicate Hh signaling in TNBC pathogenesis. Herein, we review the evidence for a pathophysiologic role of Hh signaling in TNBC and explore mechanisms of crosstalk between the Hh pathway and other key signaling networks as well as their potential implications for Hh-targeted interventions in TNBC.

Cortes, J., H. S. Rugo, C. Twelves, A. Awada, E. A. Perez, S. A. Im, C. Zhao, U. Hoch, D. Tomkinson, J. Buchanan, M. Tagliaferri, A. Hannah and J. O’Shaughnessy (2016). “Safety and tolerability of etirinotecan pegol in advanced breast cancer: Analysis of the randomized, phase 3 beacon trial.” Springerplus 5(1): 1033.

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PURPOSE: New treatments with novel mechanisms of action and non-overlapping toxicities are needed for patients with metastatic breast cancer. Etirinotecan pegol (EP) is a long-acting topoisomerase-I inhibitor with a unique toxicity profile. The randomized phase 3 BEACON study that compared EP to treatment of physician’s choice (TPC) demonstrated its clinical activity. We now present detailed safety data from the BEACON trial. METHODS: Patients with locally recurrent or metastatic breast cancer who had received at least two prior cytotoxic regimens for advanced disease were randomized to EP or TPC. Prior treatment with an anthracycline, a taxane and capecitabine was required. The frequencies of treatment-emergent AEs (TEAEs) and serious TEAEs were evaluated for the safety population, comprising all patients who received at least one dose of assigned treatment. RESULTS: A total of 831 patients were evaluated (n = 425, EP; n = 406, TPC). Compared with TPC, EP was associated with a slightly higher median relative dose intensity (98.3 vs. 92.8 %, respectively) and significantly fewer grade >/=3 toxicities (48.0 vs. 63.1 %, P < 0.0001). The most commonly reported grade >/=3 toxicities in the EP arm were diarrhea (9.6 %) and neutropenia (9.6 %) and in the TPC arm, neutropenia (30.8 %). Median time to onset of grade >/=3 diarrhea was delayed with EP relative to TPC (43 vs. 7 days, respectively). CONCLUSIONS: The differentiated mechanism of action of EP resulted in a safety profile that is substantially distinguished from that of current widely used therapies for the treatment of women with advanced breast cancer.

Peterson, D. E., J. A. O’Shaughnessy, H. S. Rugo, S. Elad, M. M. Schubert, C. T. Viet, C. Campbell-Baird, J. Hronek, V. Seery, J. Divers, J. Glaspy, B. L. Schmidt and T. F. Meiller (2016). “Oral mucosal injury caused by mammalian target of rapamycin inhibitors: Emerging perspectives on pathobiology and impact on clinical practice.” Cancer Med 5(8): 1897-1907.

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In recent years oral mucosal injury has been increasingly recognized as an important toxicity associated with mammalian target of rapamycin (mTOR) inhibitors, including in patients with breast cancer who are receiving everolimus. This review addresses the state-of-the-science regarding mTOR inhibitor-associated stomatitis (mIAS), and delineates its clinical characteristics and management. Given the clinically impactful pain associated with mIAS, this review also specifically highlights new research focusing on the study of the molecular basis of pain. The incidence of mIAS varies widely (2-78%). As reported across multiple mTOR inhibitor clinical trials, grade 3/4 toxicity occurs in up to 9% of patients. Managing mTOR-associated oral lesions with topical oral, intralesional, and/or systemic steroids can be beneficial, in contrast to the lack of evidence supporting steroid treatment of oral mucositis caused by high-dose chemotherapy or radiation. However, steroid management is not uniformly efficacious in all patients receiving mTOR inhibitors. Furthermore, technology does not presently exist to permit clinicians to predict a priori which of their patients will develop these lesions. There thus remains a strategic need to define the pathobiology of mIAS, the molecular basis of pain, and risk prediction relative to development of the clinical lesion. This knowledge could lead to novel future interventions designed to more effectively prevent mIAS and improve pain management if clinically significant mIAS lesions develop.

Li, W., J. A. O’Shaughnessy, D. F. Hayes, M. Campone, I. Bondarenko, I. Zbarskaya, E. Brain, M. Stenina, O. Ivanova, M. P. Graas, P. Neven, D. S. Ricci, T. W. Griffin, T. Kheoh, M. K. Yu, M. Gormley, J. Martin, M. Schaffer, K. Zelinsky, P. De Porre and S. R. Johnston (2016). “Biomarker associations with efficacy of abiraterone acetate and exemestane in postmenopausal patients with estrogen receptor-positive metastatic breast cancer.” Clin Cancer Res: 2016 June [Epub ahead of print].

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PURPOSE: Abiraterone may suppress androgens that stimulate breast cancer growth. We conducted a biomarker analysis of circulating tumor cells (CTCs), formalin-fixed paraffin-embedded tissues (FFPETs), and serum samples from postmenopausal estrogen receptor (ER)+ breast cancer patients to identify subgroups with differential abiraterone sensitivity. METHODS: Patients (randomized 1:1:1) were treated with 1,000 mg/d abiraterone acetate + 5 mg/d prednisone (AA), AA + 25 mg/d exemestane (AAE), or exemestane. The biomarker population included treated patients (n = 293). The CTC population included patients with {greater than or equal to} 3 baseline CTCs (n = 104). Biomarker (e.g., androgen receptor [AR], ER, Ki-67, CYP17) expression was evaluated. Cox regression stratified by prior therapies in the metastatic setting (0/1 vs. 2) and setting of letrozole/anastrozole (adjuvant vs. metastatic) was used to assess biomarker associations with progression-free survival (PFS). RESULTS: Serum testosterone and estrogen levels were lowered and progesterone increased with AA. Baseline AR or ER expression was not associated with PFS in CTCs or FFPETs for AAE versus exemestane but dual positivity of AR and ER expression was associated with improved PFS (HR 0.41 [95% confidence interval (CI), 0.16-1.07], P = 0.070). For AR expression in FFPETs obtained < 1 year prior to first dose (n = 67), a trend for improved PFS was noted for AAE versus exemestane (HR 0.56 [95% CI, 0.24-1.33], P = 0.19). CONCLUSIONS: An AA pharmacodynamic effect was shown by decreased serum androgen and estrogen levels and increased progesterone. AR and ER dual expression in CTCs and newly obtained FFPETs may predict AA sensitivity.