Joyce O'Shaughnessy M.D.

Miles, D., D. Cameron, M. Hilton, J. Garcia and J. O’Shaughnessy (2017). “Overall survival in meridian, a double-blind placebo-controlled randomised phase iii trial evaluating first-line bevacizumab plus paclitaxel for her2-negative metastatic breast cancer.” Eur J Cancer: 2017 Nov [Epub ahead of print].

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The MERiDiAN trial was designed to investigate prospectively plasma VEGF-A as a potential predictive biomarker for bevacizumab effect on investigator-assessed PFS in HER2-negative mBC. The co-primary objectives were met: bevacizumab significantly improved PFS in both the ITT population (stratified hazard ratio [HR] 0.68, 99% confidence interval [CI]: 0.51–0.91; log-rank p = 0.0007) and the VEGF-Ahigh population (stratified HR 0.64, 96% CI: 0.47–0.88; log-rank p = 0.0038). However, results did not support the use of baseline plasma VEGF-A level to identify the patients benefitting most from bevacizumab.

O’Shaughnessy, J., K. Petrakova, G. S. Sonke, P. Conte, C. L. Arteaga, D. A. Cameron, L. L. Hart, C. Villanueva, E. Jakobsen, J. T. Beck, D. Lindquist, F. Souami, S. Mondal, C. Germa and G. N. Hortobagyi (2017). “Ribociclib plus letrozole versus letrozole alone in patients with de novo hr+, her2- advanced breast cancer in the randomized monaleesa-2 trial.” Breast Cancer Res Treat: 2017 Nov [Epub ahead of print].

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PURPOSE: Determine the efficacy and safety of first-line ribociclib plus letrozole in patients with de novo advanced breast cancer. METHODS: Postmenopausal women with HR+ , HER2- advanced breast cancer and no prior systemic therapy for advanced disease were enrolled in the Phase III MONALEESA-2 trial (NCT01958021). Patients were randomized to ribociclib (600 mg/day; 3 weeks-on/1 week-off) plus letrozole (2.5 mg/day; continuous) or placebo plus letrozole until disease progression, unacceptable toxicity, death, or treatment discontinuation. The primary endpoint was investigator-assessed progression-free survival; predefined subgroup analysis evaluated progression-free survival in patients with de novo advanced breast cancer. Secondary endpoints included safety and overall response rate. RESULTS: Six hundred and sixty-eight patients were enrolled, of whom 227 patients (34%; ribociclib plus letrozole vs placebo plus letrozole arm: n = 114 vs. n = 113) presented with de novo advanced breast cancer. Median progression-free survival was not reached in the ribociclib plus letrozole arm versus 16.4 months in the placebo plus letrozole arm in patients with de novo advanced breast cancer (hazard ratio 0.45, 95% confidence interval 0.27-0.75). The most common Grade 3/4 adverse events were neutropenia and leukopenia; incidence rates were similar to those observed in the full MONALEESA-2 population. Ribociclib dose interruptions and reductions in patients with de novo disease occurred at similar frequencies to the overall study population. CONCLUSIONS: Ribociclib plus letrozole improved progression-free survival vs placebo plus letrozole and was well tolerated in postmenopausal women with HR+, HER2- de novo advanced breast cancer.

Blum, J. L., P. J. Flynn, G. Yothers, L. Asmar, C. E. Geyer, Jr., S. A. Jacobs, N. J. Robert, J. O. Hopkins, J. A. O’Shaughnessy, C. T. Dang, H. L. Gomez, L. Fehrenbacher, S. J. Vukelja, A. P. Lyss, D. Paul, A. M. Brufsky, J. H. Jeong, L. H. Colangelo, S. M. Swain, E. P. Mamounas, S. E. Jones and N. Wolmark (2017). “Anthracyclines in early breast cancer: The abc trials-usor 06-090, nsabp b-46-i/usor 07132, and nsabp b-49 (nrg oncology).” J Clin Oncol 35(23): 2647-2655.

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Purpose Docetaxel and cyclophosphamide (TC) was superior to doxorubicin and cyclophosphamide (AC) in a trial in early breast cancer. However, activity of TC relative to AC regimens with a taxane (TaxAC) is unknown. Methods In a series of three adjuvant trials, women were randomly assigned to TC for six cycles (TC6) or to a standard TaxAC regimen. US Oncology Research (USOR) 06-090 compared TC6 with docetaxel, doxorubicin, and cyclophosphamide (TAC6). National Surgical Adjuvant Breast and Bowel Project (NSABP) B-46-I/USOR 07132 compared TC6, TAC6, or TC6 plus bevacizumab. NSABP B-49 compared TC6 with several standard AC and taxane combination regimens. Before any analysis of individual trials, a joint efficacy analysis of TC versus the TaxAC regimens was planned, with invasive disease-free survival (IDFS) as the primary end point. Patients who received TC6 plus bevacizumab on NSABP B-46-I/USOR 07132 were not included. A hazard ratio (HR) from a stratified Cox model that exceeded 1.18 for TC6 versus TaxAC was predefined as inferiority for TC6. The prespecified interim monitoring plan was to report for futility if the HR was > 1.18 when 334 IDFS events were observed (50% of 668 events required for definitive analysis). Results A total of 2,125 patients were randomly assigned to receive TC6 regimens and 2,117 patients were randomly assigned to receive TaxAC regimens. The median follow-up time was 3.3 years. There were 334 IDFS events, and the HR for TC6 versus TaxAC was 1.202 (95% CI, 0.97 to 1.49), which triggered early reporting for futility. The 4-year IDFS was 88.2% for TC6 and was 90.7% for TaxAC ( P = .04). Tests for treatment interaction by protocol, hormone receptor status, and nodal status were negative. Conclusion The TaxAC regimens improved IDFS in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer compared with the TC6 regimen.

Pierobon, M., C. Ramos, S. Wong, K. A. Hodge, J. Aldrich, S. Byron, S. P. Anthony, N. J. Robert, D. W. Northfelt, M. Jahanzeb, L. Vocila, J. Wulfkuhle, G. Gambara, R. I. Gallagher, B. Dunetz, N. Hoke, T. Dong, D. W. Craig, M. Cristofanilli, B. Leyland-Jones, L. A. Liotta, J. A. O’Shaughnessy, J. D. Carpten and E. F. Petricoin (2017). “Enrichment of pi3k-akt-mtor pathway activation in hepatic metastases from breast cancer.” Clin Cancer Res 23(16): 4919-4928.

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Purpose: Little is known about the molecular signatures associated with specific metastatic sites in breast cancer. Using comprehensive multi-omic molecular profiling, we assessed whether alterations or activation of the PI3K-AKT-mTOR pathway is associated with specific sites of breast cancer metastasis.Experimental Design: Next-generation sequencing-based whole-exome sequencing was coupled with reverse-phase protein microarray (RPPA) functional signaling network analysis to explore the PI3K-AKT-mTOR axis in 32 pretreated breast cancer metastases. RPPA-based signaling data were further validated in an independent cohort of 154 metastatic lesions from breast cancer and 101 unmatched primary breast tumors. The proportion of cases with PI3K-AKT-mTOR genomic alterations or signaling network activation were compared between hepatic and nonhepatic lesions.Results:PIK3CA mutation and activation of AKT (S473) and p70S6K (T389) were detected more frequently among liver metastases than nonhepatic lesions (P < 0.01, P = 0.056, and P = 0.053, respectively). However, PIK3CA mutations alone were insufficient in predicting protein activation (P = 0.32 and P = 0.19 for activated AKT and p70S6K, respectively). RPPA analysis of an independent cohort of 154 tumors confirmed the relationship between pathway activation and hepatic metastasis [AKT (S473), mTOR (S2448), and 4EBP1 (S65); P < 0.01, P = 0.02, and P = 0.01, respectively]. Similar results were also seen between liver metastases and primary breast tumors [AKT (S473) P < 0.01, mTOR (S2448) P < 0.01, 4EBP1 (S65) P = 0.01]. This signature was lost when primary tumors were compared with all metastatic sites combined.Conclusions: Breast cancer patients with liver metastasis may represent a molecularly homogenized cohort with increased incidence of PIK3CA mutations and activation of the PI3K-AKT-mTOR signaling network.

Dickler, M. N., S. M. Tolaney, H. S. Rugo, J. Cortes, V. Dieras, D. Patt, H. Wildiers, C. A. Hudis, J. O’Shaughnessy, E. Zamora, D. A. Yardley, M. Frenzel, A. Koustenis and J. Baselga (2017). “Monarch 1, a phase ii study of abemaciclib, a cdk4 and cdk6 inhibitor, as a single agent, in patients with refractory hr+/her2- metastatic breast cancer.” Clin Cancer Res 23(17): 5218-5224.

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Purpose: The phase II MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone receptor-positive (HR+), HER2- metastatic breast cancer (MBC).Experimental Design: MONARCH 1 was a phase II single-arm open-label study. Women with HR+/HER2- MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible. Abemaciclib 200 mg was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity. The primary objective of MONARCH 1 was investigator-assessed objective response rate (ORR). Other endpoints included clinical benefit rate, progression-free survival (PFS), and overall survival (OS).Results: Patients (n = 132) had a median of 3 (range, 1-8) lines of prior systemic therapy in the metastatic setting, 90.2% had visceral disease, and 50.8% had >/=3 metastatic sites. At the 12-month final analysis, the primary objective of confirmed objective response rate was 19.7% (95% CI, 13.3-27.5; 15% not excluded); clinical benefit rate (CR+PR+SD>/=6 months) was 42.4%, median progression-free survival was 6.0 months, and median overall survival was 17.7 months. The most common treatment-emergent AEs of any grade were diarrhea, fatigue, and nausea; discontinuations due to AEs were infrequent (7.6%).Conclusions: In this poor-prognosis, heavily pretreated population with refractory HR+/HER2- metastatic breast cancer, continuous dosing of single-agent abemaciciclib was well tolerated and exhibited promising clinical activity.