Joyce O'Shaughnessy M.D.

Cobleigh, M., D. Yardley, A. M. Brufsky, H. S. Rugo, S. M. Swain, P. A. Kaufman, D. Tripathy, S. A. Hurvitz, J. O’Shaughnessy, G. Mason, V. Antao, H. Li, L. Chu and M. Jahanzeb (2019). “Baseline Characteristics, Treatment Patterns, and Outcomes in Patients with HER2-Positive Metastatic Breast Cancer by Hormone Receptor Status From SystHERs.” Clin Cancer Res Nov 26. [Epub ahead of print].

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BACKGROUND: We report treatments and outcomes in a contemporary patient population with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) by hormone receptor (HR) status from the Systemic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs). METHODS: SystHERs (NCT01615068) was an observational, prospective registry study of US-based patients with newly diagnosed HER2-positive MBC. Endpoints included treatment patterns and clinical outcomes. RESULTS: Of 977 eligible patients (enrolled from 2012-2016), 70.1% (n=685) had HR-positive and 29.9% (n=292) had HR-negative disease. Overall, 59.1% (405/685) of patients with HR-positive disease received any first-line endocrine therapy (with or without HER2-targeted therapy or chemotherapy); 34.9% (239/685) received HER2-targeted therapy + chemotherapy + sequential endocrine therapy. Patients with HR-positive versus HR-negative disease had longer median overall survival (OS; 53.0 vs. 43.4 months; hazard ratio 0.70, 95% confidence interval 0.56-0.87). Compared with patients with high HR-positive staining (10-100%, n=550), those with low HR-positive staining (1%-9%, n=60) received endocrine therapy less commonly (64.2% vs. 33.3%) and had shorter median OS (53.8 vs. 40.1 months). Similar median OS (43.4 vs. 40.1 months) was observed in patients with HR-negative versus low HR-positive tumors (1%-9%). CONCLUSIONS: Despite evidence that first-line HER2-targeted therapy, chemotherapy, and sequential endocrine therapy improves survival in patients with HR-positive, HER2-positive disease, only 34.9% of patients in this real-world setting received such treatment. Patients with low tumor HR positivity (1%-9%) had lower endocrine therapy use and worse survival than those with high tumor HR positivity (10%-100%).

Tan, A. R., G. S. Wright, A. R. Thummala, M. A. Danso, L. Popovic, T. J. Pluard, H. S. Han, Z. Vojnovic, N. Vasev, L. Ma, D. A. Richards, S. T. Wilks, D. Milenkovic, Z. Yang, J. M. Antal, S. R. Morris and J. O’Shaughnessy (2019). “Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial.” Lancet Oncology 20(11): 1587-1601.

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BACKGROUND: Trilaciclib is an intravenous cell-cycle inhibitor that transiently maintains immune cells and haemopoietic stem and progenitor cells in G1 arrest. By protecting the immune cells and bone marrow from chemotherapy-induced damage, trilaciclib has the potential to optimise antitumour activity while minimising myelotoxicity. We report safety and activity data for trilaciclib plus gemcitabine and carboplatin chemotherapy in patients with metastatic triple-negative breast cancer. METHODS: In this randomised, open-label, multicentre, phase 2 study, adult patients (aged >/=18 years) with evaluable, biopsy-confirmed, locally recurrent or metastatic triple-negative breast cancer who had no more than two previous lines of chemotherapy were recruited from 26 sites in the USA, three in Serbia, two in North Macedonia, one in Croatia, and one in Bulgaria; sites were academic and community hospitals. Availability of diagnostic samples of tumour tissue confirming triple-negative breast cancer was a prerequisite for enrolment. Eligible patients were randomly assigned (1:1:1) by an interactive web-response system, stratified by number of previous lines of systemic therapy and the presence of liver metastases, to receive intravenous gemcitabine 1000 mg/m(2) and intravenous carboplatin (area under the concentration-time curve 2 mug x h/mL) on days 1 and 8 (group 1), gemcitabine and carboplatin plus intravenous trilaciclib 240 mg/m(2) on days 1 and 8 (group 2), or gemcitabine and carboplatin on days 2 and 9 plus trilaciclib on days 1, 2, 8, and 9 (group 3) of 21-day cycles. Patients continued treatment until disease progression, unacceptable toxicity, withdrawal of consent, or discontinuation by the investigator. The primary objective was to assess the safety and tolerability of combining trilaciclib with gemcitabine and carboplatin chemotherapy. The primary endpoints were duration of severe neutropenia during cycle 1 and the occurrence of severe neutropenia during the treatment period. Overall survival was included as a key secondary endpoint. Analyses were in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with EudraCT, 2016-004466-26, and ClinicalTrials.gov, NCT02978716, and is ongoing but closed to accrual. FINDINGS: Between Feb 7, 2017, and May 15, 2018, 142 patients were assessed for eligibility and 102 were randomly assigned to group 1 (n=34), group 2 (n=33), or group 3 (n=35). Of all patients, 38 (37%) had received one or two lines of previous chemotherapy in the metastatic setting. Median follow-up was 8.4 months (IQR 3.8-13.6) for group 1, 12.7 months (5.5-17.4) for group 2, and 12.9 months (6.7-16.8) for group 3. Data cutoff for myelosuppression endpoints was July 30, 2018, and for antitumour activity endpoints was May 17, 2019. During cycle 1, mean duration of severe neutropenia was 0.8 day (SD 2.4) in group 1, 1.5 days (3.5) in group 2, and 1.0 day (2.6) in group 3 (group 3 vs group 1 one-sided adjusted p=0.70). Severe neutropenia occurred in nine (26%) of 34 patients in group 1, 12 (36%) of 33 patients in group 2, and eight (23%) of 35 patients in group 3 (p=0.70). Overall survival was 12.6 months (IQR 5.8-15.6) in group 1, 20.1 months (9.4-not reached) in group 2, and 17.8 months (8.8-not reached) in group 3 (group 3 vs group 1 two-sided p=0.0023). The most common treatment-emergent adverse events were anaemia (22 [73%] of 34), neutropenia (21 [70%]), and thrombocytopenia (18 [60%]) in group 1; neutropenia (27 [82%] of 33), thrombocytopenia (18 [55%]) and anaemia (17 [52%]) in group 2; and neutropenia (23 [66%] of 35), thrombocytopenia (22 [63%]), and nausea (17 [49%]) in group 3. There were no treatment-related deaths. INTERPRETATION: No significant differences were observed in myelosuppression endpoints with trilaciclib plus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer; however, the regimen was generally well tolerated and overall survival results were encouraging. Further studies of trilaciclib in this setting are warranted. FUNDING: G1 Therapeutics.

Paul, D., S. J. Vukelja, F. Ann Holmes, J. L. Blum, K. J. McIntyre, D. L. Lindquist, C. R. Osborne, I. J. Sanchez, J. H. Goldschmidt, Y. Wang, L. Asmar, L. Strauss and J. O’Shaughnessy (2019). “Randomized phase-II evaluation of letrozole plus dasatinib in hormone receptor positive metastatic breast cancer patients.” NPJ Breast Cancer Nov 5: 8(21). [Epub 2019 Oct 18].

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The non-receptor tyrosine kinase Src activation plays a role in the malignant progression of breast cancer, including development of endocrine therapy resistance and survival of bone metastases. This study investigated whether adding Src kinase inhibitor dasatinib to aromatase inhibitor (AI) therapy improved outcomes in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (MBC). Postmenopausal patients with ER-positive, HER2-negative MBC (0-1 prior chemotherapies and no prior AI for MBC) were eligible for this non-comparative, parallel group, phase-II study. Patients were randomized to letrozole (2.5 mg/day PO) alone or with dasatinib (100 mg/day PO). Patients with disease progression on letrozole alone could crossover to dasatinib plus continued letrozole. The primary endpoint was clinical-benefit-rate (CBR; complete response + partial response + stable disease >/=6 months). A total of 120 patients were randomized. The CBR of 71% (95% CI 58-83%) was observed with letrozole + dasatinib versus the projected CBR of the combination of 56%. The CBR of 66% (95% CI 52-77%) with letrozole alone also exceeded the projected CBR of 39% with letrozole alone. The CBR was 23% in the crossover arm of letrozole plus dasatinib in patients progressing on letrozole alone. Median progression-free survival with the combination was 20.1 months and 9.9 months with letrozole alone. Letrozole plus dasatinib was well tolerated, although 26% of patients required dasatinib dose reductions. In this non-comparative phase-II trial, the CBR of 71% and the median PFS of 20.1 months with letrozole + dasatinib are encouraging and suggest that dasatinib may inhibit the emergence of acquired resistance to AI therapy.

Tripathy, D., A. Brufsky, M. Cobleigh, M. Jahanzeb, P. A. Kaufman, G. Mason, J. O’Shaughnessy, H. S. Rugo, S. M. Swain, D. A. Yardley, L. Chu, H. Li, V. Antao and S. A. Hurvitz (2019). “De Novo Versus Recurrent HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from the SystHERs Registry.” Oncologist Oct 14. [Epub ahead of print].

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BACKGROUND: Limited data exist describing real-world treatment of de novo and recurrent HER2-positive metastatic breast cancer (MBC). MATERIALS AND METHODS: The Systemic Therapies for HER2-Positive Metastatic Breast Cancer Study (SystHERs) was a fully enrolled (2012-2016), observational, prospective registry of patients with HER2-positive MBC. Patients aged >/=18 years and less-than-or-equal-to 6 months from HER2-positive MBC diagnosis were treated and assessed per their physician’s standard practice. The primary endpoint was to characterize treatment patterns by de novo versus recurrent MBC status, compared descriptively. Secondary endpoints included patient characteristics, progression-free and overall survival (PFS and OS, by Kaplan-Meier method; hazard ratio [HR] and 95% confidence interval [CI] by Cox regression), and patient-reported outcomes. RESULTS: Among 977 eligible patients, 49.8% (n = 487) had de novo and 50.2% (n = 490) had recurrent disease. A higher proportion of de novo patients had hormone receptor-negative disease (34.9% vs. 24.9%), bone metastasis (57.1% vs. 45.9%), and/or liver metastasis (41.9% vs. 33.1%), and a lower proportion had central nervous system metastasis (4.3% vs. 13.5%). De novo patients received first-line regimens containing chemotherapy (89.7%), trastuzumab (95.7%), and pertuzumab (77.8%) more commonly than recurrent patients (80.0%, 85.9%, and 68.6%, respectively). De novo patients had longer median PFS (17.7 vs. 11.9 months; HR, 0.69; 95% CI, 0.59-0.80; p < .0001) and OS (not estimable vs. 44.5 months; HR, 0.55; 95% CI, 0.44-0.69; p < .0001). CONCLUSION: Patients with de novo versus recurrent HER2-positive MBC exhibit different disease characteristics and survival durations, suggesting these groups have distinct outcomes. These differences may affect future clinical trial design. Clinical trial identification number. NCT01615068 (clinicaltrials.gov). IMPLICATIONS FOR PRACTICE: SystHERs was an observational registry of patients with HER2-positive metastatic breast cancer (MBC), which is a large, modern, real-world data set for this population and, thereby, provides a unique opportunity to study patients with de novo and recurrent HER2-positive MBC. In SystHERs, patients with de novo disease had different baseline demographics and disease characteristics, had superior clinical outcomes, and more commonly received first-line chemotherapy and/or trastuzumab versus those with recurrent disease. Data from this and other studies suggest that de novo and recurrent MBC have distinct outcomes, which may have implications for disease management strategies and future clinical study design.

Hasan, M. M., L. Thompson-Snipes, G. Klintmalm, A. J. Demetris, J. O’Leary, S. Oh and H. Joo (2019). “CD24(hi)CD38(hi) and CD24(hi)CD27(+) Human Regulatory B Cells Display Common and Distinct Functional Characteristics.” J Immunol 203(8): 2110-2120.

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Although IL-10-producing regulatory B cells (Bregs) play important roles in immune regulation, their surface phenotypes and functional characteristics have not been fully investigated. In this study, we report that the frequency of IL-10-producing Bregs in human peripheral blood, spleens, and tonsils is similar, but they display heterogenous surface phenotypes. Nonetheless, CD24(hi)CD38(hi) transitional B cells (TBs) and CD24(hi)CD27(+) B cells (human equivalent of murine B10 cells) are the major IL-10-producing B cells. They both suppress CD4(+) T cell proliferation as well as IFN-gamma/IL-17 expression. However, CD24(hi)CD27(+) B cells were more efficient than TBs at suppressing CD4(+) T cell proliferation and IFN-gamma/IL-17 expression, whereas they both coexpress IL-10 and TNF-alpha. TGF-beta1 and granzyme B expression were also enriched within CD24(hi)CD27(+) B cells, when compared with TBs. Additionally, CD24(hi)CD27(+) B cells expressed increased levels of surface integrins (CD11a, CD11b, alpha1, alpha4, and beta1) and CD39 (an ecto-ATPase), suggesting that the in vivo mechanisms of action of the two Breg subsets are not the same. Lastly, we also report that liver allograft recipients with plasma cell hepatitis had significant decreases of both Breg subsets.