Joyce O'Shaughnessy M.D.

Wu, T. C., K. Xu, J. Martinek, R. R. Young, R. Banchereau, J. George, J. Turner, K. I. Kim, S. Zurawski, X. Wang, D. Blankenship, H. M. Brookes, F. Marches, G. Obermoser, E. Lavecchio, M. K. Levin, S. Bae, C. H. Chung, J. L. Smith, A. M. Cepika, K. L. Oxley, G. J. Snipes, J. Banchereau, V. Pascual, J. O’Shaughnessy and K. Palucka (2018). “IL-1 receptor antagonist controls transcriptional signature of inflammation in patients with metastatic breast cancer.” Cancer Res Jul 16. [Epub ahead of print].

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Inflammation affects tumor immune surveillance and resistance to therapy. However, no approved treatments aimed at decreasing chronic tumor-associated inflammation are available, largely due to incomplete understanding of pathogenesis. Here we show that production of interleukin (IL)-1beta in primary breast cancer (BC) tumors is linked to advanced disease and originates from tumor-infiltrating CD11c+ myeloid cells. IL-1beta production was triggered by cancer cell membrane-derived TGF-beta, and neutralizing TGF-beta or IL-1 receptor prevented BC progression in a humanized mouse model. Patients with metastatic HER2-negative BC displayed a transcriptional signature of inflammation in the blood leukocytes, which was attenuated by IL-1 blockade. When present in primary BC tumors, this signature discriminated patients with poor clinical outcomes in two independent public datasets (TCGA and METABRIC).

Health-related quality of life of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated with ribociclib + letrozole: results from MONALEESA-2.

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PURPOSE: Evaluate patient-reported outcomes (PROs) for postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer treated with first-line ribociclib plus letrozole. METHODS: In the phase III MONALEESA-2 study (NCT01958021), 668 patients were randomized 1:1 to ribociclib (600 mg/day; 3-weeks-on/1-week-off) plus letrozole (2.5 mg/day) or placebo plus letrozole. PROs were assessed using the European Organisation for Research and Treatment of Cancer core quality-of-life (EORTC QLQ-C30) and breast cancer-specific (EORTC QLQ-BR23) questionnaires. Changes from baseline and time to deterioration in health-related quality of life (HRQoL) were analyzed using linear mixed-effect and stratified Cox regression models, respectively. Exploratory analysis of area-under-the-curve for change from baseline in pain score (AUC-pain) was performed. RESULTS: On-treatment HRQoL scores were consistently maintained from baseline and were similar between arms. A clinically meaningful (> 5 points) reduction in pain score was observed as early as Week 8 and was maintained up to Cycle 15 in the ribociclib arm. A statistically significant increase in mean AUC-pain was also observed in the ribociclib arm. Scores for all other EORTC QLQ-C30 and EORTC QLQ-BR23 domains were maintained from baseline and were similar between arms. CONCLUSIONS: HRQoL was consistently maintained from baseline in postmenopausal women with HR+, HER2- advanced breast cancer receiving ribociclib plus letrozole and was similar to that observed in the placebo plus letrozole arm. Together with the improved clinical efficacy and manageable safety profile, these PRO results provide additional support for the benefit of ribociclib plus letrozole in this patient population.

O’Shaughnessy, J., A. DeMichele, C. X. Ma, P. Richards, D. A. Yardley, G. S. Wright, K. Kalinsky, R. Steis, S. Diab, G. Kennealey, R. Geschwindt, W. Jiang and H. S. Rugo (2018). “A randomized, double-blind, phase 2 study of ruxolitinib or placebo in combination with capecitabine in patients with advanced HER2-negative breast cancer and elevated C-reactive protein, a marker of systemic inflammation.” Breast Cancer Res Treat 170(3): 547-557.

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PURPOSE: The Janus-associated kinase (JAK)/signal transducer and activator of transcription pathway is a key regulator of inflammatory signaling, associated with tumorigenesis, cell survival, and progression. This randomized phase 2 trial evaluated the efficacy and safety of the addition of ruxolitinib, a JAK1/JAK2 inhibitor, to capecitabine in patients with HER2-negative advanced breast cancer and high systemic inflammation (modified Glasgow Prognostic Score [mGPS] >/= 1). METHODS: Patients with 2 or fewer prior chemotherapy regimens for advanced or metastatic disease or hormone receptor-positive patients with disease progression on prior hormonal therapies were randomized 1:1 to 21-day cycles of ruxolitinib (n = 76) or placebo (n = 73) plus capecitabine. The primary endpoint was overall survival (OS). RESULTS: Baseline characteristics were well balanced between groups. For ruxolitinib plus capecitabine versus placebo plus capecitabine, median OS was 11.2 months versus 10.9 months (log-rank test P = 0.762); median progression-free survival (PFS) was 4.5 months versus 2.5 months (log-rank test P = 0.151); and overall response rate (ORR) was 28.9% versus 13.7% (Cochran-Mantel-Haenszel test P = 0.024), respectively. A more favorable change in health-related quality of life (HRQoL) was observed with ruxolitinib plus capecitabine versus placebo plus capecitabine. Both regimens were generally tolerable. A higher incidence of grade 3/4 anemia (25.4% vs 5.6%) and a lower incidence of grade 3/4 palmar-plantar erythrodysesthesia (1.4% vs 12.7%) occurred with ruxolitinib plus capecitabine versus placebo plus capecitabine. CONCLUSIONS: The addition of ruxolitinib to capecitabine for patients with advanced breast cancer and high systemic inflammation was generally tolerable; ORR was numerically greater, a more favorable change in HRQoL was observed, but neither OS nor PFS was improved compared with placebo plus capecitabine.

Rugo, H. S., J. Cortes, A. Awada, J. O’Shaughnessy, C. Twelves, S. A. Im, A. Hannah, L. Lu, S. Sy, K. Caygill, D. A. Zajchowski, D. W. Davis, M. Tagliaferri, U. Hoch and E. A. Perez (2018). “Change in Topoisomerase 1-Positive Circulating Tumor Cells Affects Overall Survival in Patients with Advanced Breast Cancer after Treatment with Etirinotecan Pegol.” Clin Cancer Res 24(14): 3348-3357.

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APurpose: Preplanned exploratory analyses were performed to identify biomarkers in circulating tumor cells (CTC) predictive of response to the topoisomerase 1 inhibitor etirinotecan pegol (EP).Experimental Design: The BEACON trial treated patients with metastatic breast cancer (MBC) with EP or treatment of physician’s choice (TPC). Blood from 656 of 852 patients (77%) was processed with ApoStream to enrich for CTCs. A multiplex immunofluorescence assay measured expression of candidate response biomarkers [topoisomerase 1 (Top1), topoisomerase 2 (Top2), Ki67, RAD51, ABCG2, gammaH2AX, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)] in CTCs. Patients were classified as Top1 low (Top1Lo) or Top1 high (Top1Hi) based on median CTC Top1 expression. Correlation of CTC biomarker expression at baseline, cycle 2 day 1 (C2D1), and cycle 4 day 1 with overall survival (OS) was investigated using Cox regression and Kaplan-Meier analyses.Results: Overall, 98% of samples were successfully processed, of which 97% had detectable CTCs (median, 47-63 CTCs/mL; range, 0-2,020 CTCs/mL). Top1, Top2, and TUNEL expression was detected in 52% to 90% of samples; no significant associations with OS were observed in pretreatment samples for either group. EP-treated patients with low C2D1Top1(+) CTCs had improved OS compared with those with higher positivity (14.1 months vs. 11.0 months, respectively; HR, 0.7; P = 0.02); this difference was not seen in TPC-treated patients (HR, 1.12; P = 0.48). Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS benefit from EP (HR, 0.57; P = 0.01).Conclusions: CTC Top1 expression following EP treatment may identify patients with MBC most likely to have an OS benefit. Clin Cancer Res; 24(14); 3348-57. (c)2018 AACR.

Verma, S., J. O’Shaughnessy, H. A. Burris, M. Campone, E. Alba, D. Chandiwana, A. A. Dalal, S. Sutradhar, M. Monaco and W. Janni (2018). “Health-related quality of life of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated with ribociclib + letrozole: results from MONALEESA-2.” Breast Cancer Res Treat. Apr 13. [Epub ahead of print].

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PURPOSE: Evaluate patient-reported outcomes (PROs) for postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer treated with first-line ribociclib plus letrozole. METHODS: In the phase III MONALEESA-2 study (NCT01958021), 668 patients were randomized 1:1 to ribociclib (600 mg/day; 3-weeks-on/1-week-off) plus letrozole (2.5 mg/day) or placebo plus letrozole. PROs were assessed using the European Organisation for Research and Treatment of Cancer core quality-of-life (EORTC QLQ-C30) and breast cancer-specific (EORTC QLQ-BR23) questionnaires. Changes from baseline and time to deterioration in health-related quality of life (HRQoL) were analyzed using linear mixed-effect and stratified Cox regression models, respectively. Exploratory analysis of area-under-the-curve for change from baseline in pain score (AUC-pain) was performed. RESULTS: On-treatment HRQoL scores were consistently maintained from baseline and were similar between arms. A clinically meaningful (> 5 points) reduction in pain score was observed as early as Week 8 and was maintained up to Cycle 15 in the ribociclib arm. A statistically significant increase in mean AUC-pain was also observed in the ribociclib arm. Scores for all other EORTC QLQ-C30 and EORTC QLQ-BR23 domains were maintained from baseline and were similar between arms. CONCLUSIONS: HRQoL was consistently maintained from baseline in postmenopausal women with HR+, HER2- advanced breast cancer receiving ribociclib plus letrozole and was similar to that observed in the placebo plus letrozole arm. Together with the improved clinical efficacy and manageable safety profile, these PRO results provide additional support for the benefit of ribociclib plus letrozole in this patient population.