Excellence in Science

21-gene assay to inform chemotherapy benefit in node-positive breast cancer

Background

The recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary lymph-node–negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear.

Methods

In a prospective trial, we randomly assigned women with hormone-receptor–positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease–free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse–free survival.

Results

A total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease–free survival differed according to menopausal status (P=0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease–free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer [breast cancer or another type], or death, 1.02; 95% confidence interval [CI], 0.82 to 1.26; P=0.89). Among premenopausal women, invasive disease–free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P=0.002), with a similar increase in distant relapse–free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P=0.009). The relative chemotherapy benefit did not increase as the recurrence score increased.

Conclusions

Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease–free survival and distant relapse–free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037. opens in new tab.)

Kevin Kalinsky, William E. Barlow, Julie R. Gralow, Funda Meric-Bernstam, Kathy S. Albain, Daniel F. Hayes, Nancy U. Lin, Edith A. Perez, Lori J. Goldstein, Stephen K.L. Chia, Sukhbinder Dhesy-Thind, Priya Rastogi, Emilio Alba, Suzette Delaloge, Miguel Martin, Catherine M. Kelly, Manuel Ruiz-Borrego, Miguel Gil-Gil, Claudia H. Arce-Salinas, Etienne G.C. Brain Eun Sook Lee, Jean Yves Pierga, Begoña Bermejo, Manuel Ramos-Vazquez, Kyung Hae Jung, Jean Marc Ferrero, Anne F. Schott, Steven Shak, Priyanka Sharma, Danika L. Lew, Jieling Miao, Debasish Tripathy, Lajos Pusztai, Gabriel N. Hortobagyi

Read more in The New England Journal of Medicine

NEAT1 is essential for metabolic changes that promote breast cancer growth and metastasis

Accelerated glycolysis is the main metabolic change observed in cancer, but the underlying molecular mechanisms and their role in cancer progression remain poorly understood. Here, we show that the deletion of the long noncoding RNA (ln-cRNA) Neat1 in MMTV-PyVT mice profoundly impairs tumor initiation, growth, and metastasis, specifically switching off the penultimate step of glycolysis. Mechanistically, NEAT1 directly binds and forms a scaffold bridge for the assembly of PGK1/PGAM1/ENO1 complexes and thereby promotes substrate channeling for high and efficient glycolysis. Notably, NEAT1 is upregulated in cancer patients and correlates with high levels of these complexes, and genetic and pharmacological blockade of penultimate glycolysis ablates NEAT1-dependent tumorigenesis. Finally, we demonstrate that Pinin mediates glucose-stimulated nuclear export of NEAT1, through which it exerts isoform-specific and paraspeckle-independent functions. These findings establish a direct role for NEAT1 in regulating tumor metabolism, provide new insights into the Warburg effect, and identify potential targets for therapy.

Mi Kyung Park, Li Zhang, Kyung Won Min, Jung Hyun Cho, Chih Chen Yeh, Hyesu Moon, Daniel Hormaechea-Agulla, Hyejin Mun, Seungbeom Ko, Ji Won Lee, Sonali Jathar, Aubrey S. Smith, Yixin Yao, Nguyen Thu Giang, Hong Ha Vu, Victoria C. Yan, Mary C. Bridges, Antonis Kourtidis, Florian Muller, Jeong Ho Chang, Su Jung Song, Shinichi Nakagawa, Tetsuro Hirose, Je Hyun Yoon, Min Sup Song

Read more in Cell Metabolism

Axicabtagene ciloleucel as second-line therapy for large b-cell lymphoma

Background

The prognosis of patients with early relapsed or refractory large B-cell lymphoma after the receipt of first-line chemoimmunotherapy is poor.

Methods

In this international, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with large B-cell lymphoma that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy to receive axicabta-gene ciloleucel (axi-cel, an autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy). The primary end point was event-free survival accord-ing to blinded central review. Key secondary end points were response and overall survival. Safety was also assessed.

Results

A total of 180 patients were randomly assigned to receive axi-cel and 179 to receive standard care. The primary end-point analysis of event-free survival showed that axi-cel therapy was superior to standard care. At a median follow-up of 24.9 months, the median event-free survival was 8.3 months in the axi-cel group and 2.0 months in the standard-care group, and the 24-month event-free survival was 41% and 16%, respectively (hazard ratio for event or death, 0.40; 95% confidence interval, 0.31 to 0.51; P<0.001). A response occurred in 83% of the patients in the axi-cel group and in 50% of those in the standard-care group (with a complete response in 65% and 32%, respectively). In an interim analysis, the estimated overall survival at 2 years was 61% in the axi-cel group and 52% in the standard-care group. Adverse events of grade 3 or higher occurred in 91% of the patients who received axi-cel and in 83% of those who received standard care. Among patients who received axi-cel, grade 3 or higher cytokine release syndrome occurred in 6% and grade 3 or higher neurologic events in 21%. No deaths related to cytokine release syn-drome or neurologic events occurred.

Conclusions

Axi-cel therapy led to significant improvements, as compared with standard care, in event-free survival and response, with the expected level of high-grade toxic effects.

Frederick L. Locke, M.D., David B. Miklos, M.D., Ph.D., Caron A. Jacobson, M.D., Miguel-Angel Perales, M.D., Marie-José Kersten, M.D., Ph.D., Olalekan O. Oluwole, M.B., B.S., M.D., Armin Ghobadi, M.D., Aaron P. Rapoport, M.D., Joseph McGuirk, D.O., John M. Pagel, M.D., Ph.D., Javier Muñoz, M.D., Umar Farooq, M.D., Tom van Meerten, M.D., Ph.D., Patrick M. Reagan, M.D., Anna Sureda, M.D., Ph.D., Ian W. Flinn, M.D., Ph.D., Peter Vandenberghe, M.D., Ph.D., Kevin W. Song, M.D., Michael Dickinson, M.B., B.S., D.Med.Sci., Monique C. Minnema, M.D., Ph.D., Peter A. Riedell, M.D., Lori A. Leslie, M.D., Sridhar Chaganti, M.D., Yin Yang, M.D., Simone Filosto, Ph.D., Jina Shah, M.D., Marco Schupp, M.D., Christina To, M.D., Paul Cheng, M.D., Ph.D., Leo I. Gordon, M.D., and Jason R. Westin, M.D. for All ZUMA-7 Investigators and Contributing Kite Members

Read more in The New England Journal of Medicine