B0006421 Breast cancer cells

Breast cancer in low-income countries: India as a model


Background: Developing countries contribute substantially to breast cancer mortality worldwide, as early-stage diagnosis and effective adjuvant therapies have decreased breast cancer-specific mortality in developed countries. Unfortunately, the costs of breast cancer screening programs and treatments limit translation of these results to developing nations. Methods: We retrospectively analyzed the tumor characteristics and modalities of management in 454 patients with Stage I-III invasive breast cancer in a single tertiary cancer center (Rajiv Gandhi Cancer Institute & Research Center) in New Delhi, India treated in 2010.

Results: The median age at diagnosis was 52 (range 25-88). Stage II tumors predominated, with tumors ≤ 5 cm in size in 93% of patients. 84% of patients underwent modified radical mastectomy, while 14% underwent breast-conservation therapy (BCT). Overall, 79% of patients received adjuvant or neo-adjuvant chemotherapy and 49% received radiotherapy. Receptor characterization revealed: ER+/PR+/Her2-, 52.9%; ER+/PR+/Her2+, 10.2%; ER-/PR-/Her2+, 13.8%; and triple-negative, 23%. Of the ER+/PR+ patients, 58% were node-positive, 79% received chemotherapy and 100% were advised hormonal therapy. Of the Her-2 positive patients, 23% received trastuzumab.

Conclusions: Breast cancer management strategies vary in Indian and US populations. Indian patients are younger with tumor sizes amenable to BCT followed by loco-regional radiotherapy. Despite this, only a minority of patients opted for BCT. In the hormone-positive population, majority of patients received chemotherapy in addition to hormone therapy due to high incidence of node positivity, tumor size>2 cm and unaffordability of genomic assays. In the Her2+ population, trastuzumab use was limited, reportedly due to cost. Overall, management is adapted to limited resources and follow-up is inconsistent. It may be beneficial to set up Indian national breast cancer guidelines to promote multidisciplinary management, describe the molecular features of disease in this population, and evaluate the cost-effectiveness of expensive diagnostic and therapeutic interventions. This will encourage rational policies and help to create a comprehensive cancer treatment network.

Source: http://meetinglibrary.asco.org/content/132656-144

J Clin Oncol 32, 2014 (suppl; abstr e17517)

Mahasweta Gooptu, Dinesh Doval, Kapil Kumar, Ajay Dewan, Anurag Mehta, Ullas Batra, Kumardeep Dutta, Tiffany P. Avery, Rebecca J. Jaslow, Edith P. Mitchell, Afzal Naiyer, John Manavalan, Massimo Cristofanilli; Thomas Jefferson University, Philadelphia, PA; Rajiv Gandhi Cancer Institute & Research Centre, Delhi, India; Department of Medical Oncology, Rajiv gandhi cancer Institute and Research center, Delhi, India; Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA; Star Health Network, New York, NY; Kimmel Cancer Center at Jefferson, Philadelphia, PA


A Targeted Agent for Triple-Negative Breast Cancer

Glycoprotein NMB (gpNMB) is a transmembrane protein and tumor-associated antigen that is expressed at higher levels in certain malignancies than in normal tissues. Glembatumumab vedotin (CDX-011) is an antibody-drug conjugate consisting of a fully human IgG2 monoclonal antibody against gpNMB linked to the microtubule inhibitor monomethyl auristatin E (MMAE). By targeting and binding to cells overexpressing gpNMB, the antibody is internalized, allowing for intracellular release of the cytotoxic MMAE.

A prior phase I/II trial of CDX-011 for refractory advanced breast cancer demonstrated an acceptable toxicity profile and an objective response rate (ORR) of 12% (NEJM JW Oncol Hematol Nov 2014 and J Clin Oncol 2014; 32:3619). In the subset of patients with triple-negative breast cancer (TNBC), the ORR was 20%, and progression-free survival (PFS) was 4.1 months; in TNBC patients with gpNMB-expressing tumors the ORR was 25%, and the PFS was 5.1 months. Now, investigators have conducted an industry-supported, randomized phase II trial (EMERGE) of CDX-011 versus investigator choice of chemotherapy (IC) in 124 refractory breast cancer patients with tumors overexpressing gpNMB (defined as ≥5% of malignant epithelial or stromal cells with any expression).

ORR was similar overall for patients receiving CDX-011 or IC (6% and 7%, respectively) and for those with gpNMB-expressing tumors (12% for both). ORR was higher with CDX-011 versus IC in patients with ≥25% of tumor cells expressing gpNMB (30% vs. 9%) as well as in TNBC patients (18% vs. 0%) and TNBC patients with overexpression of gpNMB (40% vs. 0%). Dose reduction occurred in 25% of patients in both treatment arms. The most common CDX-011 toxicities were rash, fatigue, nausea, neutropenia, and neuropathy.

The attraction of targeted therapy with an antibody delivery system is that it directs the cytotoxic agent preferentially to the malignant cell population, potentially enhancing efficacy and minimizing systemic toxicity. The use of ado-trastuzumab emtansine for HER2-positive breast cancer demonstrates the success of this approach (NEJM JW Oncol Hematol Sep 2014 and J Clin Oncol 2014; 32:2750). The signal that CDX-011 is active in TNBC is exciting, but the observations from this study are based on very small numbers of patients. A larger, pivotal phase II trial (METRIC) is under way to more fully investigate this compound in TNBC.

Yardley D et al. EMERGE: A randomized phase II study of the antibody-drug conjugate glembatumumab vedotin in advanced glycoprotein NMB–expressing breast cancer. J Clin Oncol 2015 Apr 6; [e-pub]. (http://dx.doi.org/10.1200/JCO.2014.56.2959)