As the new review noted, TNBC accounts for 12% to 17% of all breast cancers. The 5-year overall survival rate is worse than other breast cancers and, once metastatic, patients with TNBC have shorter overall survival compared with those with other subtypes — 12 to 18 months median vs 50 to 60 months for estrogen receptor (ER)-positive cancers.
Until recently, treatment options were largely unchanged for more than 2 decades.
“Relatively few clinically important therapeutic advances have occurred in the treatment of triple-negative breast cancer (TNBC) since the introduction of taxanes as adjuvant therapy over 20 years ago,” according to a study published in February.4
“However,” that study went on to say, “this is rapidly changing due to a variety of conceptually important clinical trials and emerging new options such as immune checkpoint inhibitors and antibody-drug conjugates. Evidence also increasingly supports that platinum drugs and inhibitors of poly (ADP-ribose) polymerase, or PARP, are particularly effective in the treatment of germline BRCA-mutant cancers, including TNBC.”
In all, the study’s authors said, “after 2 decades of relatively few improvements in the management of TNBC, a number of important new trials and novel drugs have started to move the field forward. …There are nearly 50 ongoing (or soon to open) clinical investigations of the role of immune checkpoint inhibitors and other immune-targeted agents in breast cancer.”
Notch inhibitors belong on that list, the new review’s authors argued.
Breast cancer stem cell “populations show an upregulation of Notch gene expression, and blocking Notch activity using a GSI or a neutralizing antibody to Notch4 reduced the mammosphere-forming ability of these cells in culture,” they wrote. “As such, TNBC seems well suited for attempts at developing anticancer therapy through inhibition of Notch pathways.”
That may, however, not happen soon. GSIs are associated with side effects including fatigue, myelosuppression, fever, rash, chills, anorexia, and hypophosphatemia. And, while Notch inhibitors show some promise in the treatment of a variety of cancers, the review’s authors concluded, “the low toxicity profile of some GSIs and not satisfying efficacy results caused the discontinuation or the slowing down of development program of GSIs in breast cancer.”
- Locatelli M, Curigliano G. Notch inhibitors and their role in the treatment of triple negative breast cancer: promises and failures. Curr Opin Oncol. 2017;29(6):411-27. doi: 10.1097/CCO.0000000000000406
- Jhappan C, Gallahan D, Stahle C, et al. Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands. Genes Dev. 1992;6(3):345-55.
- Clementz AG, Rogowski A, Pandya K, Miele L, Osipo C. NOTCH-1 and NOTCH-4 are novel gene targets of PEA3 in breast cancer: novel therapeutic implications. Breast Cancer Res. 2011;13(3):R63. doi: 10.1186/bcr2900
- Székely B, Silber AL, Pusztai L. New therapeutic strategies for triple-negative breast cancer. Oncology (Williston Park). 2017;31(2):130-7.