Searching for Positives in Triple-Negative Breast Cancer

Lisa A. Carey, MD

Defining Subsets and Targets

Treatments for triple-negative breast cancer (TNBC) have made significantly less progress in comparison with other subtypes. Patients with TNBC have poor prognosis, and the primary therapeutic approach for this breast cancer subtype is still chemotherapy, which is often inadequate for many patients, according to Lisa A. Carey, MD, division chief of Hematology and Oncology, University of North Carolina, Durham.“The majority of breast cancer has markers that can identify targetable subtypes such as the estrogen receptor (ER), the progesterone receptor, and human epidermal growth factor receptor 2 (HER2),” said Brian Lehmann, PhD, assistant professor, Department of Biochemistry, Vanderbilt University, Nashville, Tennessee. “Clinicians can use tests to identify these populations of breast cancers, and order targeted therapies for them. The absence of these markers renders TNBC a disease of exclusion, and it comes as no surprise that it is a heterogeneous collection of biologically distinct cancers.”

Although in its early stages, research into the potential subsets that comprise TNBC is making progress. Lehmann said, “Our recent work has given some insight into this heterogeneous disease by examining the similarities of global transcriptional profiles from just triple-negative breast cancers. These studies indicate that there are at least six distinct subsets based on transcriptional profiles and that cell-line models differentially respond to chemotherapeutics and targeted therapies. These subtypes include two basal-like subtypes (BL1 and BL2), an immunomodulatory subtype (IM), two mesenchymal subtypes (M and MSL), and a luminal androgen receptor (LAR) subtype.” Defining these transcriptional profiles may be useful in biomarker selection, drug discovery, and clinical trial design, all with the goal of matching patients with TNBC with appropriate targeted therapies.¹Lehmann added, “We are trying to refine these subtypes and look for genomic aberrations that are shared within these subtypes that may be targetable.”

One targeted therapy being investigated is glembatumumab vedotin (CDX-011), an antibody-drug conjugate that targets glycoprotein NMB (GPNMB). GPNMB is a protein overexpressed by multiple tumor types, including breast cancer and melanoma. A randomized, multicenter pivotal study of CDX-011 in patients with metastatic, GPNMB over-expressing TNBC (The METRIC Study) is currently enrolling participants. The study’s purpose is to determine the efficacy and safety of CDX-011 in this patient population. Primary endpoints include overall response rate and progression-free survival. Eligible patients will be randomly assigned to receive treatment with CDX-011 or with capecitabine. Final data collection date for primary outcomes is scheduled for September 2015 (NCT01997333).

Other potential therapeutic targets for TNBC are also being investigated. For example, “Growth factor pathways keep popping up as being important in TNBC,” said Carey. She added, “Some TNBCs look like they don’t repair their DNA very well. So strategies that exploit that as an Achilles’ heel for those tumors might be important.” In addition, she said, “We’re pretty close withBRCA-associated tumors— tumors arising from an inherited mutation inBRCA1, which are mostly triple negative, or inBRCA2. The data are pretty strong that poly(ADPribose) polymerase (PARP) inhibitors actually work in that group. For those tumors, I suspect that PARP inhibitors will be part of the treatment options in the not-too-distant future.”

Maximizing Current Treatment Options

Lehmann further explained, “About 10% of triplenegative breast cancers express the androgen receptor (AR) and, at least in cell culture models, they seem to be more sensitive to the AR inhibitors (the ones that are approved for prostate cancer). So we may have an ideal marker and potential therapy for these patients.” Because all of these potential targets are still only in early investigational stages, Carey said, “Clinical trials should be considered at every step of the way,” whether patients are receiving firstline therapy, have progressed or recurred, or have early or metastatic disease. She added, however, “It may be that there isn’t one targeted therapy, that you have to use combinations of targeted therapies” to shut down these pathways.While much research is concentrating on targeted therapy options, there are still ways to maximize the treatment options that are now available to patients. In metastatic TNBC, Carey spoke of doing a retrial with a drug that was already used. “Some of our best drugs sometimes get omitted, because the patient received them in the adjuvant setting and the doctor is afraid that they didn’t work. But just because it didn’t eradicate the tumor when the purpose of the treatment was to cure, doesn’t mean that it can’t help control the cancer when the goal of therapy is control,” she said

Also, according to Lisa A. Newman, MD, MPH, professor of Surgery, director, Breast Care Center, University of Michigan Comprehensive Cancer Center, Ann Arbor, TNBC tumors tend to be associated with an increased risk of local recurrence as well as distant organ recurrence (metastatic spread). The risk of local recurrence is seen regardless of whether these patients pursue breast-conserving surgery or mastectomy, and survival is related to the risk of distant metastases. It is therefore not appropriate to counsel patients with TNBC against breast-conserving surgery, as long as they appear to be otherwise lumpectomy-eligible. TNBC tumors tend to respond rapidly to neoadjuvant chemotherapy. Therefore, Newman said that TNBC status is an appropriate feature to triage patients for preoperative chemotherapy, in hopes of primary breast tumor downstaging/ shrinkage and improved breast-conserving surgery eligibility.

Racial Disparities

Carey agreed: “People should pay attention to some of the neoadjuvant studies coming up, because I think that the proof of principle will be coming for some of these drugs in the neoadjuvant setting sooner than in the other settings.”Because women of African descent are up to three times more likely to be diagnosed with TNBC than are Caucasian or Hispanic women,²“this epidemiologic pattern has important implications with regard to issues such as screening mammography, prevention strategies, genetic counseling, and research,” said Newman. For example, she said, “There has been a lot of controversy recently regarding the age at which women should initiate breast cancer screening with mammography. Many experts (including the United States Preventive Services Task Force) have contested the longstanding American Cancer Society recommendation that women begin screening mammography at age 40 years, in favor of deferred screening beginning at age 50 years.^3,4Since African-American women have a higher incidence of the biologically aggressive TNBC tumors at both younger and older age ranges, early detection is especially important for this population. Deferred mammographic screening could delay the diagnosis of these cancers and worsen race/ethnicity-associated breast cancer outcome disparities.”

Along the lines of screening, Carey pointed out the implications that this epidemiologic factor may have on prevention strategies: “If some of the data about risk factors for triple-negative or basal-like breast cancer seem a little bit different—eg, the implication of body weight increasing risk,⁵the protective effect of breastfeeding possibly lowering risk⁶—if those and other differences prove to be true, then there are prevention strategies that could be particularly relevant for African-American communities and may need to be promoted differently, since prevention strategies in general have to be handled differently in different communities. But at this point, we don’t know that this is true.”

One of the ways to tailor prevention and screening strategies is to learn more about the genetic factors of the disease in these women, and to counsel them appropriately about their genetic profiles. “Diagnosis of TNBC is a risk factor for a BRCA1 mutation— associated breast cancer, and indicates a need for genetic counseling to check for hereditary susceptibility/ predisposition. Since African-American women have an increased risk for TNBC, we need to aggressively pursue genetic counseling in African- American women, so that we can learn more about the breast cancer-predisposing mutations that may be more prevalent in African-American families,” said Newman. Another example of this characterization is that tumors from African-American patients have been found to be more likely of basal-like subtypes, while many samples from European and American women correspond to mesenchymal-like or luminal and AR-driven subtypes, giving clues about potential genetic profiles for counseling.⁷

“Research regarding TNBC subsets is very exciting and promising with regard to treatment innovations. If we are to comprehensively define the full spectrum of TNBC subtypes, then we must be aggressive in evaluating TNBC in women with African ancestry, and this work should involve African- American women as well as African women, as it is already documented that TNBC accounts for most breast cancers detected in western, sub-Saharan Africa,” said Newman.⁸

The best way to ensure that future treatments are aligned with the patients who are most highly represented in the disease is to include these patients in the subtyping, transcriptional, and clinical trial research now taking place, according to Newman. Then, trial-based research may place TNBC with other types of breast cancer as appropriate for targeted treatment options for a large number of patients with TNBC.

References

1. Lehmann BD, Bauer JA, Chen X, et al. Identification of human triplenegative breast cancer subtypes and preclinical models for selection of targeted therapies.J Clin Invest. 2011;121(7):2750-2767.
2. Kwan ML, Kushi LH, Weltzien E, et al. Epidemiology of breast cancer subtypes in two prospective cohort studies of breast cancer survivors.Breast Cancer Res. 2009;11(3):R31.
3. US Preventive Services Task Force. Screening for breast cancer: US Preventive Services Task Force recommendation statement.Ann Intern Med. 2009;151(10):716-726.
4. American Cancer Society. Breast cancer: early detection. http:// www.cancer.org/acs/groups/cid/documents/webcontent/003165- pdf.pdf. Accessed January 9, 2014.
5. Phipps AI, Chlebowski RT, Prentice R, et al. Body size, physical activity, and risk of triple-negative and estrogen receptor-positive breast cancer.Cancer Epidemiol Biomarkers Prev. 2011;20:454-463.
6. Faupel-Badger JM, Arcaro KF, Balkam JJ, et al. Postpartum remodeling, lactation, and breast cancer risk: summary of a National Cancer Institute-sponsored workshop.J Natl Cancer Inst. 2013;105(3):166- 174.
7. Lindner R, Sullivan C, Offor O, et al. Molecular phenotypes in triple negative breast cancer from African American patients suggest targets for therapy.PLoS One. 2013;8(11):e71915.
8. Stark A, Kleer CG, Martin I, et al. African ancestry and higher prevalence of triple-negative breast cancer: findings from an international study.Cancer. 2010;116(21):4926-4932.