Triple-Negative Breast Cancer: Not Entirely Negative

September 15, 2013

Triple-negative breast cancer (TNBC) remains a very challenging entity today, but with the identification of new targets and further optimization of therapy, the landscape for TNBC may not look so negative. In the future, “TNBC” may be considered an antiquated misnomer, as we will have identified various breast cancer subgroups based on what they “are” rather than what they “are not.”

Triple-negative breast cancer (TNBC) is not a single entity but a heterogeneous group of diseases that are characterized by the low or absent expression of the most common receptors tested in the clinical setting: the estrogen receptor alpha (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). In this issue of ONCOLOGY, Drs. Herold and Anders have performed a comprehensive review of the most current information about TNBC and emerging targets for this difficult-to-treat disease.[1] It is well known that these tumors are refractory to anti-hormonal and anti-HER2 therapies, and that they have a predisposition for early relapse and distant metastasis-particularly visceral metastasis and metastasis to the brain. As the authors mention, this subtype of breast cancer has rightly been the subject of extensive research due to its lack of therapeutic targets and poor prognosis.

Identification of a target has been the challenge to therapeutically targeting TNBC. Clinically, considerable heterogeneity is seen in TNBC, with some patients achieving a pathologic complete response (pCR) to preoperative chemotherapy and subsequent long-term cure, and other patients demonstrating poor responses to chemotherapy that culminate in early death.[2] Leh-mann et al have described six subtypes of TNBC based on gene expression profiles,[3] including two basal-like subtypes (BL1 and BL2), as well as immunomodulatory (IM), mesenchymal (M), mesenchymal stem cell–like (MSL), and luminal androgen receptor (LAR) subtypes. Representative cell lines of each subtype have responded to different therapies. BL1 and BL2 subtypes responded to cisplatin; M and MSL subtypes have responded to NVP-BEZ235 (a phosphatidylinositol 3-kinase [PI3K]/mammalian target of rapamycin [mTOR] inhibitor) and dasatinib (an Abl/Src inhibitor); and LAR was sensitive to the androgen receptor (AR) antagonist bicalutamide. This preclinical study potentially represents a huge step forward in understanding the heterogeneity of TNBC and the variable outcomes seen with this disease. Follow-up data presented at the American Society of Clinical Oncology (ASCO) annual meeting in 2013 showed that the TNBC subtypes as defined above were significantly associated with, and independent predictors of, pCR.[4] After receiving neoadjuvant therapy with sequential taxane-based and anthracycline-based regimens, patients with the BL1 subtype had the highest pCR rate (52%), whereas the pCR rate was lowest in those with the BL2 (pCR, 0%) and LAR (pCR, 10%) subtypes. It is noteworthy that although the terms basal-like and TNBC are frequently used interchangeably, there is even heterogeneity in regard to response within this subset. These data represent perhaps the best early step toward individualizing therapy for TNBC, and further validation in larger data sets would be of interest.

Some of the most studied targeted therapies for TNBC have been agents that target DNA repair deficiency and “BRCAness.” Observations of phenotypic and genotypic similarities between basal-like and BRCA mutation–related TNBCs, which were later corroborated in the TCGA datasets,[5] led to the study of both macro-targeted therapies, such as platinum salts, and micro-targeted therapies, such as poly (ADP-ribose) polymerase (PARP) inhibitors. Both platinums and PARP inhibitors appear to have the greatest efficacy in patients with germline BRCA mutations.[6-8] In one phase II study, however, nearly 40% of those with advanced TNBC demonstrated response to cisplatin; and in the neoadjuvant setting, close to 60% of TNBC patients achieved a pCR when treated with paclitaxel, non-pegylated liposomal doxorubicin, bevacizumab, and carboplatin.[2] Data from the Cancer and Leukemia Group B (CALGB) study are eagerly awaited (National Cancer Institute ClinicalTrials.gov Identifier: NCT00861705).

Single-agent PARP inhibition is likely not going to be a significant strategy for sporadic TNBC.[6] The efficacy seen with combinations of chemotherapy and PARP inhibition has been highly variable, depending on the chemotherapy backbone used.[9,10] However, there is clearly activity with chemotherapy and PARP inhibition in diverse tumor types,[10,11] as well as reports of durable responses in aggressive TNBC. The next step will need to be randomized studies in order to help us truly understand what benefit PARP inhibition is providing beyond chemotherapy alone, and whether there is any breast tumor type besides BRCA-mutated that will be particularly sensitive. Further characterization of the population of patients with sporadic (nonhereditary) TNBC should help to define those most likely to respond to therapy, and biomarker analysis of tissues collected in these studies is eagerly awaited. Much of these data are from phase I and early phase II trials; larger, randomized studies are needed to understand the most appropriate use of PARP inhibitors in sporadic TNBC. While a rapid pace of progress is desperately needed for women suffering with advanced TNBC, we should be cautious when interpreting early results, such as those seen with iniparib.[12,13] Despite the seemingly disappointing findings with that agent, ongoing work to understand iniparib’s mechanism of action and to further explore the benefit seen in subset analysis of early-phase trials needs to be applauded. Iniparib may still have potential benefit in the management of TNBC.

Use of the angiogenesis-targeted agent bevacizumab has been tested in many large randomized phase III studies. One of the first was the Eastern Cooperative Oncology Group (ECOG) 2100 study, which showed a progression-free survival (PFS) benefit from adding bevacizumab to paclitaxel compared with paclitaxel alone (11.8 months vs 5.9 months); a PFS benefit was also seen in the TNBC subgroup (8.8 months vs 4.6 months).[14] Although the AVastin And DOcetaxel (AVADO) trial also demonstrated superior PFS for the combination of bevacizumab and docetaxel in both hormone receptor–positive (HR+) breast cancer and TNBC.[15] The Regimens In Bevacizumab for Breast ONcology (RIBBON-1) trial failed to demonstrate this advantage in patients with TNBC.[16] In contrast, RIBBON-2 showed a clear PFS benefit from adding bevacizumab to second-line chemotherapy regimens in TNBC patients (6 months vs 2.7 months).[17] None of these studies showed improvement in overall survival (OS); thus, the US Food and Drug Administration (FDA) ultimately ruled that the benefits in PFS did not outweigh the toxicity seen with the addition of bevacizumab, while the European Medicines Agency (EMA) continued in its approval of bevacizumab for ER+ breast cancer and TNBC as a whole. Boneberg et al have reported that the levels of messenger RNA expression of a dozen different pro-angiogenic growth factor genes-including vascular endothelial growth factor (VEGF)-were greater in adjacent normal tissues than in the primary tumor tissue,[18] so perhaps the focus of angiogenesis research should be shifted from the “seed,” that is, whether the breast tumor is HR+ or HR−, to the “soil.”

While the role of drugs like bevacizumab is as confusing and contradictory in TNBC as in breast cancer as a whole, it is exciting that many new therapies are being explored for patients with TNBC. Blockade of the androgen receptor and the folate receptor, inhibition of the PI3K/mTOR and MEK [mitogen-activated protein/extracellular signal–regulated kinase kinase] pathways, and inhibition of checkpoint kinase 1 (Chk1) are all promising strategies for the treatment of TNBC. Each of the studies reviewed by Drs. Herold and Anders highlights that although results with currently available therapies are modest in unselected patients with TNBC, there is hope that the correlative and biomarker data will provide the most important lessons from these trials, to inform future therapy of TNBC. It would be particularly important if less toxic, targeted therapies, such as bicalutamide, were available as alternatives to chemotherapy.

In summary, the review by Drs. Herold and Anders thoroughly describes the many targets and pathways being investigated in TNBC. Most of the agents are in early phases of development, and further research clearly is needed in order to obtain a better understanding of which treatment may be most suitable for each TNBC subtype. There continue to be great strides in our understanding of the diversity of TNBC. As the authors mention, increasing clinical trial participation is mandatory so that we can advance our current knowledge and offer patients access to novel drugs. In the era of personalized cancer therapy, clinical trials need to be designed to answer the important question of who benefits the most from an experimental treatment. TNBC remains a very challenging entity today, but with the identification of new targets and further optimization of therapy, the landscape for TNBC may not look so negative. In the future, “TNBC” may be considered an antiquated misnomer, as we will have identified various breast cancer subgroups based on what they “are” rather than what they “are not.”

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

REFERENCES

1. Herold CI, Anders CK. New targets for triple-negative breast cancer. Oncology (Williston Park). 27:846-864.

2. von Minckwitz G, Schneeweiss A, Salat C, et al. A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). J Clin Oncol. 2013;31:abstr 1004.

3. Lehmann BD, Bauer JA, Chen X, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121:2750-67.

4. Masuda H, Baggerly KA, Wang Y, et al. Differential pathologic complete response rates after neoadjuvant chemotherapy among molecular subtypes of triple-negative breast cancer. J Clin Oncol. 2013;31(suppl):abstr 1005.

5. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61-70.

6. Gelmon K, Hirte H, Robidoux A, et al. Can we define tumors that will respond to PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer. J Clin Oncol. 2010;28(15 suppl):3002.

7. Byrski T, Gronwald J, Huzarski T, et al. Neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Heredit Cancer Clin Pract. 2011;9:A4.

8. Silver D, Richardson A, Eklund A, et al. Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J Clin Oncol. 2010;28:1145-53.

9. Isakoff SJ, Overmoyer B, Tung NM, et al. A phase II trial expansion cohort of the PARP inhibitor veliparib (ABT888) and temozolomide in BRCA1/2-associated metastatic breast cancer. Cancer Res. 2011;71(24 suppl):abstr P3-16-05.

10. Puhalla SL, Appleman LJ, Beumer JH, et al. Two phase I trials exploring different dosing schedules of carboplatin (C), paclitaxel (P), and the poly-ADP-ribose polymerase (PARP) inhibitor, veliparib (ABT-888) (V) with activity in triple negative breast cancer (TNBC). Cancer Res 2012;72(24 Suppl):abstr PD09-06.

11. Appleman LJ, Beumer JH, Jiang Y, et al. A phase I study of veliparib (ABT-888) in combination with carboplatin and paclitaxel in advanced solid malignancies. J Clin Oncol. 2012;30(suppl):abstr 3049.

12. O’Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364:205-14.

13. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). J Clin Oncol. 2011;29:abstr 1007.

14. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breastcancer. N Engl J Med. 2007;357:2666-76.

15. Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010;28:3239-47.

16. Robert NJ, Diéras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011;29:1252-60.

17. Brufsky AM, Hurvitz S, Perez E, et al. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011;29:4286-93.

18. Boneberg EM, Legler DF, Hoefer MM, et al. Angiogenesis and lymphangiogenesis are downregulated in primary breast cancer. Br J Cancer. 2009;101:605-14.