Breast Cancer Outlook for 2017: Keeping the Accelerator to the Floor

December 1, 2016

Expansion of precision medicine approaches will play a key role in optimizing care and improving outcomes for breast cancer patients in 2017. Here we highlight some of the studies and FDA approvals we are most anxious to see in the coming year.

Expansion of precision medicine approaches will play a key role in optimizing care and improving outcomes for breast cancer patients in 2017. The breakneck pace of genomic and targeted therapy discoveries of the last decade will continue to pay dividends in the near future in the form of expected reporting of several practice-changing clinical trials and new US Food and Drug Administration (FDA) drug approvals. Here we highlight some of the studies and approvals we are most anxious to see in the coming year.

Ductal Carcinoma in Situ (DCIS)

We continue to grapple with overtreatment of low-risk, noninvasive breast disease. Ongoing and upcoming trials will help define which DCIS patients can avoid surgery and/or radiation therapy (RT). Highly anticipated data from the Eastern Cooperative Oncology Group/American College of Radiology Imaging Network E4112 trial, which is prospectively evaluating the role of imaging and gene expression analysis in surgical and RT decision making for DCIS, will be seen at the close of 2016. The first data reported will address how MRI influences conversion of planned local excision to mastectomy.

Estrogen Receptor (ER)-Positive Breast Cancer

Our understanding of mechanisms of endocrine resistance, optimal combinations of endocrine and targeted agents, and duration of adjuvant endocrine treatment will continue to evolve in 2017. Drugs targeting the phosphoinositide 3 (PI3)-kinase/AKT/mammalian target of rapamycin (mTOR) pathway have been the focus of recent trials looking to overcome estrogen pathway resistance that arises in formerly hormone-responsive breast cancer. The mTOR inhibitor everolimus has been FDA-approved since 2014 in second-line metastatic, ER-positive breast cancer, and recent results of the first-line phase II BOLERO-4 trial will possibly move this agent into competition for earlier-line use.[1] PIK3CA mutations are extremely common in ER-positive breast cancer, and the resulting mutant protein is constitutively active and can be targeted with very specific inhibitors. Approval of the first PI3-kinase inhibitor, buparlisib, may be on the horizon following the recent reporting of the BELLE-2 trial.[2] Although cancers with a PIK3CA mutation showed larger benefit from the addition of buparlisib to fulvestrant, the PIK3CA wild-type group also had some degree of benefit. Developing reproducible companion biomarker assays to aid in selecting appropriate targeted agents remains a high priority.

Multiple agents targeting the CDK4/6 cell cycle have shown benefit when paired with endocrine therapy, with palbociclib being the first to receive FDA approval. Two additional CDK4/6 inhibitors, ribociclib and abemaciclib, have been granted FDA breakthrough status designation and are expected to be reviewed in the near future. The phase III MONALEESA-2 trial recently reported positive results for the combination of ribociclib and letrozole,[3] and correlative science studies are expected in 2017. Promising data from the MONARCH 1 phase II trial of single-agent abemaciclib was presented at the American Society of Clinical Oncology 2016 Annual Meeting,[4] and reporting of the MONARCH 2 trial of fulvestrant ± abemaciclib is expected in 2017. Distinguishing toxicity and efficacy differences between the CDK4/6 inhibitors is critical. Neutropenia is dose-limiting with palbociclib and ribociclib, necessitating interrupted dosing (21 continuous days followed by a 7-day break). Abemaciclib targets CDK4 (the isoform believed to be more important in breast cancer) preferentially over CDK6, leading to less neutropenia but more gastrointestinal toxicity. Abemaciclib can be dosed continuously, which may explain its efficacy even when used as a single agent. To date, no biomarkers have been reported that predict benefit from CDK4/6 inhibitors.

Additional data addressing the issue of whether to extend the duration of adjuvant aromatase inhibitor (AI) therapy should soon be forthcoming from the National Surgical Adjuvant Breast and Bowel Project B-42 trial, and will add to the recent MA.17 trial findings showing benefit for extended AI use in early-stage, postmenopausal breast cancer.[5] Understanding the true magnitude of benefit for extended therapy, selecting which patients benefit most, and balancing efficacy vs toxicity will be critical when incorporating these findings into clinical practice. Both everolimus and palbociclib are under investigation in actively accruing phase III adjuvant trials, so understanding their role in early-stage breast cancer appears to be several years in the future. Data from the ER-positive subset of the MA.32 trial of adjuvant metformin may be on the horizon, following last year’s early closure of the triple-negative subset due to futility. Sorting out the order in which to optimally sequence targeted agents, and determining whether we can truly define populations of ER-positive breast cancer patients who will benefit from specific agents and pathways while avoiding use of these agents in patients with minimal-to-no expectation of benefit, are high priorities in both early-stage and metastatic ER-positive breast cancer.

HER2-Overexpressed Breast Cancer

In metastatic breast cancer, the addition of the anti–human epidermal growth factor receptor 2 (HER2) monoclonal antibody pertuzumab has led to substantial improvements in progression-free and overall survival. The much anticipated results of the APHINITY trial are expected in early 2017; this study is evaluating the role of 1 year of adjuvant pertuzumab in combination with trastuzumab/chemotherapy regimens. The FDA has granted pertuzumab accelerated approval in the preoperative setting, with full approval in early-stage breast cancer, pending the APHINITY results. The oral HER2-targeted tyrosine kinase inhibitor neratinib will also be looking for a potential FDA indication in 2017, with the positive results from the ExteNET trial showing benefit for the addition of neratinib after completion of adjuvant chemotherapy/trastuzumab regimens.[6] Neratinib also successfully “graduated” from the innovative preoperative I-SPY 2 trial, which demonstrated an increase in pathologic complete responses, further supporting a possible role for this agent in HER2-positive early-stage breast cancer.[7] What is unclear is how pertuzumab and neratinib will be prioritized in the early breast cancer setting.

For patients with advanced HER2-overexpressed breast cancer, a number of new pipeline agents will have further results reported in 2017. The HER2-selective oral tyrosine kinase inhibitor tucatinib (ONT-380) has received fast track designation by the FDA, in large part due to promising early data in brain metastases.[8] The ongoing HER2CLIMB study is further evaluating this agent. Results of the recently presented phase III Heritage study of the trastuzumab biosimilar Myl-1401O may soon lead to the first approval of an anticancer monoclonal antibody biosimilar.[9] Interesting phase III trials of HER2-targeted agents being conducted in the metastatic setting include the SOPHIA trial evaluating margetuximab, a HER2 antibody with a modified Fc receptor to enhance immune activation, and the HERMIONE trial of the HER2/liposomal doxorubicin antibody-drug conjugate MM-302.[10]

Triple-Negative Breast Cancer

For triple-negative breast cancer (TNBC; ER-negative, progesterone receptor–negative, HER2-negative), the promising Trop-2–targeted antibody-drug conjugate sacituzumab govitecan (IMMU-132) has received FDA breakthrough and fast track designations.[11] The cytotoxic included in this molecule, SN-38, is the active metabolite of irinotecan. Publication of phase II trial data is eagerly awaited in the upcoming year. Another antibody-drug conjugate, glembatumumab vedotin,[12] which targets glycoprotein NMB, is being compared against capecitabine in the ongoing METRIC trial, a phase II registrational study expected to complete enrollment in 2017. At least five poly (ADP-ribose) polymerase (PARP) inhibitors are in competition for the BRCA-mutated and/or homologous recombination–deficient TNBC population, with olaparib approved for ovarian cancer but no PARP inhibitor yet approved for breast cancer. The OlympiAD trial of olaparib in metastatic BRCA-mutated breast cancer has met its accrual goal, and the OlympiA trial in the adjuvant setting is ongoing. Veliparib successfully “graduated” from the I-SPY 2 preoperative trial in combination with carboplatin in TNBC[13] and is being included in the randomized phase II metastatic Southwest Oncology Group S1416 trial. Niraparib, talazoparib, and rucaparib are being studied for various indications, including BRCA-mutated breast cancer. To date, immunotherapy has not shown the same success in breast cancer as in other cancer types, but immune checkpoint inhibitors have shown some activity in the TNBC subset.[14] Evaluation of programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitors are ongoing and planned in the metastatic and adjuvant settings. Based on the finding that some TNBCs express androgen receptor (AR), several trials are evaluating agents in the AR pathway. Promising early data have been presented for enzalutamide and bicalutamide.[15,16] Enobosarm is an interesting selective AR modulator agent under investigation.

Bone Metastases

Although a meta-analysis of adjuvant bisphosphonates in early breast cancer reported a reduction in relapses and deaths in postmenopausal women, routine clinical uptake has not yet occurred in the United States.[17] Updated practice guidelines addressing the use of these agents are expected in 2017. Whether receptor activator of nuclear factor κ B (RANK)-ligand inhibitors will show similar benefit has yet to be determined, although a recent presentation of an interim analysis of the Austrian Breast & Colorectal Cancer Study Group-18 trial of adjuvant denosumab suggested a benefit in disease-free survival in early-stage, ER-positive breast cancer.[18] More mature analysis of the secondary endpoints, including overall survival, are expected within the next year, and we await the larger D-CARE registration study of adjuvant denosumab.

Conclusion

Additional clinical priorities will be addressed in anticipated work in the areas of big data/genomics, precision medicine, cost-effectiveness, financial toxicity, and access to oncology medicines and services. Looking forward, much is expected from the breast cancer research enterprise in the coming year. Efforts in the treatment of breast cancer will continue to focus on personalizing treatment to the patient and the tumor. Let’s hope, for our patients’ sakes, that we can keep up the pace on delivering on many of our promises.

Financial Disclosure:Dr. Gadi receives research funding from Roche/Genentech and has part ownership in SEngine Precision Medicine. Dr. Gralow receives research funding from Novartis and Roche/Genentech; serves on steering committees for Pfizer and Roche/Genentech; and serves on data safety monitoring committees for Merck, Novartis, and Roche/Genentech.

References:

1. Royce M, Villanueva C, Ozguroglu M, et al. BOLERO-4: phase 2 trial of first-line everolimus plus letrozole in estrogen receptor-positive, HER-2 negative metastatic breast cancer. Ann Oncol. 2016;27(suppl 6):vi68-vi99.

2. Baselga J, Im S-A, Iwata H, et al. PIK3CA status in circulating tumor DNA predicts efficacy of buparlisib plus fulvestrant in postmenopausal women with endocrine-resistant HR+/HER2– advanced breast cancer: first results from the randomized, phase III BELLE-2 trial. San Antonio Breast Cancer Symposium 2015. San Antonio, TX; December 8–12, 2015. Abstr S6-01.

3. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016 Oct 7. [Epub ahead of print]

4. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH1: results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease. J Clin Oncol. 2016;34(suppl):abstr 510.

5. Goss PE, Ingle JN, Pritchard KI, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med. 2016;375:209-19.

6. Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17:367-77.

7. Park JW, Liu MC, Yee D, et al. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016;375:11-22.

8. Borges VF, Ferrario C, Aucoin N, et al. Efficacy results of a phase 1b study of ONT-380, a CNS-penetrant TKI, in combination with T-DM1 in HER2+ metastatic breast cancer, including patients with brain metastases. J Clin Oncol. 2016;34(suppl):abstr 513.

9. Rugo HS, Barve A, Waller CF, et al. Heritage: a phase III safety and efficacy trial of the proposed trastuzumab biosimilar Myl-1401O versus Herceptin. J Clin Oncol. 2016;34(suppl):abstr LBA503.

10. Miller K, Cortes J, Hurvitz SA, et al. HERMIONE: a randomized phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician’s choice plus trastuzumab in patients with previously treated, anthracycline-naïve, HER2-positive, locally advanced/metastatic breast cancer. BMC Cancer. 2016;16:352.

11. Bardia A, Diamond R, Mayer A, et al. Safety and efficacy of anti-Trop-2 antibody drug conjugate, sacituzumab govitecan (IMMU-132), in heavily pretreated patients with TNBC. San Antonio Breast Cancer Symposium 2015. San Antonio, TX; December 8–12, 2015. Abstr PD3-06.

12. Rugo HS, Olopade OI, DeMichele A, et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med. 2016;375:23-34.

13. Yardley DA, Weaver R, Melisko ME, 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;33:1609-19.

14. Nanda R, Chow LQ, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol. 2016;34:2460-7.

15. Gucalp A, Tolaney S, Isakoff SJ, et al. Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer. Clin Cancer Res. 2013;19:5505-12.

16. Traina TA, Miller K, Yardley DA, et al. Results from a phase 2 study of enzalutamide, an androgen receptor inhibitor, in advanced AR+ triple-negative breast cancer. J Clin Oncol. 2015;33(suppl):abstr 1003.

17. Coleman R, Powles T, Paterson A, et al. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet. 2015;386:1353-61.

18. Gnant M, Pfeiler G, Dubsky PC, et al. The impact of adjuvant denosumab on disease-free survival: results from 3,425 postmenopausal patients of the ABCSG-18 trial. San Antonio Breast Cancer Symposium 2015. San Antonio, TX; December 8–12, 2015. Abstr S2-02.