Future of Breast Cancer Brings Evolving Paradigms in Treatments

Joyce A. O’Shaughnessy, MD

Joyce A. O’Shaughnessy, MD

The 14th Annual International Congress on the Future of Breast Cancer^®kicks off July 16, 2015, at the Hyatt Regency in Huntington Beach, CA. Joyce A. O’Shaughnessy, MD, chair, breast cancer service at Baylor-Sammons Cancer Center, Texas Oncology, US Oncology in Dallas, has chaired the Congress for many years. O’Shaughnessy is a Diplomate of the American Board of Internal Medicine, with subspecialty certification in medical oncology. She has treated thousands of patients with breast cancer while pursuing new clinical strategies to fight the disease. O’Shaughnessy providedTargeted Oncologywith a sneak peek into some of the recent advances in breast cancer that will be discussed at the upcoming Congress.

Practice Management Changes

According to O’Shaughnessy, significant practice management changes have occurred in the past couple of years in breast cancer, a key one being the accelerated approval by the US Food and Drug Administration (FDA) in February 2015 of the kinase inhibitor palbociclib (Ibrance) for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for metastatic disease.¹

“Also, the use of adjuvant pertuzumab (Perjeta) in addition to neoadjuvant pertuzumab has been another really important change,” said O’Shaughnessy. Updates in version 2.2015 of the National Comprehensive Cancer Network (NCCN) Guidelines for breast cancer state that a pertuzumab-containing regimen may be administered preoperatively to patients with greater or equal to T2 or greater or equal to N1 HER2-positive breast cancer; this applies to early-stage, invasive, and inflammatory breast cancer.²

“Another extremely important change has been the whole issue of ovarian suppression and ablation in premenopausal, estrogen-positive breast cancer. That has been a really important advance in the last year,” O’Shaughnessy said. Data released at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting from a joint analysis of 2 phase III trials involving a total of 4690 premenopausal women with hormone-receptor—positive (HR+) breast cancer demonstrated that adjuvant use of the aromatase inhibitor (AI), exemestane, reduced relative risk of developing subsequent invasive cancer by 28% compared with tamoxifen when both agents were combined with ovarian function suppression (OFS). The exemestane plus OFS treatment arm also showed a relative 34% reduction in risk of breast cancer recurrence.³

PARP inhibitors inBRCA1/2-Mutated Breast Cancer

Olaparib (Lynparza) received accelerated approval from the FDA on December 19, 2014, as monotherapy in patients withBRCA-mutated advanced ovarian cancer (as detected by the BRACAnalysis CDx test) who have been treated with 3 or more prior lines of chemotherapy.⁴Various clinical trials are studying olaparib inBRCA1/2-mutated metastatic breast cancer (mBC).

O’Shaughnessy stressed the importance of one multicenter, phase III study that aims to assess the efficacy and safety of olaparib versus placebo as adjuvant treatment in patients with germlineBRCA1/2mutations and high risk HER2-negative primary breast cancer who have completed definitive local treatment and neoadjuvant or adjuvant chemotherapy.⁵

“It is really important for general medical oncologists to look into where their patients can go to participate in the OlympiA trial. It is very important for general oncologists to refer their patients to adjuvant treatment after they finish the standard adjuvant chemotherapy or when they are in the middle of their endocrine therapy,” O’Shaughnessy said. The study is recruiting participants and is sponsored by AstraZeneca in collaboration with the Breast International Group, the Frontier Science & Technology Research Foundation, Inc, NRG Oncology, and Myriad Genetics, Inc.

O’Shaughnessy cited other clinical trials under way inBRCA1/2-mutated mBC. A 3-arm, phase III study⁶is evaluating the safety and efficacy of adding the polyADP ribose polymerase (PARP) inhibitor veliparib (ABT-888) plus carboplatin versus the addition of carboplatin to standard neoadjuvant chemotherapy versus standard neoadjuvant chemotherapy in subjects with early-stage triple-negative breast cancer (TNBC). “In breast cancer, the PARP inhibitors are still in clinical trials, but they are advancing in terms of entering into the adjuvant setting,” she said.

Emerging Strategies in TNBC

O’Shaughnessy stated that some oncologists are adding carboplatin or cisplatin to standard chemotherapy in the adjuvant or neoadjuvant setting for patients who are at high risk for TNBC or for patients withBRCAgermline mutations, but she contended that the most exciting information coming out of the metastatic TNBC investigations are clinical trials studying checkpoint inhibitors.

Pembrolizumab (Keytruda), Merck’s anti-programmed cell death-1 (PD-1) agent, has demonstrated activity and acceptable safety in a phase Ib study⁷that includes a cohort of patients with metastatic TNBC.

Genentech’s programmed cell death ligand 1 (PD-L1) inhibitor MPDL3280A showed a 19% objective response rate (ORR), with 75% of these responses ongoing in pretreated patients with metastatic TNBC, according to findings from an ongoing phase I study⁸presented at the 2015American Association for Cancer Research(AACR) Annual Meeting. O’Shaughnessy pointed out that this agent will soon be studied in a randomized, phase III clinical trial in combination with nab-paclitaxel as a first-line therapy for patients with metastatic TNBC.

O’Shaughnessy referred to another trial of checkpoint inhibitors that is enrolling participants, a phase I study⁹of the anti—PD-L1 antibody, MEDI4736, in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, tremelimumab, in patients with advanced solid tumors, including TNBC. This study is evaluating the safety, efficacy, and best dose of MEDI4736 in this potential combination regimen.

“It is a similar to what is being successfully administered in melanoma patients, where they are giving the Bristol-Meyers Squibb anti-PD-1 nivolumab (Opdivo) withipilimumab (Yervoy),an anti-CTLA-4, and that [combination] has been very successful in melanoma, so that is an analogous strategy with Astra Zeneca’s anti-PD-L1 and its anti-CTLA-4 (MEDI4736/tremelimumab), which is ongoing in TNBC right now,” she said.

Ruxolitinib (Jakafi), another new drug that O’Shaughnessy finds interesting for potential treatment of ER-positive breast cancer and TNBC, is a kinase inhibitor indicated for treatment of patients with postpolycythemia vera, myelofibrosis, and postessential thrombocythemia.¹⁰The drug is in a randomized phase II study¹¹in patients with both ER-positive breast cancer and metastatic TNBC. “It is a brand new mechanism. It basically decreases inflammation and interleukin-6—driven paracrine growth of cancers,” O’Shaughnessy said.

Other Congress Highlights

The Congress will also discuss the importance of genomic and proteomic assays in making treatment decisions. “These assays continue to evolve in terms of the management of mBC and in terms of identifying therapeutic targets,” she said. “A number of these gene expression profiles are [being] developed to help understand which patients will benefit from long-term endocrine therapies. There is also the [Myriad’s]homologous recombination deficiency(HRD) score to try to understand which patients may benefit from preoperative use of platinum,” O’Shaughnessy said.

Treatments that may be very important for breast cancer in the months ahead, such as AKT inhibitors, will be discussed at the Congress. The Congress includes a session on how to optimize duration and address adherence with adjuvant endocrine therapies. There will be discussions on how obesity affects early-stage breast cancer treatment strategies. The Congress will assess new strategies for reducing breast cancer development and recurrence; will include sessions on how locoregional treatment strategies are evolving; and  will discuss the implications of health care reform for oncology practices. For more information or to register for the Congress, visit www.gotoper.com.

References

1.      Ibrance [prescribing information]. New York, New York: Pfizer Inc; February 2015. Revised January 2015.

2.      National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines). Breast Cancer. Version 2.2015. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed May 6, 2015.

3.      Pagani O, Regan MM, Walley B, et al; SOFT and TEXT Investigators and International Breast Cancer Study Group. Randomized comparison of adjuvant aromatase inhibitor (AI) exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Joint analysis of IBCSG TEXT and SOFT. Presented at the Annual Meeting of ASCO, June 1, 2014. Abstract LBA1.

4.      FDA News Release. FDA approves Lynparza to treat advanced ovarian cancer. Silver Spring, MD.http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427554.htm. Published December 19, 2015. Accessed May 6, 2015.

5.      Clinicaltrials.gov. ClinicalTrials.gov Identifier: NCT02032823.https://clinicaltrials.gov/ct2/show/NCT02032823. Last updated: March 30, 2015. Accessed May 6, 2015.

6.      Clinicaltrials.gov. ClinicalTrials.gov Identifier: NCT02032277.https://www.clinicaltrials.gov/ct2/show/NCT02032277?term=veliparib%2C+triple-negative+breast+cancer&rank=2. Last updated: April 21, 2015. Accessed April 6, 2015.

7.      Clinicaltrials.gov. ClinicalTrials.gov Identifier: NCT01848834.https://clinicaltrials.gov/show/NCT01848834. Last updated: April 9, 2015. Accessed April 6, 2015.

8.      Emens LA, Braiteh FS, Cassier P, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC). Presented at: 2015 AACR Annual Meeting; April 18-22; Philadelphia, PA. Abstract 6317.

9.      Clinicaltrials.gov. ClinicalTrials.gov Identifier: NCT02261220.https://www.clinicaltrials.gov/ct2/show/NCT02261220?term=NCT02261220&rank=1. Last updated: January 20, 2015. Accessed May 7, 2015.

10. Jakafi [prescribing information]. Wilmington, DE: Incyte Corporation; December 2014.

11. Clinicaltrials.gov. ClinicalTrials.gov Identifier: NCT02120417.https://www.clinicaltrials.gov/ct2/show/NCT02120417?term=NCT02120417&rank=1. Last updated: April 17, 2015. Accessed May 7, 2015.