The Changing Landscape of Targeted Breast Cancer Therapies

Dr. Hunter is an Assistant Professor of Oncology in the breast oncology group at the University of Washington. Her research interests include circulating tumor DNA and clinical biomarker development.

Dr. Davidson serves as President of the Seattle Cancer Care Alliance, Senior Vice President and Director of the Clinical Research Division of the Fred Hutchinson Cancer Research Center, and Chief of the Division of Medical Oncology at the University of Washington. She served as President of the American Society of Clinical Oncology from 2007-2008 and President of the American Association of Cancer Research from 2016-2017.

Targeted therapies have traditionally played a huge role in breast cancer treatment, and this will only increase. As we learn more about molecular mechanisms of breast cancer, matching the right agent with the right patient will be key, as Dr O’Shaughnessy points out. This will require excellent biomarkers, more consistent ways to obtain metastatic samples, and methods to achieve continuous surveillance for nimble–and even anticipatory–responses to tumor evolution and resistance. It also means that the world of breast cancer care will become increasingly complex for providers, raising the question of how to disseminate this burgeoning body of knowledge to all clinicians.

Dr O’Shaughnessy discusses how the FDA approval of alpelisib (Piqray) is bringing a sea change in metastatic breast cancer. As 40% of estrogen receptor-positive (ER-positive) tumors demonstrate PIK3CA mutations, molecular analysis of metastatic tissue has suddenly become critical in the clinical management of patients with metastatic breast cancer. As investigators develop even more targeted agents, obtaining metastatic specimens–possibly in a serial fashion through liquid biopsy–will likely become routine. 

But what will we measure? We all agree that accurate and validated biomarkers are essential, but this area is in tremendous flux, even with more standard markers. For example, several new agents have emerged in the human epidermal growth factor receptor 2 (HER2) space. Trastuzumab deruxtecan (Enhertu) demonstrates striking activity in HER2 low-expressing, ER-positive breast cancer; in an era where we see more “splitting” than “lumping” in targeted therapies, it is encouraging to witness a drug that may enjoy a broader application across breast cancer histologies.¹ Results from the recent SUMMIT basket trial evaluating patients with classically HER2-negative tumors suggest that patients whose tumors display ERBB2-activating mutations may benefit from the oral agent neratinib (Nerlynx).² Although the American Society of Clinical Oncology/College of American Pathologists HER2 practice guideline update released in 2018 addressed several ambiguities for clinical decision making.³ Such developments underscore that the HER2 pathway remains a fertile area of investigation. Indeed, we may move beyond classifying tumors as simply HER2-positive or HER2-negative. 

We face similar challenges with newer biomarkers. Given the results of KEYNOTE-522, we are likely to see FDA approval of pembrolizumab (Keytruda) in the neoadjuvant setting for triple-negative breast cancer (TNBC) in the coming year. But the KEYNOTE investigators (including Dr O’Shaughnessy) point out the difficulty in understanding differences in patient response based on programmed cell death protein 1 expression when they are uncertain how to define this metric.⁴ The androgen receptor (AR) is another exciting target in breast cancer therapeutics, but the definition of AR positivity remains a question. Sensitivity to Akt inhibitors such as ipatasertib may be indicated by PTEN loss, and markers that we do not currently test, such as Akt phosphorylation. Rapid and careful basic and translational research will be key to elucidate the signals that best indicate the activity of these drugs in our patients. 

Of course, the utility of a biomarker is inextricably tied to its interpretation and context. The same genomic mutation may support very different avenues of therapy, given different breast tumor histologies or multiple possible therapies for the same histology. The Akt inhibitors, which Dr O’Shaughnessy predicts may soon enter practice in breast cancer, offer an example. Ipatasertib, a potent Akt inhibitor under investigation in breast, prostate, and other solid tumors, seems to demonstrate synergistic activity with chemotherapeutic agents such as paclitaxel through activation of the PI3K/Akt pathway in the setting of mitotic stress in a tumor. Patients whose triple-negative breast tumors demonstrated alterations in PIK3CA, Akt1, or PTEN in next-generation sequencing (NGS) assays appear to derive the most benefit from the addition of this drug in early analyses.^5,6 Capivasertib has also shown a similarly stratified response among patients with TNBC with and without these mutations.⁷

Meanwhile, preliminary results from a phase IB study investigating ipatasertib, atezolizumab (Tecentriq), and paclitaxel versus nab-paclitaxel (Abraxane) for locally advanced or metastatic TNBC showed an overall response rate of 73% regardless of biomarker status.⁸ One projected mechanism for this response is downregulation of Akt, which is thought to potentiate resistance to immune checkpoint inhibition. Antagonizing the PI3K/Akt pathway may reverse this resistance and prolong response to immunotherapy.⁹

If both therapeutic pathways ultimately demonstrate benefit, it may be difficult to determine which therapy to choose in a patient with the relevant mutation(s). This is a “good” dilemma, but one we will likely face repeatedly as other targeted drugs enter the pipeline. Additional hurdles include optimizing drug combinations, which have often been limited by toxicity, and questions of sequencing and prioritizing therapies. Further research should clarify these and other issues over time, but the entire field will change and develop rapidly for the foreseeable future. 

In the face of such complexities, medical oncologists will need to seek out educational opportunities to stay abreast of a rapidly changing field. Traditionally, meetings like Miami Breast Cancer Conference® have offered updates. In the era of coronavirus disease 2019 and beyond, more virtual seminars and conferences may supplant large in-person gatherings. But even this may not be enough. In the same way that today’s hospital would not purchase a positron emission tomography (PET) scanner without hiring a radiologist who can interpret PET images, we soon may consider molecular testing reports to be of limited utility without access to high-level clinical expertise in molecular pathology and biomarker interpretation. Practices across the country are already making use of molecular tumor boards to parse the complex information offered by NGS reports. With the emergence of new drugs and novel postgenomic biomarkers, including functional protein assays, RNA testing, and epigenetic profiling, the demand for this vital specialized assistance will only increase. 

We live in an exciting and hopeful era for breast cancer therapeutics; however, advances bring challenges in matching the right therapy to the right patient at the right time. Validated biomarkers are needed along with investigations into how to best translate our new knowledge into therapeutic interventions. Clinicians must continuously educate themselves as they adjust to this shifting landscape; however, they will also need guidance in the form of strong ties to specialist molecular pathologists and tumor boards. 

References:

1.         Modi S, Park H, Murthy RK, et al. Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ib study. J Clin Oncol. 2020:JCO1902318 (in press). doi: 10.1200/JCO.19.02318.

2.         Hyman DM, Piha-Paul SA, Won H, et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature. 2018;554(7691):189-194. doi: 10.1038/nature25475.

3.         Wolff AC, Hammond MEH, Allison KH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update. J Clin Oncol. 2018;36(20):2105-2122. doi: 10.1200/JCO.2018.77.8738.

4.         Schmid P, Cortes J, Pusztai L, et al; KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821. doi: 10.1056/NEJMoa1910549.

5.         Kim SB, Dent R, Im SA, et al; LOTUS Investigators. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2017;18(10):1360-1372. doi: 10.1016/S1470-2045(17)30450-3.

6.         Oliveira M, Saura C, Nuciforo P, et al. FAIRLANE, a double-blind placebo-controlled randomized phase II trial of neoadjuvant ipatasertib plus paclitaxel for early triple-negative breast cancer. Ann Oncol. 2019;30(8):1289-1297. doi: 10.1093/annonc/mdz177.

7.         Schmid P, Abraham J, Chan S, et al. Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial. J Clin Oncol. 2020;38(5):423-433. doi: 10.1200/JCO.19.00368.

8.         Chan JJ, Tan TJY, Dent RA. Novel therapeutic avenues in triple-negative breast cancer: PI3K/AKT inhibition, androgen receptor blockade, and beyond. Ther Adv Med Oncol. 2019;11:1758835919880429. doi: 10.1177/1758835919880429.

9.         O'Donnell JS, Massi D, Teng MWL, Mandala M. PI3K-AKT-mTOR inhibition in cancer immunotherapy, redux. Semin Cancer Biol. 2018;48:91-103. doi: 10.1016/j.semcancer.2017.04.015.