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IN THE SPOTLIGHT

Targeting Apoptosis: A New Paradigm for the Treatment of Estrogen Receptor–Positive Breast Cancer Joshua Z. Drago , Sarat Chandarlapaty , and Komal Jhaveri

Memorial Sloan Kettering Cancer Center, New York, New York. Corresponding Author: Komal Jhaveri, Memorial Sloan Kettering Cancer Center, 300 E 66th Street, New York, NY 10065. Phone: 212-639-2000; Fax: 646-888-4555; E-mail: jhaverik@mskcc.org doi: 10.1158/2159-8290.CD-19-0050 ©2019 American Association for Cancer Research.

Summary: Standard treatment for estrogen receptor–positive metastatic breast cancer involves antiestrogen therapy used alone or in combination with inhibitors of CDK4/6 or mTOR; this approach works mechanistically by eliciting and reinforcing cell-cycle arrest. In this issue, Lok and colleagues diverge from this paradigm by combin-ing the BCL2 inhibitor venetoclax with tamoxifen in a phase Ib clinical trial, building on preclinical work to demon-strate that targeting apoptosis could represent a promising new strategy in the treatment of breast cancer.

See related article by Lok et al., p. 354 (6).

Approximately 70% of breast cancers express the estrogen receptor, and antiestrogen therapy is the mainstay of treat-ment for estrogen receptor–positive (ER + ) patients. In con-trast to traditional cytotoxic chemotherapies, which function largely by triggering cell damage and eliciting apoptosis, anti-estrogen therapies work by causing cell-cycle arrest in G 1 , lead-ing to inhibition of neoplastic proliferation and macroscopic tumor stasis ( 1 ). When used as monotherapy, antiestrogen treatments such as selective estrogen receptor modulators (SERM), selective estrogen receptor degraders (SERD), or aromatase inhibitors (AI) can result in prolonged clinical responses, even in patients with widely metastatic disease.

Recent clinical advances in the treatment of metastatic ER + breast cancer have built directly on this principle by adding inhibitors of CDK4/6 or mTOR to antiestrogen therapies. These newer combination treatment regimens work by rein-forcing the pressure to remain in cell-cycle arrest, and even encouraging G 1 exit into a state of quiescence/senescence. This approach has resulted in a marked improvement in progression-free survival in the fi rst- or second-line meta-static setting, and underlies the current standard of care of combining either palbociclib, ribociclib, or abemaciclib (the three FDA-approved CDK 4/6 inhibitors) with an AI or the ER downregulator fulvestrant ( 2–4 ).

Despite these signifi cant advances, resistance to antiestro-gen combination therapies is clinically inevitable, largely via mechanisms that allow for bypass of the G 1 –S checkpoint and reentry into the cell cycle ( 5 ). The emergence of endocrine therapy resistance is arguably the central challenge in the treatment of ER + breast cancer, and few therapeutic options exist to treat these patients. Other attempts to combat endo-crine resistance have focused on targeting various hallmarks

of cancer biology such as angiogenesis, immune evasion, and growth factor signaling. However, none of these strategies have led to FDA-approved therapies in ER + breast cancer or moved the needle signifi cantly with respect to clinical outcomes.

In this issue of Cancer Discovery , Lok and colleagues offer a new mechanistic strategy to address the problem of endo-crine therapy resistance, building on strong preclinical work to demonstrate that the apoptotic cascade is a targetable pathway in breast cancer. This novel approach comes in the form of a phase Ib dose escalation and expansion study of the BCL2 inhibitor venetoclax, given along with tamoxifen in patients with ER + , BCL2-expressing metastatic breast cancer ( 6 ).

By way of background, BCL2 is a prosurvival protein and a member of the apoptosis-regulating apparatus called the BCL2 family, which plays a key role in regulating mitochondrial outer membrane permeability (MOMP), considered the point of no return in intrinsic apoptosis ( 7 ). BCL2 is expressed in approximately 75% of breast cancers and is associated with low tumor grade and ER positivity ( 8 ). Inhibition of BCL2 has been shown to be cytotoxic in breast cancer cell lines and xenograft mod-els when used in combination with antiestrogen therapy, perhaps by exploiting mitochondrial priming caused by estrogen deprivation, and tipping the scales for cells to proceed toward MOMP and cell death ( 9 ). Venetoclax is FDA-approved for the treatment of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and acute myeloid leukemia (AML), but has never been studied in solid tumors.

The primary endpoint of the study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of venetoclax given with tamoxifen in patients with hormone receptor–positive metastatic breast cancer. In all, the drug appeared relatively well tolerated. No DLTs were observed at the maximum planned dose of 800 mg daily, and the observed toxicity profi le was similar to that reported in the original phase I study of venetoclax (400 mg daily) in CLL ( 10 ). As might be expected, cytopenias predominated, with

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lymphopenia occurring in 29 of 33 cases (88%), neutropenia occurring in 24 of 33 cases (73%), and anemia occurring in 13 of 33 cases (39%). Gastrointestinal side effects also occurred, including nausea, vomiting, and diarrhea. MTD was not technically reached, and pharmacokinetic studies were not performed.

Secondary endpoints in the study included overall response rate (ORR) and progression-free survival (PFS). Caution must be taken when interpreting clinical outcomes from a small, nonrandomized trial; however, these early results are promising. The group observed an ORR in 15 of 33 patients (45%), with an additional 8 patients demonstrating stable disease lasting more than 24 weeks. The overall clinical ben-efit rate reached 75% when analysis was limited to patients receiving the maximum dose, and PFS for patients in this group was 51 weeks. Because response rates appeared better at higher doses, the question remains of whether efficacy might be improved further at doses >800 mg per day.

Correlative studies were also performed, including post-treatment biopsies in a small subset of patients and meas-urement of circulating tumor DNA (ctDNA). Although post-treatment biopsies were obtained too late (after 28 days) to shed light on the mechanism of treatment effect, biopsies obtained at progression interestingly suggested that loss of BCL2 expression could not account for treatment resistance. ctDNA genotyping revealed mutations in PIK3CA and ESR1 that did not seem to modulate response to therapy in this small sample; however, significant reductions in ctDNA were observed in responders, further validating the role of ctDNA in monitoring treatment effect.

These results are compelling for several reasons. First, we draw special attention to the clinical benefit that was demonstrated in 8 of 12 patients (67%) who had received >3 lines of prior therapy for metastatic disease. This finding is encouraging, as is the finding that venetoclax seemed to be able to resurrect the efficacy of tamoxifen in several previ-ously resistant patients. It would be especially promising if this drug combination is shown to be active in patients with prior exposure to CDK4/6 inhibitors, reflecting its most likely clinical niche. To that end, a phase II trial of fulvestrant with or without venetoclax is currently ongoing in patients who have progressed on or after a CDK4/6 inhibitor (clinicaltrials.gov identifier: NCT03584009).

Looking forward, it will be interesting to explore whether expression levels of BCL2 (or other members of the BCL2 protein family) might help to predict treatment response. Developing a clinically meaningful definition of BCL2 expres-sion will also be important as we step into an era in which biomarker-stratified treatment defines the standard of care. For instance, one could foresee a future in which patients har-boring PIK3CA mutations could be treated with a SERD plus alpha-specific PI3K inhibitor (if approved based on results from the phase III SOLAR-1 trial; ref. 11), whereas PIK3CA wild-type, BCL2-overexpressing patients could be treated with a SERD plus venetoclax.

Although more robust prospective data are forthcoming, the paradigm of using BCL2 inhibitors to sensitize suscep-tible cells to drug-induced stress and apoptosis is intriguing

and may have broad potential application in breast can-cer and beyond. Within the breast cancer space specifically, future studies could potentially investigate the safety and efficacy of BCL2 inhibitors in combination with more potent antiestrogen drugs such as SERDs, or alongside PI3K inhibi-tors, mTOR inhibitors, or CDK4/6 inhibitors, which may synergize to elicit apoptosis. No doubt many of these trials will be under way soon.

In conclusion, this laudable translational effort by Lok and colleagues generates exciting questions about the modula-tion of apoptotic signaling in the treatment of cancer, and sparks optimism about the therapeutic potential of this approach. We eagerly anticipate the results of later-phase studies to elucidate the true clinical role for BCL2 as a target in breast cancer.

Disclosure of Potential Conflicts of InterestS. Chandarlapaty reports receiving a commercial research grant

from Daichi Sankyo and is a consultant/advisory board member for Eli Lilly, Sermonix, Context Therapeutics, Sun Pharma, Revolutions Medicine, Novartis, AstraZeneca, and Chugai. K. Jhaveri reports receiving commercial research support from Novartis, Genentech, Pfizer, Novita Pharmaceuticals, ADC Therapeutics, Debio Pharma-ceuticals, and Lilly Pharmaceuticals and is a consultant/advisory board member for Pfizer, Bristol-Myers Squibb, ADC Therapeutics, Jounce Therapeutics, Taiho Oncology, AstraZeneca, Novartis, and Spectrum Pharmaceuticals. No potential conflicts of interest were disclosed by the other author.

AcknowledgmentsThis work was supported by NCI Cancer Center Support Grant

P30CA08748.

Published online March 1, 2019.

REFERENCES 1. Osborne CK, Boldt DH, Clark GM, Trent JM. Effects of tamoxifen on

human breast cancer cell cycle kinetics: accumulation of cells in early G1 phase. Cancer Res 1983;43:3583–5.

2. Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med 2016;375:1925–36.

3. Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor–positive, human epidermal growth factor recep-tor 2–negative advanced breast cancer: MONALEESA-3. J Clin Oncol 2018;36:2465–72.

4. Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 2017;35:2875–84.

5. Yang C, Li Z, Bhatt T, Dickler M, Giri D, Scaltriti M, et al. Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence. Oncogene 2017;36:2255.

6. Lok SW, Whittle JR, Vaillant F, Teh CE, Lo LL, Policheni AN, et al. A phase Ib dose-escalation and expansion study of the BCL2 inhibitor venetoclax combined with tamoxifen in ER and BCL2–positive meta-static breast cancer. Cancer Discov 2019;9:354–69.

7. Tait SW, Green DR. Mitochondrial regulation of cell death. Cold Spring Harb Perspect Biol 2013;5:a008706.

Research. on June 11, 2020. © 2019 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

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8. Dawson SJ, Makretsov N, Blows FM, Driver KE, Provenzano E, Le Quesne J, et al. BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received. Br J Cancer 2010;103:668.

9. Vaillant F, Merino D, Lee L, Breslin K, Pal B, Ritchie ME, et al. Tar-geting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer. Cancer Cell 2013;24:120–9.

10. Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, et al. Targeting BCL2 with venetoclax in relapsed chronic lympho-cytic leukemia. New Engl J Med 2016;374:311–22.

11. André F, Ciruelos EM, Rubovszky G, Campone M, Loibl S, Rugo HS, et al. LBA3_PR Alpelisib (ALP)+ fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase III SOLAR-1 trial. Ann Oncol 2018;29:mdy424-010.

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2019;9:323-325. Cancer Discov   Joshua Z. Drago, Sarat Chandarlapaty and Komal Jhaveri 

Positive Breast Cancer−Estrogen Receptor Targeting Apoptosis: A New Paradigm for the Treatment of

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