Resistance Shapes New Therapeutic Options in ER-Positive Breast Cancer

Publication
Article
Oncology Live®Vol. 20/No. 16
Volume 20
Issue 16

Although hormonal manipulation was an established part of breast cancer treatment long before the underlying biology of the disease was characterized, advancements in the understanding of estrogen receptor signaling are rapidly changing the therapeutic landscape.

Although hormonal manipulation was an established part of breast cancer treatment long before the underlying biology of the disease was characterized,1 advancements in the understanding of estrogen receptor (ER) signaling are rapidly changing the therapeutic landscape. In the past 4 years,2-4 CDK4/6 inhibitors have emerged as a new class of therapy for patients with hormone receptor—positive, HER2-negative disease, yielding impressive survival gains when added to endocrine therapy in the frontline setting and after progression.5

Table. Select Clinical Trials of Novel Agents Aimed at Endocrine Therapy Resistance

The first PI3K inhibitor for breast cancer, alpelisib (Piqray), was approved in May after several years of frustrated attempts to target this pathway.6 Alpelisib is poised to change the therapeutic landscape thanks to a growing understanding of the molecular mechanisms underlying resistance to endocrine therapy.7

This challenge is driving the development of novel strategies, including combinations involving anti—PD-1/PD-L1 immune checkpoint inhibitors. Efforts are also underway to extend survival by improving the sequencing of current therapies. Targeted therapies aimed at nodes in cell-signaling networks implicated in ER resistance and next-generation endocrine therapies are among the many approaches being tested in clinical trials (Table).

A Complex Pathway and a Cancer Driver

After years of study, investigators have discovered that ER is expressed in the majority of breast cancers and ER-mediated signaling is profoundly complex.8,9 Endocrine therapies that modulate estrogen production or block ER signaling have revolutionized the management of ER-positive breast cancer across the continuum of care.10

Estrogen is a steroid hormone that plays a vital role in the development of female secondary sexual characteristics, including the formation and function of the breasts. Three major forms of estrogen exist: estrone (E1), 17β-estradiol (E2), and estriol (E3). All are produced by the action of aromatase enzymes on various precursors, including testosterone.11,12

In premenopausal women, circulating estrogen predominantly originates in the ovaries. After menopause, the ovaries shut down estrogen production, and the concentration of circulating estrogen lowers accordingly. Other tissues continue to produce small amounts of estrogen.11

Because they are derived from cholesterol, steroid hormones are highly fat soluble and pass readily across cell membranes. Estrogen exerts its cellular effects in a number of ways but mainly by binding to ERs, various forms of which are found in the nucleus and the cytoplasm and on the plasma membrane.11,12

The dominant types of ER are ERα and β, encoded by the ESR1 and ESR2 genes, respectively. The 2 are functionally quite distinct, and ERα predominates in the breast.12,13

Figure. Endocrine Therapy in Action19

ER signaling is highly complex, conducting different functional outcomes depending on the cellular context. In the classical ER signaling pathway, often called the genomic pathway, estrogen binds to nucleus-based ER, which until that point is locked in an inhibitory complex with various chaperone proteins.13

Estrogen binding induces a conformational change in the receptor, freeing it and allowing it to dimerize. The change also creates a platform for interaction with a range of coregulatory proteins that finetune ER activity. The activated dimers assemble into multiprotein complexes with coregulators and, through the ER’s DNA-binding domain, bind to sequences within the promoters of target genes called estrogen response elements, driving their transcription and thereby orchestrating a variety of physiological processes.11,14-16

In a second pathway—the nongenomic, or nonnuclear, pathway—estrogen binds to ERs in the cytoplasm or on the cell membrane, activating a distinct cascade of signaling pathways but, ultimately, albeit in a more indirect manner, also triggering gene expression.11,13,16,17

Prolonged exposure to estrogen is linked to increased risk of breast cancer development, yet the precise mechanisms of estrogen-induced carcinogenesis are still not fully elucidated.16

Undoubtedly, its effects are mediated predominantly through its binding to ERα, which is expressed in up to 70% to 80% of breast cancers, making ER-positive breast cancers the largest subgroup.15 The proportion of patients with ER positivity increases with age; in postmenopausal women, breast cancers are overwhelmingly ER positive.18

Endocrine Therapy Takes Center Stage

The idea of treating breast cancer with endocrine ablation dates back more than a century, when oophorectomy was shown to have a pronounced effect on a patient with advanced cancer.1 The era of endocrine therapies really took off in the 1970s, with the arrival of tamoxifen. Three classes of endocrine therapy now exist in breast cancer: selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs), with different mechanisms for inhibiting tumorigenic ER activity (Figure19).

Tamoxifen, which is a SERM, is a nonsteroidal compound that competes with estrogen for binding to the ER. It remains a recommended treatment option for both pre- and postmenopausal women with breast cancer and is most commonly used in the adjuvant setting in patients with early-stage disease to reduce the risk of recurrence.16,20 The National Comprehensive Cancer Network guidelines recommend 5 to 10 years of treatment with tamoxifen, based on the results of the ATLAS study.21,22

Several other SERMs have been developed, including toremifene, a chlorinated derivative of tamoxifen that has shown equivalent efficacy to tamoxifen in several clinical trials and is therefore also a recommended treatment option.23 Tamoxifen and a second SERM, raloxifene, are approved as chemopreventives for patients with a higher- than-average risk of breast cancer.20 Investigators were also studying raloxifene in the metastatic setting, but clinical development was discontinued following disappointing results in the frontline setting and in patients with tamoxifenrefractory disease.24,25

Because of its potential for ER agonism in certain tissues or contexts, tamoxifen is associated with serious adverse events (AEs) with long-term use, such as an increased risk of endometrial cancer and thrombotic events.20,21

SERDs have a high affinity for the receptor, with none of the agonist activities of the SERMs.26 Currently, fulvestrant (Faslodex) is the only FDA-approved SERD in the breast cancer setting. First approved in 2002 for patients with tamoxifen-resistant breast cancer, fulvestrant subsequently received a regulatory nod in the frontline setting in 2017 in postmenopausal women who have not received prior endocrine therapy, based on the results of the FALCON trial.27 The most significant limitation of fulvestrant is its intramuscular route of administration.

AIs, the third class of endocrine therapy, are designed to block the activity of the aromatase enzyme and reduce circulating levels of estrogen to block ER activation. Three drugs in this category are FDA approved: anastrozole, letrozole, and exemestane.28

The 3 AIs are distinguished by structural differences—exemestane is steroidal, and letrozole and anastrozole are nonsteroidal—which means their binding to aromatase is either irreversible (exemestane) or reversible (letrozole and anastrozole). Beyond this, their mechanism of action is identical, and all 3 reduce estrogen levels by more than 80%.29-31

AIs are among the recommended treatment options in the adjuvant setting, either as initial adjuvant therapy or following tamoxifen. In the metastatic setting, they are the recommended first-line endocrine therapy option, demonstrating advantages over tamoxifen.22,32-34

For a number of reasons, AIs are less effective in inhibiting ovarian estrogen production, and initially, AIs were reserved for the treatment of postmenopausal patients. Because of the exquisite sensitivity of the ovarian aromatase gene to changes in luteinizing hormone (LH), LH-releasing hormone analogues have been developed for ovarian suppression in premenopausal women and have helped to extend the use of AIs to this setting.19,35

Targeted Therapy Combinations Boost Outcomes

Although endocrine therapy is associated with significant clinical benefits across the continuum of ER-positive breast cancer treatment, the development of intrinsic and acquired resistance is a major challenge.

As investigators have unraveled the complexities of the ER pathway, the understanding of the potential mechanisms of resistance has translated into improved clinical outcomes with the introduction of drugs that target the broader ER signaling pathway and other networks with which it interacts.

Among the many mechanisms of resistance, those that are currently the most clinically relevant are cross-talk with other signaling pathways and mutations in the ligand-binding domain of the ESR1 gene. Originally, ESR1 mutations were thought to be present at a very low frequency in primary breast cancers, but more recent studies using more sensitive technologies suggest a slightly higher prevalence of up to 7%.36 In metastatic ER-positive breast cancer samples, however, especially from patients treated with AIs, the prevalence is much higher—between 11% and 39%.37

ESR1 mutations have been shown to induce potent estrogen-independent transcriptional activity of the ER and resistance to endocrine therapy. Their predictive and prognostic value is still being worked out, but clinicians will likely increasingly use them to guide therapy.37

Activated ERs cross-talk with and activate various intracellular signaling pathways. Central among them are the PI3K/AKT/mTOR and CDK4/6 pathways. The former plays a critical role in mediating cell growth and survival, and the latter regulates the progression of the cell cycle.24

Based on the results of the BOLERO-2 study, the FDA approved the mTOR inhibitor everolimus (Afinitor) in 2012, in combination with exemestane, for the treatment of postmenopausal women with advanced, ER-positive breast cancer, following progression on previous AI therapy.38,39

However, the development of CDK4/6 inhibitors represents the most significant advance. Three agents in this class are now approved by the FDA: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio).2-4 On the basis of randomized clinical trials demonstrating greatly prolonged progression-free survival (PFS) with combination therapy, all 3 CDK4/6 inhibitors are indicated in the frontline setting in combination with a nonsteroidal AI. Ribociclib is also approved in combination with fulvestrant in postmenopausal women and in combination with an AI and ovarian function suppression in premenopausal women.

Approvals have also been secured for the treatment of postmenopausal patients who have relapsed following prior endocrine therapy for all 3 CDK4/6 inhibitors in combination with fulvestrant. Abemaciclib is the only CDK inhibitor currently approved as monotherapy.2-5

Ongoing clinical trials are evaluating the use of CDK inhibitor combinations in the adjuvant and neoadjuvant settings in patients with ER-positive disease. Other key research focuses on delineating which drugs and combinations are optimal in the frontline setting and following progression. There is very little to distinguish the efficacy of the CDK inhibitors currently, but differences in ease of use and toxicity profiles can aid decision making.2-4

PI3K Inhibitors Finally Achieve Success

Another major blow was struck to resistant tumors with the recent approval of a PI3K inhibitor for the treatment of ER-positive breast cancer following progression on AIs. Mutations in the PIK3CA gene, which encodes the PI3K α isoform, and alterations in the broader PI3K signaling pathway are common in breast cancer, particularly in the ER-positive subtype, and have been shown to confer resistance to endocrine therapy.40,41 This served as the rationale for the development of PI3K inhibitors in this setting.

Initial development efforts focused on drugs that blocked all the PI3K isoforms, most promisingly with buparlisib. Despite early signs of efficacy, clinical development was limited by AEs arising from off-target effects.41

The focus then shifted to more specific inhibitors. The PI3K β—sparing inhibitor taselisib improved PFS when combined with fulvestrant in the SANDPIPER phase III trial but significantly increased the risk of toxicity.42

The PI3K α—specific inhibitor alpelisib, however, has finally achieved success. Its approval in May was based on the results of the SOLAR-1 trial. Patients (N = 572) with ER-positive, HER2-negative breast cancer that progressed after AI therapy were randomized to a combination of alpelisib plus fulvestrant or placebo plus fulvestrant.

The combination significantly improved PFS among 341 patients with PIK3CA mutations (11.0 vs 5.7 months, respectively; HR, 0.65; P <.001). Grade ≥3 AEs that were more pronounced with the combination included hyperglycemia and rash.7 The FDA also approved a companion diagnostic, the Therascreen PIK3CA RGQ PCR Kit, to enable detection of PIK3CA mutations in the tissue or via liquid biopsy.43

Preclinical studies have demonstrated synergy between PI3K inhibitors and CDK inhibitors in models of ER-positive breast cancer. Clinical trials are evaluating triplet treatment regimens in patients with endocrine resistance.28

Ongoing efforts are targeting other components of the PI3K/AKT/mTOR pathway, including AKT inhibitors and dual PI3K/mTOR inhibitors. Capivasertib is an inhibitor of AKT1, 2, and 3, and results from the phase II FAKTION trial were presented at the 2019 American Society for Clinical Oncology (ASCO) Annual Meeting.

PFS was more than doubled in patients receiving a combination of capivasertib and fulvestrant compared with fulvestrant monotherapy (10.3 vs 4.8 months; HR, 0.58; P = .004). Postmenopausal women (n = 140) with ER-positive, HER2-negative metastatic breast cancer (MBC) were treated in the trial. The most common AEs of any grade were diarrhea, rash, nausea, hyperglycemia, vomiting, and infections.44

Other trials of capivasertib in ER-positive breast cancer have proved disappointing, however, as have trials of other AKT inhibitors, such as MK-2206.45,46 This may be because the drugs have been employed in unselected patient populations. Several ongoing clinical trials are recruiting patients with AKT mutations and other alterations in the PI3K pathway.

Sacituzumab govitecan is an antibody— drug conjugate that targets the trophoblast cell surface antigen 2 (Trop2), an antigen overexpressed in most epithelial cancers. A Trop2-targeting antibody is conjugated to SN-38, the active metabolite of irinotecan. The results of a phase I/II basket trial were presented at the 2018 ASCO Annual Meeting.

Among patients with ER-positive, HER2- negative MBC who had received more than 1 prior endocrine therapy (n = 54), the overall response rate (ORR) was 31%, with 17 partial responses (PRs), and the clinical benefit rate was 48%. Among patients who had received prior CDK4/6 inhibitor therapy, the ORR was 24%. Grade 3 toxicities included neutropenia and leukopenia.47

Next-Generation Antiestrogens

In the vast majority of cases, tumors that become resistant to endocrine therapy, even those with ESR1 mutations, remain dependent on ER signaling, suggesting that more potent or novel endocrine therapies could have clinical benefit.15

Lasofoxifene is a next-generation SERM that has demonstrated activity in patients with ESR1 mutations. The FDA recently granted it fast track designation for use in patients with ER-positive, HER2-negative breast cancer with these mutations, as detected in cell-free circulating tumor DNA.48

The phase II ELAINE trial is ongoing in patients with ER-positive disease that has progressed on an AI plus CDK4/6 inhibitor combination. The hybrid SERM/SERDs bazedoxifene and elacestrant are also being developed.49

To overcome the major limitation of fulvestrant, a range of oral SERDs are also in the early stages of clinical development. Results from an ongoing phase I/II dose-escalation study of SAR439859 were presented at the 2019 ASCO Annual Meeting. Postmenopausal patients (n = 16) with ER-positive, HER2-negative MBC treated with a median of 3 prior anticancer therapies received 20- to 600-mg once-daily doses of SAR439859. One patient had a confirmed PR and 8 had stable disease. No dose-limiting toxicities we observed, and the most frequent AEs were fatigue, hot flushes, nausea, diarrhea, constipation, and decreased appetite.50

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