Navigating the Evolving Landscape of ER-Positive Metastatic Breast Cancer Treatment

Therapeutic options for patients with estrogen receptor-positive (ER+) breast cancer (BC) have expanded substantially over the decades, driven by the introduction of novel treatments that enhance responses and reduce the toxic burden on patients. These therapies represent a significant advancement in managing this BC subtype by improving clinical outcomes and providing more personalized treatment options tailored to each patient’s unique characteristics.

Breast cancer cells | Image Credit: © Green Creator - stock.adobe.com

At the 2024 San Antonio Breast Cancer Symposium in San Antonio, Texas, experts discussed the latest advancements in treatment for ER+ BC, highlighting the role of endocrine therapies (ET), CDK4/6 inhibitors, the PI3K inhibitors, and the emerging antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd, Enhertu; Daiichi Sankyo) and sacituzumab govitecan-hzi (SG, Trodelvy; Gilead Sciences, Inc).¹

ER+ BC is a prevalent subtype of BC, characterized by high levels of estrogen in malignant cells and accounting for approximately 70%-80% of all BC diagnoses. While ER+ BC tends to grow more slowly compared to other subtypes, it can progress to metastatic disease, which remains incurable. Over the years, the treatment landscape for metastatic ER+ BC has rapidly evolved, with the introduction of targeted therapies such as CDK4/6 and PI3K inhibitors, as well as ADCs, which have demonstrated significant efficacy in improving progression-free survival (PFS) and overall outcomes. These advancements have broadened treatment options, allowing for more precise, individualized care and better management of this complex disease.^2,3

CDK4/6 Inhibitors

The FDA approved CDK4/6 inhibitors have demonstrated meaningful improvements in PFS, driving their move to the standard of care (SOC) treatment for BC. In the investigator-initiated, multicenter, randomized phase 3 SONIA study (NCT03425838), investigating sequencing of CDK4/6 inhibitors and ET in the treatment of metastatic ER+ BC. The patients were randomly assigned 1:1 to receive either a CDK4/6 inhibitor (palbociclib [Ibrance; Pfizer], ribociclib [Kisqali; Novartis], or abemaciclib [Verzenio; Eli Lilly]) plus an aromatase inhibitor (AI) upfront, followed by fulvestrant (Faslodex; AstraZeneca) at progression; or an AI alone upfront, followed by a CDK4/6 inhibitor plus fulvestrant at progression. The primary end point was PFS 2, which looked at the time to second progression event.⁴

According to the study results, using the CDK4/6 inhibitor-AI combination upfront resulted in a significantly improved PFS2 compared to starting with the AI alone, suggesting that giving the CDK4/6 inhibitor-based regimen earlier in the treatment sequence may provide greater overall disease control. However, the use of a CDK4/6 inhibitor as the first-line treatment was associated with a 40% increase in grade 3 and 4 adverse events (AE). Additionally, this upfront treatment option led to an extra $200,000 in drug costs per patient compared to other treatments.

“This data was quite provocative and interesting, and really made a lot of us think about the patient before us, and whether or not we can start with a single agent, [ET],” said Sara Hurvitz, MD, FACP, medical oncologist at the Fred Hutchinson Cancer Center, Seattle, Washington.

The data provides valuable insights into the benefits and opportunities of sequencing CDK4/6 inhibitors and endocrine therapy. It also highlights the potential trade-offs between improved PFS2 and increased toxicity and cost when using these combinations earlier in the treatment course.

PI3K Inhibitors

PI3K inhibitors have emerged as another pivotal treatment option, particularly for patients who are resistant to traditional ETs. However, they have presented challenges with toxicity management, particularly with regards to hyperglycemia. Alpelisib (Piqray, Novartis Pharmaceuticals Corporation) is a PI3K inhibitor approved by the FDA on May 24, 2019, in combination with fulvestrant for postmenopausal women, and men, with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic BC. Despite demonstrating favorable PFS in the SOLAR-1 trial (NCT02437318), the majority of AEs were metabolic toxicities.^5,6

“With alpelisib [Piqray; Novartis], we have over a third of patients with grade 3 or higher hyperglycemia,” said Neil Vasan, MD, PhD, clinical oncologist at Columbia University Medical Center. “And the patient population that was investigated had an A1c less than 6.5%. This is very stringent. We have so many patients who don't fit these very, very strict criteria, and we have to make decisions about whether this is the best drug for them or not.”

Early data suggests that mutant-selective PI3K inhibitors are a potential strategy to address the toxicity concerns associated with these drugs. These inhibitors, namely STX-478 and RLY-2608, are designed to selectively target the mutant form of the PI3K enzyme in cancer cells, rather than inhibiting the wild-type form that is important for normal metabolism. As a result, they may have a more favorable toxicity profile.

“We now have a new class of drugs—mutant-selective PI3K inhibitors,” explained Vasan. “We know how crucial PI3K is for normal metabolism in humans, and any alteration in that pathway can lead to a wide range of side effects. One innovative approach we’re seeing to manage these toxicities is to specifically target the mutant PI3K found in cancer cells, rather than inhibiting the wild type, unmutated PI3K that is present in muscle, fat, and liver. This strategy helps avoid the on-target side effects like hyperglycemia.”

Genomic testing, particularly using liquid biopsy, plays a critical role in identifying actionable PI3K mutations in patients with metastatic ER+ BC, helping clinicians determine which patients would most likely benefit from these therapies. The use of liquid biopsy was presented as a minimally invasive method to identify these genetic alterations, potentially reducing the need for repeated tissue biopsies. However, there are limitations to liquid biopsy as some patients may have low levels of circulating tumor DNA, which can make it challenging to reliably detect specific mutations.

ADCs

Due to the versatility of ADCs, they have become valuable additions to the first-line, SOC treatment for ER+ BC, offering patients targeted therapies with improved efficacy and reduced toxicities.

Antibody drug conjugate in green | Image Credit: © huenstructurebio.com - stock.adobe.com

T-DXd is a HER2-targeting ADC that was approved by the FDA on April 5, 2024, for adult patients with unresectable or metastatic HER2-positive solid tumors. In the DESTINY-Breast06 trial(NCT04494425), T-DXd demonstrated improvements in PFS and objective response rate (ORR) (approximately 60%) compared with SOC chemotherapy in patients with metastatic ER+, HER2-low BC. These data support the potential use of T-DXd in first-line settings, particularly in patients with high disease burden or rapidly progressing disease.^7,8

“The objective response rate, in my opinion, was the most remarkable result of this study. It has been a key factor in guiding how I incorporate T-DXd in the frontline setting,” shared Sara Hurvitz, MD, FACP, medical oncologist at the Fred Hutchinson Cancer Center, Seattle, Washington. “The confirmed [ORR] was nearly 60% with T-DXd, which is noteworthy for an exclusively ER+, HER2– [BC] population—setting a historical benchmark. For patients with symptomatic disease burden or organ-threatening complications, these data are incredibly valuable in informing treatment decisions.”

However, T-DXd is strongly associated with interstitial lung disease, which resulted in 3 deaths during the trial, underscoring the importance of careful patient selection, close monitoring, and proactive management of side effects. Additionally, limited data on the optimal sequencing of T-DXd with other therapies, such as CDK4/6 inhibitors or PI3K inhibitors highlights the need for further research.

Another emerging agent is sacituzumab govitecan-hzi (SG, Trodelvy; Gilead Sciences, Inc), which showed improved PFS in the TROPIC-02 (NCT03901339) trial evaluating heavily pretreated patients who failed 2 to 4 prior lines of therapy. Similar to T-DXd, the toxicity profile of SG was highlighted as a potential concern, with a 74% rate of grade 3 or higher adverse events.⁹

Treatment Considerations

Given the growing number of treatment options, an individualized, patient-centered approach is essential—one that carefully considers factors such as disease characteristics, genomic profile, and patient preferences.

For patients with rapidly progressing or high-burden disease, achieving a deep and durable response is a critical goal to mitigate symptomatic burden and prevent organ-threatening complications. This often requires a more aggressive treatment approach with agents that can deliver high initial response rates, helping to alleviate symptoms, stabilize organ function, and potentially delay the need for subsequent lines of therapy sooner. Therefore, selecting such agents must carefully account for the patient’s unique clinical characteristics and the balance between response and durability to optimize outcomes.

Patient and doctor planning treatment | Image Credit: © bongkarn - stock.adobe.com

Patient preferences can also influence treatment approaches and decisions, so shared decision-making between the health care team and the patient is essential to ensure optimal outcomes. Many patients with metastatic ER+ BC express a strong preference for oral therapies over intravenous options due to their convenience and the reduced burden of frequent clinic visits. Balancing these preferences with the potential impact of adverse effects, such as fatigue, joint pain, diarrhea, and other gastrointestinal issues, is critical to maintaining quality of life while achieving treatment goals.

Prior therapy and endocrine sensitivity are crucial factors in developing treatment plans for patients with metastatic ER+ BC, and utilizing information regarding their response to previous ETs offers valuable insights into the likelihood of sustained endocrine sensitivity. For example, patients with shorter response durations to prior ETs may be less likely to benefit from further endocrine-based treatments, making the addition of targeted agents such as CDK4/6 inhibitors or PI3K inhibitors necessary to overcome endocrine resistance and improve outcomes. Conversely, those with longer response durations are more likely to maintain endocrine sensitivity and may be better suited for endocrine-based combinations in the metastatic setting.

Future Directions

Effective management of ER+ BC requires careful consideration of the risks associated with each treatment option and the need to tailor these therapies to individual patients. Identifying the most suitable treatment for each patient involves balancing efficacy with potential side effects, ensuring the right treatment approach to optimize outcomes and minimize risks. Additionally, the role of liquid biopsy in detecting actionable genomic alterations was highlighted as a pivotal factor in guiding treatment decisions for ER+ BC.

Exploring these therapies, particularly in patients who have failed prior treatments, is essential for optimizing patient outcomes. Moving forward, a patient-centered approach will be key to overcoming risks and ensuring the most effective treatment for each patient.

REFERENCES

1. Gradishar W, Hurvitz S, Oliphant M, et al. Educational session 6: case based clinical approach to ER Positive metastatic breast cancer - In honor of Dr. V. Craig Jordan. Presented at: 2024 San Antonio Breast Cancer Symposium. December 11, 2024. San Antonio, TX.

2. Breast cancer hormone receptor status. Breastcancer.org. November 13, 2024. Accessed December 12, 2024. https://www.breastcancer.org/pathology-report/hormone-receptor-status

3. Breast cancer hormone receptor status. American Cancer Society. November 8, 2021. Accessed December 12, 2024. https://www.cancer.org/cancer/types/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-hormone-receptor-status.html#:~:text=Hormone%20receptor%2Dpositive%20cancers%20tend,back%20many%20years%20after%20treatment

4. Endocrine therapy plus CDK4/​6 in first or second line for hormone (SONIA) receptor positive advanced breast cancer. ClinicalTrials.gov Identifier: NCT03425838. Updated August 18, 2023. Accessed December 13, 2024. https://www.clinicaltrials.gov/study/NCT03425838

5. FDA approves alpelisib for metastatic breast cancer. FDA. May 24, 2019. Accessed December 12, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-alpelisib-metastatic-breast-cancer

6. Study assessing the efficacy and safety of alpelisib plus fulvestrant in men and postmenopausal women with advanced breast cancer which progressed on or after aromatase inhibitor treatment. (SOLAR-1). ClinicalTrials.gov Identifier: NCT02437318. November 18, 2023. Accessed December 12, 2024. https://clinicaltrials.gov/study/NCT02437318

7. Paving the way for better outcomes in HER2+ early breast cancer treatment. Pharmacy Times. December 12, 2024. Accessed December 12, 2024. https://www.pharmacytimes.com/view/paving-the-way-for-better-outcomes-in-her2-early-breast-cancer-treatment

8. Study of trastuzumab deruxtecan (T-DXd) vs investigator's choice chemotherapy in HER2-low, hormone receptor positive, metastatic breast cancer (DB-06). ClinicalTrials.gov Identifier: NCT04494425. Updated October 10, 2024. Accessed December 12, 2024. https://clinicaltrials.gov/study/NCT04494425

9. Study of sacituzumab govitecan-hziy versus treatment of physician's choice in participants with HR+/​HER2- metastatic breast cancer (TROPiCS-02). ClinicalTrials.gov Identifier: NCT03901339. Updated October 21, 2024. Accessed December 12, 2024. https://clinicaltrials.gov/study/NCT03901339