Biomarker testing where appropriate and novel tailored combination therapies targeting multiple pathways simultaneously may address the high unmet need and optimize treatment outcomes in hormone receptor–positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (mBC) patients who develop resistance or have disease recurrence while on endocrine-based therapy (ET), said Professor Sherko Kümmel of the Interdisciplinary Breast Unit Clinics, Essen-Mitte, Germany, who spoke at the 14th Asia-Pacific Breast Cancer Summit (APBCS 2026).
High unmet need in HR+/HER2- management
“About 70 percent of BC patients have HR+/HER2- disease. It is common for us to encounter patients with a wide spectrum of HR+ disease, ranging from those who are highly sensitive to ET, to those who are resistant and pose great treatment challenges,” stated Kümmel. [www.seer.cancer.gov/statfacts/html/breast-subtypes.html]
“Despite therapeutic advances, there remains a high unmet need, as up to one-third of patients who receive adjuvant ET eventually relapse, and about half of patients with disease recurrence after ET for early BC have endocrine resistance [ER],” Kümmel noted. [Cancers (Basel) 2021;13:369; Cancer Res Treat 2021;53:409-423; Ann Oncol 2025;36:762-774; Int J Cancer 2025;156:1770-1782]
“Furthermore, more than half of patients develop progressive disease [PD] or die within 2 years of receiving ET plus CDK4/6 inhibitor [CDK4/6i] as first-line [1L] treatment for mBC. However, current second-line [2L] standard-of-care [SoC] treatment options [post-CDK4/6i] have limited efficacy, providing short median progression free-survival [mPFS] not exceeding 6 months,” he added. [Clin Breast Cancer 2019;19:317-325; J Clin Oncol 2023;41:4004-4013; Cancers 2025;17:884; Clin Breast Cancer 2022;22:143-148; Olivera M, et al, ESMO Breast Cancer 2023, abstract 1870]
Appropriate biomarker testing to guide Tx decisions
“Treatment decision-making in HR+/HER2- mBC is based on both clinical and molecular factors,” said Kümmel.
Clinical factors include patient factors such as age and comorbidities, and whether ER is primary or secondary. [Psychooncology 2024;33:e6294; J Natl Compr Can Netw 2024;22:e237111; Breast 2024;76:103756; Ann Oncol 2021;32:1475-1495]
Molecular factors include mechanisms of resistance – whether intrinsic (eg, PI3K/ALT pathway, gBRCA1/2 mutations, TP53 mutations) or acquired (eg, ESR1 and NF1 mutations under selective pressure of ET). [Front Endocrinol 2019;10:245; JCO Precis Oncol 2025;9:e2400841; Cancer Med 2021;8581-8594; Breast Cancer Res Treat 2024;207:599-609; Clin Cancer Res 2020;26:608-622]
The evolving treatment landscape of HR+ mBC increasingly requires more extensive biomarker testing. “However, it may not be feasible to test for every biomarker. Testing should be performed if their results are expected to meaningfully guide therapeutic decisions,” Kümmel recommended. “Timely and accurate testing is hence critical for identifying actionable biomarkers and determining eligibility for targeted treatments.”
Actionable biomarkers include PI3K/ALT/mTOR pathway mutations as well as ESR1 mutations, both of which are associated with poor prognosis and significantly (about 5–8.4 months) shorter median overall survival. [BMC Cancer 2022;22:1002; Clin Cancer Res 2022;28:3433-3442]
Presence of PIK3CA mutations (found in 35–40 percent of HR+ BC), for example, is thus predictive of treatment benefit with PI3K/AKT inhibitors, and presence of ESR1 mutations (found in only about 1 percent of patients with early BC, but occurrence increases to about 40 percent in those who have received ≥2L treatments for mBC) is predictive of benefit with oral selective oestrogen receptor degraders (SERDs; eg, elacestrant, giredestrant). [Breast Cancer Res 2020;22:45; N Eng J Med 2023;388:2058-2070; Breast Cancer Res Treat 2024;207:599-609; J Clin Oncol 2024;42:2149-2160; N Engl J Med 2025;392:1189-1202]
“Treating patients upfront with the most efficacious therapy for their disease may help maximize outcomes,” said Kümmel. “For example, combining inavolisib [a PI3K inhibitor] with palbociclib and fulvestrant [CDK4/6i + ET; an established 1L SoC for HR+/HER2- mBC but not a biomarker-selected treatment] in the INAVO120 trial led to significantly longer mPFS than placebo + palbociclib–fulvestrant [15 vs 7.3 months] in patients with PIK3CA-mutated, HR+/HER2- locally advanced or mBC who had experienced relapse during/within 12 months after completing adjuvant ET.” [N Engl J Med 2024;391:1584-1596]
Other doublet (PI3K-3, AKT or PAM inhibitor + ET) and triplet combinations have also shown similar benefits as 1L or ≥2L treatment in this ER population, such as in the CAPItello-291, FINER, and VIKTORIA-1 trials. [N Engl J Med 2023;388:2058-2070; Lancet Oncol 2024;25:655-667; Ann Oncol 2025;36(S2):LBA20]
Pushing beyond the 6-month mPFS ceiling after CDK4/6i
Although these trials demonstrated clinical benefits in the overall study populations, subgroup analyses showed that 2L mPFS was significantly shorter among patients who had previously received CDK4/6i – regardless of whether these agents were used in biomarker-selected regimens. In most cases, 2L mPFS did not exceed 6 months, compared with substantially longer durations in CDK4/6i‑naïve patients (eg, 5.5 vs 11.0 months in the CAPItello‑291 trial). [J Clin Oncol 2023;41;4004-4013; Cancers 2025;17:884; Clin Breast Cancer 2022;22:143-148; Olivera M, et al, ESMO Breast Cancer 2023, abstract 1870; N Engl J Med 2023;388:2058-2070]
Similarly, efficacy is limited with 2L oral SERD monotherapy in patients with ESR1‑mutated disease, as reported in the EMERALD and EMBER‑3 trials (mPFS, 3.4 and 5.4 months). [J Clin Oncol 2022;40:3246-3256; N Engl J Med 2025;392:1189-1202]
“Ongoing phase III trials have shown promising results in diversification of the 2L landscape in terms of providing tailored combination therapies according to disease biology,” said Kümmel. In the evERA trial, for example, benefit with giredestrant + everolimus [an mTOR inhibitor] therapy was observed irrespective of ESR1 mutation status, achieving an mPFS of 9.99 months vs 5.45 months with SoC ET + everolimus for HR+/HER2- advanced BC, post-CDK4/6i with ESR1 mutations, while mPFS in the intent-to-treat [ITT] population was 8.77 and 5.49 months, respectively. [Ann Oncol 2025;36(S2);LBA16] “The treatment was well tolerated, and the combination could become the first all-oral SERD combination regimen post-CDK4/6i to be approved,” he noted.
Similarly, in the EMBER-3 trial, imlunestrant–abemaciclib combination therapy significantly improved mPFS compared with imlunestrant alone, regardless of ESR1-mutation status (mPFS, 9.4 vs 5.5 months). [N Engl J Med 2025;392:1189-1202]
“The combination of SERDs and selective oestrogen receptor modulators [SERMs] with targeted therapies, such as PI3K and CDK4/6 inhibitors, represents the future of ET‑based treatment in the CDK4/6i‑pretreated population,” noted Kümmel. “Robust, accurate biomarker testing is key for optimizing patient outcomes. Yet, while both biomarker‑guided and non–biomarker‑selected strategies can help clinicians navigate an increasingly complex therapeutic landscape, the optimal sequencing of these options remains to be established.”