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. 2024 Oct;207(3):599-609.
doi: 10.1007/s10549-024-07376-w. Epub 2024 Jun 14.

Comprehensive genomic profiling of ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(-) metastatic breast cancer: prevalence along treatment course and predictive value for endocrine therapy resistance in real-world practice

Manali A Bhave #  1 , Julia C F Quintanilha #  2 , Hanna Tukachinsky  3 , Gerald Li  3 , Takara Scott  3 , Jeffrey S Ross  3   4 , Lincoln Pasquina  3 , Richard S P Huang  3 , Heather McArthur  5 , Mia A Levy  3   6 , Ryon P Graf  3 , Kevin Kalinsky  7
Affiliations

Comprehensive genomic profiling of ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(-) metastatic breast cancer: prevalence along treatment course and predictive value for endocrine therapy resistance in real-world practice

Manali A Bhave et al. Breast Cancer Res Treat. 2024 Oct.

Erratum in

Abstract

Background: The treatment landscape for HR(+)HER2(-) metastatic breast cancer (MBC) is evolving for patients with ESR1 mutations (mut) and PI3K/AKT pathway genomic alterations (GA). We sought to inform clinical utility for comprehensive genomic profiling (CGP) using tissue (TBx) and liquid biopsies (LBx) in HR(+)HER2(-) MBC.

Methods: Records from a de-identified breast cancer clinicogenomic database for patients who underwent TBx/LBx testing at Foundation Medicine during routine clinical care at ~ 280 US cancer clinics between 01/2011 and 09/2023 were assessed. GA prevalence [ESR1mut, PIK3CAmut, AKT1mut, PTENmut, and PTEN homozygous copy loss (PTENloss)] were calculated in TBx and LBx [stratified by ctDNA tumor fraction (TF)] during the first three lines of therapy. Real-world progression-free survival (rwPFS) and overall survival (rwOS) were compared between groups by Cox models adjusted for prognostic factors.

Results: ~ 60% of cases harbored 1 + GA in 1st-line TBx (1266/2154) or LBx TF ≥ 1% (80/126) and 26.5% (43/162) in LBx TF < 1%. ESR1mut was found in 8.1% TBx, 17.5% LBx TF ≥ 1%, and 4.9% LBx TF < 1% in 1st line, increasing to 59% in 3rd line (LBx TF ≥ 1%). PTENloss was detected at higher rates in TBx (4.3%) than LBx (1% in TF ≥ 1%). Patients receiving 1st-line aromatase inhibitor + CDK4/6 inhibitor (n = 573) with ESR1mut had less favorable rwPFS and rwOS versus ESR1 wild-type; no differences were observed for fulvestrant + CDK4/6 inhibitor (n = 348).

Conclusion: Our study suggests obtaining TBx for CGP at time of de novo/recurrent diagnosis, followed by LBx for detecting acquired GA in 2nd + lines. Reflex TBx should be considered when ctDNA TF < 1%.

Keywords: AKT inhibitor; ESR1; Genomic sequencing; HR(+)HER2(−); Metastatic breast cancer.

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Conflict of interest statement

Financial disclosures: JCFQ, HT, GL, TS, JSR, LP, RSPH, MAL, and RPG are employees of Foundation Medicine, a wholly owned subsidiary of Roche and have equity interest in Roche. MB has consulted for Merck, Gilead, DSI, AstraZeneca, Pfizer, and Eli Lilly. JSR has consulted and owns equity in Celsius Therapeutics and Tango Therapeutics. HMC has consulted for Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Pfizer, Puma, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, Peregrine, Calithera, Daiichi-Sankyo, Seattle Genetics, AstraZeneca, Gilead, Crown Bioscience, and TapImmune and has research supported by Bristol-Myers Squibb; MedImmune, LLC/AstraZeneca; BTG; and Merck. KK has consulting or advisory role for Merck, Lilly, Novartis, AstraZeneca, Genentech/Roche, Immunomedics, Seattle Genetics, Oncosec, 4D pharma, Daiichi-Sankyo, Puma Biotechnology, Mersana, Menarini Silicon Biosystems, Myovant Sciences, and Takeda. Research funding (institution) from Novartis, Ascentage, Genentech/Roche, Lilly, Seattle Genetics, AstraZeneca, and Daiichi-Sankyo.

Figures

Fig. 1
Fig. 1
Prevalence of ESR1mut detected in tissue and liquid specimens of HR(+)HER2(−) mBC in the first three metastatic lines of therapy. ESR1mut detected in TBx (A) and LBx (B). AI aromatase inhibitors, chemo chemotherapy, CDK4/6i CDK 4/6 inhibitors, ET endocrine therapy, HR hormone receptor, LBx liquid biopsy, mBC metastatic breast cancer, mut mutations, SERD selective estrogen receptor degrader (fulvestrant), TBx tissue biopsy, TF ctDNA tumor fraction, Tx therapy
Fig. 2
Fig. 2
Prevalence of ESR1mut and PI3K/AKT pathway alterations detected in tissue and liquid specimens of HR(+)HER2(−) mBC in the first three metastatic lines of therapy. Alterations detected in TBx and LBx (A) and in LBx stratified by ctDNA tumor fraction (TF) (B). p-values are unadjusted. loss homozygous copy loss, mut mutation
Fig. 3
Fig. 3
Co-occurrence of ESR1mut and PI3K/AKT pathway alterations detected in tissue specimens of HR(+)HER2(−) mBC in the first three metastatic lines of therapy. loss copy loss, mut mutation, PI3K/AKT alterations include AKT1mut, PIK3CAmut, PTENmut, and PTENloss
Fig. 4
Fig. 4
Clinical outcomes of HR(+)HER2(−) metastatic breast cancer patients receiving 1st-line AI + CDK4/6i by ESR1mut detected by TBx. Kaplan–Meier plots show rwTTD (A), rwPFS (B), and rwOS (C) for ESR1mut (n = 22) vs ESR1wt (n = 551). Swimmer plot shows rwTTD (each bar represents therapy duration on 1st line of therapy) and rwPFS (dots represent progression) for patients with ESR1mut ordered by specific ERS1mut (D). AI aromatase inhibitors, ESR1mut ESR1 mutations, ESR1WT ESR1 wild-type, HR hazard ratio, OS overall survival, PFS progression-free survival, rw real-world, TBx tissue biopsy, TTD time to treatment discontinuation
Fig. 5
Fig. 5
Clinical outcomes of HR(+)HER2(−) metastatic breast cancer patients receiving 1st-line Fulvestrant + CDK4/6i by ESR1mut detected by TBx. Kaplan–Meier plots show rwTTD (A), rwPFS (B), and rwOS (C) for ESR1mut (n = 59) vs ESR1wt (n = 289). Swimmer plot shows rwTTD (each bar represents therapy duration on 1st line of therapy) and rwPFS (dots represent progression) for patients with ESR1mut ordered by specific ERS1mut (D). ESR1mut ESR1 mutations, ESR1WT ESR1 wild-type, HR hazard ratio, OS overall survival, PFS progression-free survival, rw real-world, TBx tissue biopsy, TTD time to treatment discontinuation
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References

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