Patients diagnosed with metastatic breast cancer who are receiving trastuzumab deruxtecan (T-DXd; Enhertu®; Daiichi Sankyo and AstraZeneca), fared best if they had HER2+ disease or stable HER2-low disease, compared with those experiencing changes in HER2 status.

This conclusion is based on study outcomes presented at the 46th annual San Antonio Breast Cancer Symposium, held in San Antonio, Tx, December 5 – 9, 2023.

Trastuzumab deruxtecan, an antibody-drug conjugate or ADC, is a standard treatment for patients with HER2+ and HER2-low metastatic breast cancer. However, over time, HER2 status can change between the primary tumor and metastatic recurrence. The RELIEVE study, examined how HER2 status and its changes to status influence real-world outcomes.

Machine learning
This study conducted by the Dana-Farber Cancer Institute (DFCI), analyzed plasma samples from patients with HER2+ and HER2- metastatic breast cancer receiving trastuzumab deruxtecan monotherapy.  The analyses included data from 191 patients with metastatic breast cancer who had been treated with trastuzumab deruxtecan monotherapy at Dana-Farber Cancer Institute and Duke Cancer Center.

DNADX® * subtypes was evaluated across 80 pre-treatment plasma samples, exhibited significant associations with time-to-next-treatment (TTNT) and overall survival (OS). The DNADX® HER2 signature demonstrated a significant association with TTNT, indicating its potential for predicting patient outcomes in the context of trastuzumab deruxtecan monotherapy.

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At the first follow-up, patients with HER2-positive disease stayed on trastuzumab deruxtecan without progression, death or change in treatment, a measure called time to next treatment, for a median of 10.4 months.

Patients diagnosed with HER2-low disease had a median time to next treatment of 7.6 months, and patients with HER2-0 disease 3.7 months. In addition, patients with stable HER2-low disease between their primary diagnosis and pre-trastuzumab deruxtecan biopsy had a longer median time to next treatment than those with disease that switched between HER2-low and HER2-0.

The study outcomes suggests that trastuzumab deruxtecan has promising real-world activity in pretreated patients with HER2+ or stable HER2-low disease. In this study, the performance of treatments administered immediately following progression on trastuzumab deruxtecan were short, suggesting that more options are needed in this setting.

“The ability of the DNADX test to predict patient outcomes in blood and in the context of trastuzumab deruxtecan monotherapy is remarkable. This test should be further explored in pivotal clinical trials of trastuzumab deruxtecan and other studies with targeted therapies, including antibody-drug conjugates,” noted  Sara Tolaney, MD, MPH, Chief of the Division of Breast Oncology at Dana-Farber Cancer Institute.

PARSIFAL Study
Additionally, DNADX® underwent evaluation in 122 pre-treatment plasmas from the PARSIFAL phase II trial (NCT02491983). This trial focused on hormone receptor-positive and HER2-negative (HR+/HER2-) metastatic breast cancer treated with palbociclib +/- fulvestrant or letrozole.

DNADX® was evaluated in 122 pre-treatment plasma samples. The liquid biopsy-based DNADX® subtypes exhibited a significant association with both progression-free survival (PFS) and overall survival (OS), revealing their potential to guide therapy and follow-up in patients with endocrine-sensitive HR+/HER2- advanced breast cancer.

“Prior to DNADX, no tool existed to identify patients whose tumors would progress to therapy in the first 12 months,” said Javier Cortés, MD PhD, co-founder of MEDSIR, Head of the International Breast Cancer Center and investigator of the PARSIFAL trial,” Cortés added.

“This is important as we need new therapeutic approaches for these patients. Our study shows that the DNADX subtypes in plasma are strongly associated with prognosis in patients treated with first-line endocrine therapy and a CDK4/6 inhibitor.”

These findings are consistent with validation studies of DNADX® in this context published this year in Nature Communications.

DNADX® subtypes demonstrated a positive interaction with the type of endocrine therapy in terms of PFS, suggesting a potential benefit of fulvestrant over letrozole in specific DNADX® subtypes.

“The association of DNADX subtypes with fulvestrant benefit is intriguing, and suggests that phenotypic characterization of breast tumors using DNADX might allow us to identify the optimal endocrine treatment for each patient beyond ESR1 mutation,” noted Antonio Llombart-Cussac, MD PhD, co-founder of MEDSIR, Head of the Medical Oncology Department at Hospital Arnau de Vilanova, and principal investigator of the PARSIFAL trial.

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Studies

  • PS08-09 Impact of HER2 Expression Dynamics on the Real-World Activity of Trastuzumab Deruxtecan for Metastatic Breast Cancer (RELIEVE).

Note:* DNADX® is a novel machine learning-based approach that uses sequencing DNA data from tumor tissue or plasma circulating tumor DNA to identify clinically relevant phenotypic tumor features and classify breast cancer into 4 subtypes or clusters, to analyze the samples.

Clinical trial
Palbociclib in Combination With Fulvestrant or Letrozole in Patients With ER+, HER2- Advanced Breast Cancer (PARSIFAL) – ClinicalTrials.gov Identifier: NCT02491983

Highlight of Prescription Information
Trastuzumab deruxtecan (T-DXd; Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]
Palbociclib (Ibrance®; Pfizer) [Prescribing Information]
Fulvestrant (Faslodex®; AstraZeneca)[Prescribing Information]
Letrozole (Femara®; Novartis)[Prescribing Information]

Reference
[1] Llombart-Cussac A, Pérez-García JM, Bellet M, Dalenc F, Gil-Gil M, Ruíz-Borrego M, Gavilá J, Sampayo-Cordero M, Aguirre E, Schmid P, Marmé F, Di Cosimo S, Gligorov J, Schneeweiss A, Albanell J, Zamora P, Wheatley D, Martínez-de Dueñas E, Amillano K, Malfettone A, Cortés J; PARSIFAL Steering Committee and Trial Investigators. Fulvestrant-Palbociclib vs Letrozole-Palbociclib as Initial Therapy for Endocrine-Sensitive, Hormone Receptor-Positive, ERBB2-Negative Advanced Breast Cancer: A Randomized Clinical Trial. JAMA Oncol. 2021 Dec 1;7(12):1791-1799. doi: 10.1001/jamaoncol.2021.4301. Erratum in: JAMA Oncol. 2021 Nov 1;7(11):1729. PMID: 34617955; PMCID: PMC8498933.
[2] Di Cosimo S, Pérez-García JM, Bellet M, Dalenc F, Gil Gil MJ, Ruiz Borrego M, Gavilá J, Sampayo-Cordero M, Aguirre E, Schmid P, Marmé F, Gligorov J, Schneeweiss A, Albanell J, Zamora P, Wheatley D, Martínez-De Dueñas E, Carañana V, Amillano K, Mina L, Malfettone A, Cortés J, Llombart-Cussac A. Palbociclib with Fulvestrant or Letrozole in Endocrine-Sensitive Patients with HR-Positive/HER2-Negative Advanced Breast Cancer: A Detailed Safety Analysis of the Randomized PARSIFAL Trial. Oncologist. 2023 Jan 18;28(1):23-32. doi: 10.1093/oncolo/oyac205. PMID: 36239405; PMCID: PMC9847524.

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