Mini Oral 1: mBC

In this video, Dr Kevin Punie discusses and comments on the data of some exciting studies presented at ESMO 2024 during the Mini Oral session on metastatic breast cancer.  

The first abstract is a retrospective analysis of patients with advanced HR+, HER2- mBC who underwent tumour sequencing. The study aimed to examine the differences in outcomes based on the presence of BRCA mutations within the tumour rather than the germline status. This investigation is significant because recent data suggests that BRCA mutations may be associated with shorter responses to the combination of endocrine therapy and CDK4-6 inhibitors in this population. The analysis compared overall outcomes between patients with BRCA mutations and those without. It confirmed that the presence of a BRCA mutation in advanced HR+, HER2-  breast cancer is linked to a poorer prognosis. Additionally, the study found that patients with BRCA mutations were less likely to have co-mutations in PI3K or TP53 compared to BRCA wild-type patients.

The study also looked into the sequencing of treatments, explicitly comparing patients who received CDK4-6 inhibitors first followed by PARP inhibitors versus those who received PARP inhibitors first followed by CDK4-6 inhibitors. While there was no statistically significant difference in OS between these two sequences, the interpretation is challenging due to the small number of patients who received PARP inhibitors first. In conclusion, the current standard of care remains the combination of endocrine therapy and CDK4-6 inhibitors as the first-line treatment for these patients. However, clinicians should anticipate that the PFS for patients with BRCA mutations will likely be shorter than those without BRCA mutations.

The second abstract analysed a large retrospective data set focusing on interstitial lung disease (ILD) in patients treated with trastuzumab deruxtecan (T-DXd), covering various cancer types. Most patients had received T-DXd for breast cancer due to the drug’s primary indications. The study showed that ILD incidence was similar to what has been observed in clinical trials, with 11% of approximately 600 patients developing ILD. Of those, 80% experienced low-grade ILD (grade 1 and 2). The median time to ILD onset was 50 to 60 days, indicating that most cases occur within the first few months of treatment. A key risk factor for ILD was a history of previous ILD from other causes, significantly increasing the likelihood of recurrence during T-DXd therapy. Management guidelines suggest that patients with low-grade, asymptomatic ILD (grade 1) may be considered for re-challenge with T-DXd. However, re-challenge is not recommended for patients with grade 3 or higher ILD. This emphasises the importance of early detection, which can be facilitated by regular high-resolution lung imaging during treatment. Additionally, severe ILD (grade 5) occurred in about 1% of cases, reinforcing the need for careful monitoring and consideration of risks when administering T-DXd. 

An additional translational analysis from the DAISY study was also presented. The DAISY study is a multiple-cohort, single-arm phase 2 trial conducted by Institut Gustave Roussy, investigating the efficacy of T-DXd in patients with varying levels of HER2 expression. Previous results demonstrated that responses were observed across all levels of HER2 expression, though higher HER2 levels were associated with a greater likelihood of response to T-DXd. In this analysis, the spatial distribution of ERBB2 amplification was examined. However, no significant association was found between the spatial distribution of HER2 amplification and the response to T-DXd. The study also investigated mutational signatures and found that within the HER2-low cohort, specific mutational signatures related to DNA mismatch repair or oxidative stress strongly predicted response to T-DXd. An essential finding of this analysis was the identification of mutations located in the HER2 receptor’s binding site, which may be associated with resistance to T-DXd. While it remains unclear whether these mutations are responsible for primary or secondary resistance, as only post-treatment samples were available, these mutations could explain why some patients with HER2-expressing tumours do not respond as expected to T-DXd. Although these findings are intriguing, the sample size is small, and further validation is required before these results can influence clinical practice.

Two noteworthy abstracts presented at this session focused on downstream analysis from the recently reported DESTINY-Breast06 study. This study, previously presented at ASCO 2023, investigated patients with advanced HR+, HER2- breast cancer who exhibited either HER2-low or HER2-ultra-low expression. Patients were randomised to receive either T-DXd or single-agent chemotherapy chosen by their physician. The primary analysis demonstrated superior PFS for patients treated with T-DXd compared to those on traditional chemotherapy, confirming T-DXd’s effectiveness in this first-line chemotherapy-like setting. One of the critical aspects discussed during the session was the challenge of accurately categorising HER2 expression levels, particularly HER2-ultra-low. Pathologist Prof Giuseppe Viale presented a deeper analysis of the discordances between local pathology assessments used to recruit patients and the central testing that ultimately determined eligibility for the study. In cases where patients were classified as HER2-low by their local pathologist, the central assay confirmed this classification in over 90% of cases. However, more than 50% of patients initially categorised as HER2-IHC0 by local pathologists were later reclassified as either HER2-low or HER2-ultra-low after central reassessment. 

This finding underscores the importance of not relying solely on local HER2 assessments, particularly when determining eligibility for T-DXd. As reimbursement policies change to cover potentially HER2-ultra-low cases, it becomes essential to ask for a reassessment of HER2 status, especially in cases initially deemed IHC0. Furthermore, Viale’s presentation showed that HER2 expression was consistent between tissue samples from earlier disease stages and those taken from metastatic biopsies. Additionally, it was reconfirmed that patients in the HER2-ultra-low group, as well as those classified as IHC2+, IHC1+, or HER2-ultra-low, derived clinical benefits from T-DXd treatment, regardless of the specific level of HER2 expression. 

A Chinese researcher from Fudan University presented the QoL data from the DESTINY-Breast06 study. This analysis focused on comparing the impact of T-DXd on QoL to standard single-agent chemotherapy. Reassuringly, the study found no significant deterioration in QoL for patients receiving T-DXd, even though these patients remained on treatment longer than those on chemotherapy. Interestingly, some specific aspects of QoL, such as pain symptoms, showed improvement. Patients treated with T-DXd experienced less pain and had a longer time to deterioration in pain symptoms compared to those receiving chemotherapy of the physician’s choice. This highlights a potential benefit of T-DXd in managing certain aspects of quality of life. The only adverse finding related to gastrointestinal toxicity, as T-DXd was associated with worse gastrointestinal symptoms, which is an expected side effect of this treatment. However, these symptoms did not significantly affect the overall QoL assessments reported by patients. On the positive side, T-DXd was associated with fewer mucosal and skin-related side effects than chemotherapy. In conclusion, this QoL data is consistent with expectations and supports the clinical efficacy of T-DXd.