Actionable co-alterations in breast tumors with pathogenic mutations in the homologous recombination DNA damage repair pathway
Authors:
Arielle L. Heeke, Joanne Xiu, Filipa Lynce, Paula R. Pohlmann, Gregory A. Vidal, Claudine Isaacs, Sandra M. Swain, Lee S. Schwartzberg, Antoinette R. Tan
INTRODUCTION AND PURPOSE
Homologous recombination deficiency (HRD) is common in breast cancer, with somatic frequencies of 15.6% previously reported1.
Targeted therapies including PARP inhibitors may provide effective and tolerable therapies for patients with breast cancer harboring germline or somatic HRD.
We evaluated the relationship between HRD and the presence of additional mutations that may impact responsiveness to targeted therapies beyond PARP inhibitors in patients with breast cancer.
METHODS
Comprehensive molecular profiling of 4,647 breast tumors was performed at Caris Life Sciences, Inc using 592-gene Next Generation Sequencing (NGS), average depth 500X.
Complete molecular profiles were retrospectively reviewed to identify pathogenic or presumed pathogenic somatic mutations in the homologous recombination DNA damage repair (HR-DDR) genes ARID1A, ATM, ATRX, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CHEK1/2, FANCA/C/D2/E/F/G/L, KMT2D, MRE11, NBN, RAD50/51/51B, PALB2 & WRN, as well 39 markers that may be associated with treatment response to targeted anti-cancer therapies.
Frequencies of co-alterations (mutation/overexpression) of interest were calculated and compared between breast tumors that had a pathogenic or presumed pathogenic somatic mutation in a gene involved in the HR-DDR pathway (HR-MT) and breast tumors with an intact HR-DDR pathway (HR-WT), and by breast cancer subtype (hormone receptor [hr] positive, HER2 positive, and triple negative).
RESULTS
HRD was identified in 17.9% of the 4,647 evaluable breast tumors and was most commonly seen in HER2 negative disease (hr positive/HER2 negative 18.3%, triple negative 18.2%, hr positive/HER2 positive 15.6%, hr negative/HER2 positive 12.9%). [Table 1/Figure 1a]
Markers of response to immunotherapy [Table 2] were more commonly appreciated among HR-MT breast tumors:
Mean TMB higher for HR-MT tumors across all breast subtypes (9.2mut/Mb HR-MT vs 7.6mut/Mb HR-WT, p=<0.0001), and independent of microsatellite status.
Tumor PD-L1 overexpression more frequent among HR-MT breast tumors (13.2% HR-MT vs 11.0% HR-WT , p=0.08).
Microsatellite instability more common in HR-MT breast tumors (2.1% HR-MT vs 0.2% HR-WT, p=<0.0001), particularly HER2 negative (hr+/HER2- 2.3%, triple negative 1.4%, HER2+ 0%).
Mutations in chromatin remodeling genes more common in HRMT (71.5%), vs HR-WT (9.0%) breast tumors (p=<0.0001)
Frequency of co-alterations associated with response to targeted therapy [Table 4] were similar between HR-MT and HR-WT tumors, with the notable exception of PIK3CA (30.3% HR-WT vs 26.4% HR-MT, p=0.024) and AKT1 (3.7% HR-WT vs 2.1% HR-MT, p=0.021) mutations, which were more common in HR-WT tumors. Additional findings include:
AR overexpression common, particularly in hormone receptor positive tumors (76.9% hr+ vs 24.3% hr- , p=<0.001).
PIK3CA mutations less common in hormone receptor negative tumors (35.9% hr+ vs 20.0% hr-, p=<0.001).
ERBB2 mutations seen in 3.5% of hr+/HER2- and 1.2% of TNBC tumors, and 3.5% of HER2+ tumors.
JAK1/2 mutations were identified in HER2- tumors only.
Frequency of mutations associated with resistance to therapy [Table 5] were similar for HR-MT and HR-WT tumors.
ESR1 mutations seen exclusively in hormone receptor positive tumors.
RB1 mutations more common in TNBC, 7.6% vs 2.7% non-TNBC
CONCLUSIONS
In breast cancer, HR-MT is common and is associated with markers of response to immunotherapy.
Co-alterations (mutation/overexpression) were identified in both HR-MT and HR-WT tumors that suggest other targets for treatment.
94.9% of these co-alterations predict responsiveness to currently available treatments
We use cookies on our website to give you the most relevant experience by remembering your preferences and repeat visits. By clicking “Accept,” you consent to the use of all cookies.
This website uses cookies to improve your experience while you navigate through the website. Out of these, the cookies that are categorized as necessary are stored on your browser as they are essential for the working of basic functionalities of the website. We also use third-party cookies that help us analyze and understand how you use this website. These cookies will be stored in your browser only with your consent. You also have the option to opt-out of these cookies. But opting out of some of these cookies may affect your browsing experience.
Necessary cookies are absolutely essential for the website to function properly. These cookies ensure basic functionalities and security features of the website, anonymously.
Cookie
Duration
Description
cookielawinfo-checkbox-analytics
11 months
This cookie is set by GDPR Cookie Consent plugin. The cookie is used to store the user consent for the cookies in the category "Analytics".
cookielawinfo-checkbox-functional
11 months
The cookie is set by GDPR cookie consent to record the user consent for the cookies in the category "Functional".
cookielawinfo-checkbox-necessary
11 months
This cookie is set by GDPR Cookie Consent plugin. The cookies is used to store the user consent for the cookies in the category "Necessary".
cookielawinfo-checkbox-others
11 months
This cookie is set by GDPR Cookie Consent plugin. The cookie is used to store the user consent for the cookies in the category "Other.
cookielawinfo-checkbox-performance
11 months
This cookie is set by GDPR Cookie Consent plugin. The cookie is used to store the user consent for the cookies in the category "Performance".
viewed_cookie_policy
11 months
The cookie is set by the GDPR Cookie Consent plugin and is used to store whether or not user has consented to the use of cookies. It does not store any personal data.
Functional cookies help to perform certain functionalities like sharing the content of the website on social media platforms, collect feedbacks, and other third-party features.
Performance cookies are used to understand and analyze the key performance indexes of the website which helps in delivering a better user experience for the visitors.
Analytical cookies are used to understand how visitors interact with the website. These cookies help provide information on metrics the number of visitors, bounce rate, traffic source, etc.
Advertisement cookies are used to provide visitors with relevant ads and marketing campaigns. These cookies track visitors across websites and collect information to provide customized ads.