Nearly 75% of breast cancers detected in New Zealand women are hormone receptor (HR) positive/HER2 receptor negative. BCAC’s Libby Burgess and Louise Malone, attending Breast Cancer Trials’ recent scientific meeting in Hobart, were pleased to learn that this is an active field of research, with treatment options expanding beyond endocrine therapies like aromatase inhibitors and tamoxifen, and CDK4/6 inhibitors.
In particular, researchers are gaining a deeper understanding of the molecular signalling pathways that drive tumour cell growth, how they respond to hormones and growth factors, and the impacts of particular genetic mutations on these pathways. This knowledge is important for understanding why and how HR+/HER2- tumours develop resistance to endocrine therapy. This in turn aids the selection of effective ‘later line’ treatments to improve the quality of and extend life for those with advanced disease.
Several different signalling pathways, such as the PI3K/AKT pathway, the ER (oestrogen receptor) pathway and the CDK4/6 pathway, are known to be involved in breast cancer and there is ‘cross-talk’ between them. This means that treatments to block more than one pathway may be more effective (so-called ‘triple blockade’).
Genomic testing for known mutations affecting these pathways is important for making treatment decisions for those with advanced HR+/HER2- breast cancer whose tumours have become resistant to endocrine and CDK4/6 inhibitor therapies. For example, those with a PIK3CA mutation (about 40% of those with HR+/HER2- breast cancer) may benefit from drugs like alpelisib (brand name Piqray®) which inhibit PI3K; those with AKT1 or PTEN mutations may benefit from capivasertib (brand name Truqap®) which inhibits AKT; those with an ESR1 mutation may benefit from treatment with a SERD (selective oestrogen receptor degrader) like elascestrant (brand name Orserdu®); and those with BRCA1 or PALB2 mutations may benefit from treatment with olaparib (brand name Lynparza®). These are known as ‘actionable mutations’.
Dr Stephen Luen from the Peter MacCallum Cancer Centre in Melbourne explained the various genomic tests that can be performed to detect mutations affecting breast cancer. Germline (heritable) mutation testing involves taking a blood sample or cheek cell swab and can reveal BRCA1/2, PALB2, TP53 mutations. Biopsy samples from tumours and sometimes also blood tests can reveal ‘somatic’ mutations such as PIK3CA, ESR1 or TP53. About half of all HR+ breast cancer patients have one of the following mutations: PIK3CA, PTEN or AKT1. There are various methods for processing the samples; some are faster than others which is important as patients often do not want to wait before beginning treatment. However, accuracy in the results is also crucial. Next Generation Sequencing (NGS) tests like FoundationOne® are useful and produce reasonably quick results. (This test is not publicly funded in New Zealand and costs about $4950.)
Professor Elgene Lim from the Kinghorn Cancer Centre in Sydney described how genetic mutation information has been used in clinical trials. The SOLAR-1 trial divided participants with advanced HR+/HER2- breast cancer, whose cancer had progressed after endocrine therapy, into groups with or without the PIK3CA mutation before treating them with alpelisib plus fulvestrant or fulvestrant alone. Those with the PIK3CA mutation benefited from the alpelisib treatment, in terms of both progression-free and overall survival. Read more here.
In the INAVO120 trial, all participants had the PIK3CA mutation and were treated with palbociclib (CDK4/6 inhibitor) and fulvestrant. In addition, those in the treatment arm were given inavolisib (brand name Itovebi®), a powerful inhibitor and degrader of the PI3K enzyme. Overall survival benefits for those who were given inavolisib were reported at the 2025 meeting of the American Society of Clinical Oncology (ASCO). Read more here.
Participants in the CAPItello-291 trial who had tumours with PIK3CA, AKT1 or PTEN mutations and received capivasertib (an AKT inhibitor) had better overall survival (median 38.9 vs 20.0 months) than those who did not.
Alpelisib, inavolisib and capivasertib are not yet publicly funded in New Zealand. BCAC will be encouraging pharma companies to register and seek funding from Pharmac for these new medicines. BCAC will also be advocating for increased government funding for Pharmac and for Pharmac to expedite any new applications for breast cancer medicines.
Professor Lim also mentioned RLY-2608 and STX-478, two new experimental medicines that target the PI3K pathway and are currently in Phase 1 trials, and gedatolisib, a dual inhibitor of the PI3K and mTOR enzymes.
Professor Lim announced that new NCCN (National Comprehensive Cancer Network) Guidelines for the treatment of HR+ breast cancer have just been published, giving oncologists and patients an up-to-date algorithm to help make treatment decisions.
6 August 2025
