Personalized therapy of breast cancer
Breast cancer therapy has improved significantly over the last decades. However, more than 3.300 Norwegian women are diagnosed with breast cancer (BC) and approximately 600 die from the disease annually, demonstrating that BC is a major health problem.
Currently there are few predictive biomarkers for BC therapy. Thus, while patients may be selected for endocrine and HER2 targeted therapies based on hormone receptor status and HER2 expression, we still can not precisely predict who will respond to each individual type of therapy for the majority of patients. In our recently completed PETREMAC trial (completed accrual in August 2018), we systematically explored the benefits of different therapeutic options, selected based on established parameters (receptor status and HER2), but in addition TP53 (“the guardian of the genome”) mutation status. Tumors classified as Luminal A-like tumors (accounting for ~40% of all BC), characterized by high levels of hormone receptors and TP53 wt status, were treated with endocrine therapy in concert with a novel targeting agent alone. We
confirmed endocrine therapy to be as efficient as chemotherapy. However, while endocrine therapy provided a high clinical response rate, few patients in this group achieved a pathological complete response (pCR). pCR is considered a good surrogate marker for long-term outcome in triple-negative and HER2 amplified breast cancers where neoadjuvant treatment is usually very efficient. In contrast, the impact of pCR is less clear for conventional neoadjuvant chemotherapy in luminal A-like breast cancer, where cytotoxic drugs are generally less effective.
In our next trial of personalized breast cancer therapy (PETREMAC2), we take a novel approach by implementing new endocrine regimens proven effective in metastatic breast cancer, into early treatment of Luminal A-like tumors. If successful, this may substantially enhance the benefit of endocrine therapy, to facilitate higher pCR rates and hopefully improved survival. Moreover, we amend the chemotherapy program for the other tumor subtypes, applying new types of targeted therapy aiming at improving pCR, but at the same time limiting toxicity. Importantly, systematic exploration of molecular parameters will allow for improved identification of patients for whom different treatment options may be optimal. Each tumour will be analysed for additional potential predictive factors; for tumors treated with endocrine therapy our main goal is to identify parameters predicting benefit from endocrine therapy, for tumors undergoing chemotherapy we focus on DNA repair defects, but also potential defects in the p53 pathway and other cell cycle regulators. By doing so, we aim at identifying predictive factors allowing individual therapy selection for patients. In the long term perspective, this may also enable development of novel therapeutic strategies.