Pooled Individual Patient Survival Analysis of Early TNBC Women Treated With Dose Dense Sequential Adjuvant Chemotherapy in the Context of 7 Studies Conducted by the Hellenic Cooperative Oncology Group

Breast cancer remains the most commonly occurring cancer and leading cause of cancer death in women worldwide. According to specific clinical, molecular and genetic characteristics of patients, breast cancer is distinguished into subtypes with differences in disease progression, response to treatment and rate of metastasis. Breast cancer treatment decisions are based mainly on the presence or absence of established prognostic and predictive biomarkers, mainly the estrogen (ER) and progesterone (PR) hormone receptors, the human epidermal growth factor receptor 2 (HER2) oncoprotein in correlation with ki67 proliferation index. Tumor size, histological grade, lymph node status are also used as prognostic factors.

Triple Negative Breast Cancer (TNBC) accounts for 10% to 20% of all breast cancer diagnoses globally and is one of the most aggressive subtypes of breast cancer, being characterized by lack of ER, PgR and HER2 expression. TNBC is characterized by extensive biological heterogeneity, rapid cell proliferation, high rates of disease progression and poor prognosis due to the lack of clear therapeutic targets and rapid development of tumor resistance to certain chemotherapeutic regimens.

TNBC is frequently characterized by Homologous Recombination Deficiency (HRD), with BRCA1/2 mutations being the most well-characterized causes, while mutations or loss of function in other homologous recombination repair (HRR) pathway genes such as ATM, PALB2, RAD51, BARD1 or epigenetic silencing, particularly through BRCA1 promoter hypermethylation are also implicated in HRD.

Depending on the age at diagnosis, family history and ethnicity, 8-16% of TNBC cases are associated with germline BRCA1 mutations. BRCA1/2 mutations frequently co-occur with TP53 mutations and they are also associated with higher genomic instability. Germline BRCA1/2 status and the associated genomic instability is critical for treatment selection, rendering the cancer cells highly vulnerable to targeted agents like PARP inhibitors and highly sensitive to platinum-based chemotherapies. Of note, differences in tumor genotypes with respect to germline status and the prognostic interaction between germline BRCA1-related and tumor TP53 mutation status prompt for combined germline and tumor genotyping for the classification of TNBC, particularly in the context of clinical trials evaluating synthetic lethality drugs.

Therefore, despite the fact that combination chemotherapy with anthracyclines and taxanes remains the standard treatment practice for patients with TNBC, new treatment options have recently emerged for patients with advanced TNBC, while various drugs have been investigated in clinical trials, especially for tumors PD-L1+ or with a genetic mutation of the BRCA gene.

However, as only a fraction of these patients responds to immune checkpoint or PARP inhibitors and even those who do respond often develop resistance and relapse, the identification of biomarkers with prognostic significance for TNBC patients remains of paramount importance and various new agents and combination strategies have been explored to further understand molecular and immunological aspects of TNBC.

The aim of this study is to assess long-term survival and explore the association of clinical, immunophenotypic, genetic and genomic characteristics of TNBC patients enrolled in 7 adjuvant clinical studies conducted by the Hellenic Cooperative Oncology Group (HeCOG) with the primary goal of identifying biomarkers of prognostic value, via NGS tumor genotyping and consequent analysis of the impact of mutation patterns on patient outcome. We will also investigate whether baseline germline mutations are preserved in primary tumors from carriers and compare germline and tumor genotypes for obtaining specific patterns associated with prognosis upon anthracyclines-taxanes-based adjuvant chemotherapy, which is still used for TNBC patients. The study is expected to be completed with the collection and recording of all the necessary clinical data, within two years of its approval.