Preoperative Radiotherapy and Systemic Therapy Following Surgery in 'de Novo' Metastatic Breast Cancer

Five to eight percent of breast cancer (BC) patients present with distant metastasis at diagnosis which is known as 'de novo' metastatic breast cancer (dnMBC). These patients represent up to 25% of all MBC patients and tend to have more favorable prognosis than those who relapse during follow-up. Recent data showed that approximately 40% of dnMBC patients undergo locoregional treatment (LRT). Most of the retrospective series over the past two decades showed that LRT not only controls locoregional progression, but also contributes to overall survival (OS), moreover meta-analyses suggest that surgical resection of the primary tumor may improve OS with a hazard ratio (HR) of around 0.60. MF07-01 study, one of the first clinical randomized trials, showed that the patients with diagnosis of dnMBC undergoing LRT followed by systemic therapy had an additional 14% OS benefit by the end of the 10-year follow-up when compared with patients who received only systemic therapy.

Patient-related factors (i.e. age, comorbidities), metastatic burden (i.e. site and number of metastases) and more prominently tumor biology are major factors for therapeutic decisions in dnMBC. Metastatic sites differ according to the intrinsic BC subtypes. Bone and lymph nodes are more common sites for metastasis in hormone receptor (ER, PR) positive BC patients whereas visceral and brain metastasis is more common in Her2 positive \& triple negative BC. Tailored therapy, such as targeted therapy \& immunotherapy is based on IHC profile, genetic \& molecular features in intrinsic subtypes (i.e. luminal A-like, luminal B-like Her2 negative, luminal B-like Her2 positive, Her2 positive nonluminal \& basal-like breast cancer). Tailored therapy contributes to survival outcomes.

Aromatase inhibitors (AI: anastrozole, letrozole, exemestane) with cyclin dependent kinase 4/6 inhibitors (CDKi: ribociclib, palbociclib, abemaciclib) are standard of care as first line setting in postmenopausal metastatic Her2 negative luminal-like breast cancer (mHN-LBC) patients. In the last decade, first line AI/CDKi combination has been shown to increase progression free survival (PFS) and objective response rates (ORR). Recently, updated OS outcomes with a median follow-up of more than 6.5 years has been presented at ESMO congress in September 2021. It has been reported that first line ribociclib and letrozole combination has been shown to have significant OS advantage over letrozole in mHN- 2 LBC. So, AI/CDKi combination as first line systemic treatment in postmenopausal mHN-LBC significantly decreases both progression and mortality rates. In Turkey, ribociclib and palbociclib are available options as CDKi. Therefore, AI/CDKi (ribociclib/palbociclib) combination is also preferred as first line setting for postmenopausal mHN-LBC in our country.

Hormone receptor (ER, PR) and Her2 positivity might differ for primary \& metastatic sites in BC, especially in relapsed patients. Discordance (i.e 'positivity conversion to negativity' or 'negativity conversion to positivity') rates are reported as 10-30% for ER, 20-50% for PR and 10-15% for Her2 in relapsed MBC, but data is limited for dnMBC. It has been reported that total discordance rate as 27% for ER / PR and/or Her2 between primary tumor and metastatic sites in MBC. It was 14.26% for ER/PR \& 7.8% for Her2 status, respectively. They evaluated 16703 MBC patients in a large scale real-life multicenter French ESME cohort. In this cohort, 2169 patients had biopsy from both primary tumor and metastatic site within 6 months of MBC diagnosis, only 10% (n:1677) had optimal biopsy material for ER/PR \& Her2 discordance evaluation. Taking into account these high discordance rates, synchronous biopsy from primary tumor and metastatic sites should be preferred in prospective clinical trial designs in dnMBC. However, it might not be so easy and pragmatic in daily practice.

Moreover, radiotherapy (RT) techniques have considerably improved, allowing for the radiation dose to conform more precisely to the three-dimensional shape of the tumor, thus enabling much higher radiation doses and better tumor control with less toxicity.

Observational studies showed that bone was the most common site of metastasis (around 45% of patients) and up to 30% of patients were diagnosed with bone-only metastases. For oligometastatic disease, some retrospective and prospective series demonstrated that local treatment of all metastases, when feasible, was significantly associated with prolonged survival. Patients with oligometastatic bone-only MBC treated with stereotactic radiotherapy had better clinical outcomes than those who had metastasis at other sites. It has been reported that local breast surgery was associated with better survival outcomes for the patients with only one metastatic site involvement (i.e. bone, liver or lung), but not for brain-only metastasis when they stratified the patients according to the distant metastatic sites. Our study group (BOMET trial) demonstrated that LRT prolonged survival and decreased locoregional recurrence in a prospectively maintained registry study with a median follow-up of 3 years, previously. Timing of primary breast surgery either at diagnosis or after systemic treatment provided a survival benefit similar to systemic therapy alone in bone-only dnMBC patients. Two ongoing prospective phase III trials (NCT02089100, NCT02364557) are evaluating the role of metastases local ablation (Stereotactic Body Radiation therapy (SBRT) or surgery) with curative intent in oligometastatic breast cancer.

In conclusion, LRT of the primary tumor in dnMBC is no longer only a surgical challenge, but more the final decision of a multidisciplinary tumor board including medical oncologists, radiation oncologists and surgical oncologists. It is no longer only a question of locoregional control but rather a wider issue of improving OS, due to the possible biological link between primary tumor and metastases. A multimodal approach, including LRT with curative intent should be considered for selected dnMBC patients, especially for the subset of bone-only metastatic ones.