Invasive Breast Cancer Over Four Decades Reveals Persisting Poor Metastatic Outcomes In Treatment Resistant Subgroup – The “ATRESS” Phenomenon

Abstract

Background: Major advances in breast cancer treatment have led to a reducuction in mortality. However, there are still women who are not cured. We hypothesize there is a subgroup of women with treatmentresistant cancers causing early death. Methods: Between 1975 and 2006, 5392 women with invasive breast cancer underwent surgery at Guy's Hospital, London. Data on patient demographics, tumour characteristics, treatment regimens, local recurrence, secondary metastasis, and death were prospectively recorded. We considered four time periods (1975e1982, 1983e1990, 1991e1998, 1999e2006). Risks and time to event analysis were performed with Cox proportional hazards model and Kaplan-Meier estimation. Results: Unadjusted hazard ratios for developing metastasis and overall mortality relative to the 1975 e1982 cohort decreased steadily to 0.23 and 0.63, respectively in 1999e2006. However, metastasis-free interval shortened, with the proportion of women developing metastasis 5 years increasing from 73.9% to 83.0%. Furthermore, median post-metastatic survival decreased from 1.49 years to 0.94 years. Applying our risk criteria identified the presence of ±200 patients in each cohort who developed metastasis early and died within a much shorter time frame. Conclusions: Advances in treatment have decreased the risk of metastasis and improved survival in women with invasive breast cancer over the last 40 years. Despite this, a subpopulation with shorter metastasis-free and post-metastatic survival who are unresponsive to available treatment remains. This may be due to the ATRESS phenomenon (adjuvant therapy-related shortening of survival) secondary to preselection inherent in adjuvant therapy, successful treatment of less malignant tumour cells and treatment-induced resistance in the remaining tumour clones.

De novo and recurrent metastatic breast cancer – A systematic review of population-level changes in survival since 1995

“…38,39 Recent institution-based cohort studies of MBC treatment also provide evidence of this effect. 40,41 Proposed causal pathways include the prevention of treatment sensitive metastases in pre-treated patients, leading to an apparent shift to more aggressive metastases as treatment non-sensitive tumours dominate; and potentially adjuvant therapy induces treatment resistance. 38 At a molecular level, evidence of genomic differences between rMBC and treatment-naive dnMBC point to biological differences requiring further investigation to help elucidate the mechanisms for differences in prognosis.…”

Breast cancer: Emerging principles of metastasis, adjuvant and neoadjuvant treatment from cancer registry data

“…If the early bone METs become less frequent and the progression begins with the later CNS METs, then MET-free survival becomes longer and post-progression survival becomes shorter. 58,81 In contrast, the MET pattern in T-N-M1 (at diagnosis) has not changed in the last decades because it is untreated and mirrors the biology of BC. 65 A rationale for the duration of the therapies is not known.…”

Survival outcomes of metastatic breast cancer patients by germline BRCA1/2 status in a large multicenter real‐world database

“…Furthermore, the prognostic value of hormone receptor status in BRCA ‐related breast cancers remains uncertain. Prognostic factors may have divergent effects in different settings and this is well known in the breast cancer field, where pre‐treatment could have a strong impact on the selection of more aggressive and differently sensitive tumors 20 . Regarding g BRCA status, it has not yet been demonstrated to have a strong impact on outcomes in global populations of patients with MBC.…”