AbstractBackgroundPrevious studies investigated the changes of subtype markers [estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)] in several clinical settings, but not for second primary breast cancer (SPBC) after first primary breast cancer (FPBC).MethodsA total of 15,390 patients with SPBC were preliminarily selected from the Surveillance, Epidemiology, and End Results Program, and 3777 patients with complete information on three subtype markers in both FPBC and SPBC were included in the final analyses. The changes of subtype markers and their prognostic implications and potential influential factors were well investigated.ResultsThe overall change rates of ER, PR, and HER2 between FPBC and SPBC were 23.0% (867/3777), 35.0% (1322/3777), and 18.3% (691/3777), respectively. Gains of ER, PR, and HER2 after negative index markers were 48.7% (364/748), 37.9% (418/1103), and 11.5% (370/3211), while losses of markers after positive index markers were 16.6% (503/3029), 33.8%(904/2674), and 56.7%(321/566). Loss of ER was significantly associated with increased mortality (18.1% vs. 7.9%,p< 0.001), while gain of ER was significantly associated with decreased mortality (11.5% vs. 23.2%,p< 0.001). Similar results were observed for changes of PR status. However, loss of HER2 was significantly associated with decreased mortality (8.7% vs. 16.3%,p= 0.014), and no significant association was observed between the gain of HER2 and the prognosis of SPBC. Multivariate competing risk analyses showed similar results. HER2 status in FPBC, chemotherapy, and radiotherapy was significantly associated with changes of ER/PR (allp< 0.05), and no available therapies associated with HER2 change.ConclusionThe changes of subtype markers are observed in a considerable proportion of patients and has statistically significant prognostic implications. Biopsies should be taken as a routine procedure for better therapy management.