In this study, we determined the incidence of second primary cancers (SPCs) among early-stage BC survivors and identified several sociodemographic and clinical risk factors associated with the development of SPCs. Using the SEER-Medicare Linked Database with detailed information about Medicare beneficiaries with cancer from 19 United States (US) geographic regions, we found that the incidence of any SPC among older women with primary BC is 13%. Women of white race and those who were married were more likely to develop a SPC. Additionally, hormone receptor (HR) negative primary BC diagnosed at stage 0, treated with surgery or radiotherapy, were also associated with incidence of SPC.
While older age at BC diagnosis (ages 70–79), was associated with increased development of SPC, we observed a decline in SPC incidence among women ≥ 80 years after adjusting for competing risk of death which is consistent with other studies (5). Compared to white women, the incidence of any SPC was lower for women of non-Hispanic black, Hispanic, and other races. The higher incidence of SPC among white women may be due to their overall higher survival rates after BC diagnosis or due to increased surveillance practices (6). It is noteworthy that prolonged survival is an independent risk factor for the development of SPC (7). We also observed that married women were more likely to develop a SPC. Patients who are married are more likely to get psychosocial and financial support which may aid in early cancer detection, appropriate treatment, and prolonged survival (8).
We found that the incidence of all SPCs is higher in those with ductal primary BCs, compared to lobular, as well as in triple negative BC. After adjusting for confounders, primary BC histology was not significantly associated with SPC development, however, estrogen receptor (ER) negative cancers specifically conferred a higher risk of all SPCs. Though most studies tend to focus on combined ER/PR hormone receptor status, it has been found that most BRCA1-associated breast cancers, which are susceptible to recurrence, are ER negative (9). In general, HR negative tumors are more likely to be poorly differentiated with increased recurrence rates (10, 11). The increased recurrence rates may be explained by carcinogenesis research which demonstrated that BC stem cells are HR negative, and thus patients with HR negative tumors are predisposed to cancer early in the breast cell maturation process (12). As such, patients with HR negative breast tumors have a 10-fold increased risk of developing a second hormone negative tumor, as compared to the general population (12).
The current treatment for BC includes surgery, chemotherapy, radiotherapy, and more recently immunotherapy. Most BC survivors in our cohort (94%) received surgery as initial treatment for their primary BC, and surgery was associated with a lower hazard of developing any SPC. This is supported by other studies which showed that patients who did not receive surgery for BC conversely had a higher risk of any SPC including breast (13). Those who received surgery alone (without chemotherapy or radiation therapy) were also at higher risk for developing a contralateral BC (14). This may be due to increased surveillance of the contralateral breast post-BC treatment and suggest that a combination of surgery with or without chemotherapy and radiation therapy is the most effective treatment against BC.
We found that chemotherapy was associated with a decreased risk for breast only SPC, but increased risk of all other SPCs, which is corroborated by studies linking certain chemotherapy drugs with different types of cancers(15, 16). Li et al. reported that SPCs, particularly colon and lung cancers, were higher in patients who received chemotherapy for primary BC, even after adjusting for known confounders (13). Another SEER-based study determined that chemotherapy for BC patients was associated with increased incidence for several SPCs, except for some hematologic malignancies (17). Though the mechanism of how chemotherapy may inadvertently stimulate cancer growth remains largely unclear, it has been shown to be most linked to leukemia and myelodysplastic syndrome (18, 19).
Research regarding the risks of radiation for BC are also generally inconclusive. Some studies have concluded that radiation therapy for BC increases the risk for SPC in the healthy contralateral breast or ipsilateral lung compared to an unexposed population (20). Other studies have shown that only 8% of SPCs are related to radiotherapy (21). Here, we found that similar to chemotherapy, radiation therapy was associated with an increased risk of non-breast SPCs. Although the mechanisms underlying radiation-induced tumorigenesis is unclear, irradiation of surrounding tissues may cause secondary malignancies of these tissues particularly the lungs which was the second highest SPC in our cohort.
Finally, we observed significant associations between certain medications and the development of SPCs. Statins and anti-hypertensives were both associated with increased hazard of developing any SPC including breast SPC, A large population-based study determined that certain antihypertensives, including loop and thiazide diuretics, were associated with adverse BC outcomes, such as increased risk of breast SPCs, recurrence, and BC mortality (22, 23). Thiazide diuretics specifically are associated with insulin resistance, which has been found to be an established risk factor for BC and may also explain the risk associated with antihypertensives (22). While the biological mechanisms are unclear, statins have also been shown to impact cancer outcomes, with varying results for different cancer types. For example, a SEER-based study determined that statin use improved overall and lung cancer specific survival in patients with stage IV non-small cell lung cancer (NSCLC), citing in vitro studies that have demonstrated reduced proliferation, migration, and increased apoptosis of lung cancer cell lines with simvastatin use (24). Prior studies have also explored the use of metformin in cancer treatment, as it has been shown to have a potential antitumor effect (25, 26), though it was not significantly associated with decreased risk of SPCs in our multivariable adjusted models.
Bisphosphonates and aromatase inhibitors were associated with decreased hazard of developing any SPC including non-breast SPCs. Bisphosphonates have been shown to decrease risk of both locoregional/distant BC recurrence or second primary BC (27). Its effect on the development of other SPCs is less well understood. However, anti-tumor properties have been shown in preclinical studies(28) and it is effective in reducing the risk of bone metastases (27). Aromatase inhibitor therapy is the gold standard for the treatment of HR positive BC in post-menopausal BC survivors (29). Preclinical studies have shown that aromatase inhibitors in combination with standard cisplatin chemotherapy for NSCLC decreases tumor progression (24). Post-menopausal hormone exposure was also associated with a reduced risk for later development of NSCLC in the general population (30).
This study has some limitations. First, it is possible that certain SPCs may have been recurrence or metastases of primary BC. However, this was mitigated by excluding patients for whom the SPC was a BC diagnosed within six months of the primary BC diagnosis. In our adjusted analyses we also modeled all SPCs, breast only SPCs, and non-breast SPCs to isolate the effects of treatment and medications on the development of SPCs. Our cohort was limited to postmenopausal women; thus, our findings are not necessarily generalizable to premenopausal women. Postmenopausal women are at an increased risk of SPCs due to increasing age and comorbidities. As such, our results can assist in determining those who may benefit from increased cancer surveillance. We were unable adjust for other potential confounders, such as family history of cancer, and reproductive or lifestyle factors such as smoking or obesity. Finally, we do not have detailed treatment information such as type of chemotherapy or radiation therapy dose.