We found that the incidence of any SPC among older women with primary BC is 12%. Women of white race, who were married, and in a higher income quartile, were more likely to develop SPC. Additionally, initial BC with ductal histology, hormone positivity, treated with surgical intervention, were also associated with SPC. There are many possible explanations for these associations which will be further discussed below.
Sociodemographic factors associated with the development of SPC included older age at diagnosis, white race, being married and higher income quartile. While older age at BC diagnosis 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. Compared to white women, the incidence of any SPC was lower for women of non-Hispanic black, Hispanic, and other race. The higher incidence of SPC among white women may be due to their overall higher survival rates after BC diagnosis, thus allowing them the time to develop a SPC.2 Conversely, the incidence of a breast SPC specifically was significantly higher in black women which may be attributed to factors such as poorer access to healthcare, barriers to breast screening, and more advanced stage of BC at initial diagnosis.2 These results are consistent with Qian et al., who also investigated risk factors for SPCs in the SEER database population and found black race associated with increased risk of second BC.3
We also observed that non-married women and those who have higher income were more likely to develop a SPC. This increased risk persisted in the adjusted models for any 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.4 Prolonged survival is an independent risk factor for the development of SPC. Several studies have reported the incidence of SPC types in primary breast cancer survivors.5 We found that second BCs represented 32% of all SPCs and the incidence was higher in women with ductal carcinoma and hormone receptor positive BCs. In general, these types of BC are more responsive to treatment and result in longer survival times, whereas hormone receptor negative BCs, which comprise 30% of tumors, are known to have a more aggressive clinical course as they can not be treated with hormone therapy.6 They are thus more likely to be poorly differentiated, involve increased recurrence rates as well as increased mortality rates.6
The current treatment for BC includes surgery, chemotherapy, radiotherapy, and more recently immunotherapy. The majority of BC survivors in our cohort received surgery as initial treatment for their primary BC, and surgery was associated with a higher 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.7 Those who received surgery alone (without chemotherapy or radiation therapy) were also at higher risk for developing a contralateral breast cancer.8 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, improving survival and allowing more time for SPC to develop. We found that chemotherapy was associated with a decreased risk for breast SPC, but increased risk of all other SPCs, which is corroborated by other studies linking certain chemotherapy drugs with different types of cancers. Li et al. reported that SPCs, particularly non-breast cancers such as colon and lung cancer, were higher in patients who received chemotherapy for BC, even after adjusting for known confounders.7 Another SEER-based study determined that chemotherapy for BC patients was associated with increased incidences for all SPC, except for some hematologic malignancies.9 Though the mechanism of how chemotherapy may inadvertently stimulate cancer growth remains largely unclear, it has been shown to be most commonly linked to leukemia and myelodysplastic syndrome.
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.10 Other studies have shown that only 8% of SPCs are related to radiotherapy.11 Here, we found that similar to chemotherapy, radiation therapy had a decreased risk of second primary breast cancer, but 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. Aromatase inhibitor therapy is the gold standard for the treatment of hormone-receptor positive BC in post-menopausal BC survivors. In our study, women treated with aromatase inhibitors were less likely to develop any SPC, including. non-breast SPCs. Preclinical studies have shown that aromatase inhibitors in combination with standard cisplatin chemotherapy for non-small cell lung cancer (NSCLC) decreases tumor progression.12 Post-menopausal hormone exposure was also associated with a reduced risk for later development of NSCLC in the general population.13
Finally, we observed significant associations between certain medications and the development of SPCs, particularly statins, antihypertensives, and bisphosphonates. Statins and anti-hypertensives were both associated with increased hazard of developing any SPC including breast SPC, whereas bisphosphonates were associated with decreased hazard of developing all SPCs. Bisphosphonates have been shown to decrease risk of both locoregional/distant BC recurrence or second primary BC.14 Its effect on the development of other SPCs is less well understood. However, anti-tumor properties have been shown in preclinical studies15 and it is effective in reducing the risk of bone metastases.14 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,16 although the mechanisms to explain these associations remain unclear. Possible explanations include that patients on these antihypertensives are more unhealthy generally, and thus either did not tolerate BC treatment or are more likely to have captured adverse outcomes due to their more frequent medical visits. Additionally, thiazide diuretics specifically are associated with insulin resistance, which has been found to be an established risk factor for breast cancer, which may also explain the risk associated with antihypertensives.16 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 NSCLC, citing in vitro studies that have demonstrated reduced proliferation, migration, and increased apoptosis of lung cancer cell lines with simvastatin use.17 Another possible mechanism of statin anticancer effects posited in this study is the inhibition of tumor cell proliferation, angiogenesis, and migration by reduction of systemic cholesterol.17
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 in whom the SPC was a BC diagnosed within two 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 could not adjust for other potential confounders, such as family history of cancer, 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.