Clinical and Sociodemographic Risk Factors Associated With the Development of Second Primary Cancers Among Postmenopausal Breast Cancer Survivors

Abstract

Introduction: Advances in breast cancer (BC) diagnosis and treatment have increased the number of long-term survivors. Consequently, survivors of primary BC are at a greater risk of developing second primary cancers (SPCs). The risk factors for SPCs among BC survivors including sociodemographic, cancer treatment, comorbidities, and other medications have not been comprehensively examined. The purpose of this study is to assess the incidence and clinicopathologic factors associated with risk of SPCs.

Methods: We analyzed 170, 639 women with early-stage primary BC diagnosed between January 2000-December 2015 from the Medicare-linked Surveillance Epidemiology and End Results (SEER-Medicare) database. SPC was defined as any diagnosis of malignancy occurring within the study period and at least two months after primary BC diagnosis. Univariate analyses compared baseline characteristics between those who developed a SPC and those who did not. We evaluated the cause-specific hazard of developing a SPC in the presence of death as a competing risk.

Results: Of the study cohort, 20,838 (12%) of BC survivors developed a SPC and BC was the most common SPC type (32%). The median time to SPC was 42 months. Women who were white, older, and with fewer comorbidities were more likely to develop a SPC. While statins [hazard ratio (HR) 1.060 (1.016 - 1.106)] and anti-hypertensives [HR 1.517 (1.461 – 1.575)] increased the hazard of developing a SPC, aromatase inhibitor therapy [HR 0.588 (0.542 – 0.638)] and bisphosphonates [HR 0.897 (0.848 – 0.949)] were associated with a decreased hazard of developing any SPC, including non-breast SPCs.

Conclusion: Our study shows that specific clinical factors including type of cancer treatment, medications, and comorbidities are associated with increased risk for the development of SPCs among older BC survivors. These results can increase patient and clinician awareness, target cancer screening among BC survivors, as well as developing risk-adapted management strategies. 

Introduction

Breast cancer (BC) accounts for nearly one in three cancer cases diagnosed in women.¹ Early detection as well as improved management have contributed to the increase in survival rates of BC patients. As a result, longer life expectancy is accompanied by increased risk of developing a second primary cancer (SPC), defined as malignant tumors with differing pathologic morphologies and are not metastases from the initial primary cancer.¹

The incidence of SPCs among women with primary BC have been inconclusive, ranging from 4–17%, with varying follow up times.¹ Though prior studies show that BC survivors are more susceptible to developing a SPC, it has been difficult to quantify that risk and identify specific factors that may predispose some BC survivors to developing SPCs more than others. The American Cancer Society recommends annual mammography screenings for the general population as well as specific guidelines for those with a family history of BC or women with genetic mutations. However, there is currently not enough evidence for specific BC screening recommendations based on having a personal history of BC. There are also no comprehensive screening guidelines for other types of cancer in these cancer survivors.

The purpose of this study is to (1) assess rate and types of SPCs among an extensive cohort of older BC survivors and (2) identify clinical and sociodemographic factors associated with the development of SPCs. Our study will aid in improving clinician and patient awareness of SPCs in BC survivors and can serve as an informative model for developing risk-adapted management strategies.

Materials And Methods

Data Sources

Study participants were selected from the Surveillance, Epidemiology and End Results registry linked to Medicare claims record (SEER-Medicare). We excluded individuals in healthcare maintenance organizations and those without Medicare Parts A and B insurance, due to incomplete claims which are needed to assess comorbidities and cancer treatment (e.g., surgery, chemotherapy, radiation therapy). We excluded individuals without Medicare Part D claims data which were needed to ascertain prescription medication use.

Study Population

We identified patients >66 years of age who were diagnosed with primary BC between January 1, 2000 and December 31, 2015, in the SEER-Medicare database. We only included patients with a pathologically confirmed diagnosis. Those with diagnoses made at autopsy and death certificate were excluded. We further limited our cohort to include only female patients, with early stage (0 to III) BC.

Sociodemographic variables were extracted from linked Medicare claims and included age at diagnosis, race/ethnicity, income quartile, county/residency type, marital status, first treatment regimen, comorbidities, and medications. Comorbidity burden was assessed using the recommended NCI comorbidity index with weights specific for breast cancer. BC treatment (surgery, chemotherapy, radiotherapy) was extracted using International Classification of Diseases, Ninth Revision (ICD-9) and Health Care Procedure Coding System (HCPCS) procedure codes. Patients were considered to use medications of interest if they had used the drug within the year prior to cancer diagnosis until 6 months after diagnosis. Similarly, patients were considered to have specific comorbidities if there was at least one inpatient or two outpatient Medicare claims code for the diagnosis within 1 year prior to cancer diagnosis up until 6 months after primary BC diagnosis. This study was deemed exempt by the Mount Sinai Institutional Review Board.

Study Outcome

The primary outcome was development of SPC. SPCs diagnosed within two months of the primary cancer were excluded to remove what were likely multiple primary tumors.

Results

Discussion

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

Limitations

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.

Conclusion

In summary, SPCs pose a threat to BC survivors, though the nuances in potential biologic and epidemiologic explanations remain unclear. Our comprehensive exploration uncovered several demographic and treatment factors that may help guide more detailed recommendations for cancer prevention and screening among postmenopausal BC survivors.

Declarations

Acknowledgements

This work was supported by the National Cancer Institute of the National Institutes of Health (T32CA225617 to SB). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Data Availability

The data that support the findings of this study are available from NCI SEER-Medicare, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of NCI SEER-Medicare.

Statements and Declarations

Conflict of Interest: The authors declare that they have no conflict of interest.

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