In recent decades, major improvements in cancer treatment, including molecular targeted and immune modulation therapies, have allowed patients to survive long enough to develop subsequent primary malignancies (1). Moreover, advancements in diagnostic approaches, including new imaging techniques and cancer biomarkers, have resulted in earlier and higher detection rates of multiple primary cancers (2, 3). Defined as cancers with more than one independent primary malignancy in the same or different organs, multiple primary cancers may develop in a synchronous or metachronous fashion (4). Although this phenomenon was first described by Billroth (5) in 1889, Cahan et al. (6) in 1969 were the first to report multiple primary cancers involving the lungs. Later, Hofmann et al. (7) demonstrated the incidence of second primary lung cancer at 1.6 per 100,000 population. More recently, Hu et al. (8) identified 178 (5.0%) patients with primary lung cancer undergoing surgery who had different types of previous extrapulmonary malignancies.

While there is no doubt that multiple primary malignancies involving the lungs can occur, the therapeutic strategies and survival outcomes of patients with lung cancer with a history of extrapulmonary malignancies remain controversial. An increased risk of synchronous lung cancer in patients with breast cancer has been reported, suggesting that genetic factors may increase the risk of multiple primary malignancies (9). Additionally, the widespread use of radiotherapy and common risk factors may contribute to an increased risk of second primary lung cancer in patients with a history of head and neck cancer (10–12).

In this study, we aimed to analyze the survival differences among patients with lung cancer with and without previous extrapulmonary malignancies. Additionally, we sought to identify potential risk factors for second primary lung cancer occurrence to develop strategies aimed at prevention and early diagnosis among high-risk individuals.

Lung cancer is the leading cause of cancer mortality in the United States and worldwide (17). The outcomes of patients with lung cancer with previous extrapulmonary malignancies have received much attention in recent decades. However, the impact of previous malignancies on survival and prognosis is still not clearly defined. Our study showed that the incidence of previous extrapulmonary malignancies was 8.3% in patients with primary lung cancer. Several clinicopathological features, including age, sex, a family history of lung cancer, and preoperative CEA levels, were significantly different between the two groups. Furthermore, patients with previous breast or thyroid cancer had significantly better OS than those without previous malignancies. Conversely, patients with other previous extrapulmonary malignancies had significantly poorer OS.

The incidence of previous extrapulmonary malignancies in our study was similar to those reported previously (1–22%) (7, 8, 18–26). Corresponding to an increase in the incidence of multiple primary cancers, a surge of 5.7% in lung cancer as a second primary malignancy was also noted between 1988–1992 and 2011–2014 in the United States National Cancer Institute's Surveillance, Epidemiology, and End Results Program (19). Aside from common risk factors, such as cancer-promoting lifestyle factors and environmental interactions (27), genetic predisposition in the form of germline mutations (28, 29) and the subsequent carcinogenic effects of cancer treatment have been reported as potential mechanisms for the development of multiple primary cancers. Additional lung cancer risk was observed in patients with Hodgkin's lymphoma who were treated with radiotherapy (30, 31). A meta-analysis of 13 studies demonstrated that radiotherapy for breast cancer was significantly associated with a relative risk of 1.22 for second lung cancer (32), with an excess relative risk of 8.5% per Gray (33). Another well-established explanation for the growing incidence of multiple primary tumors is the prolonged survival rates of patients with cancer combined with increased concern over personal health and surveillance among cancer survivors (8).

Supplementary Table 2 reviews several studies that examined clinicopathological features in patients with lung cancer with previous extrapulmonary malignancies. Some reported that patients with previous extrapulmonary malignancies were older (18, 20, 23, 24). We found similar results; in our study, these patients were ~2 years older than those without previous extrapulmonary malignancies. This may be attributable to the longer exposure to carcinogens and greater genetic susceptibility in older individuals (34). These patients also had higher preoperative CEA levels. This marker underlies a distinct characteristic of extra- or intrapulmonary adenocarcinoma among patients with multiple primary malignancies (35). However, smoking habits between the two study subgroups did not differ, which agrees with the mathematical modeling of the Liverpool Lung Project (LLP). By showing a higher impact of cumulative non-smoking risk on lung cancer over smoking alone, additive effects of lung disease and environmental exposures should be recognized in the non-smoking population (36). Another significant feature that contradicted with accepted knowledge is the lower incidence of a family history of lung cancer. This may indicate a different etiology in this subgroup, corresponding with those of previous studies suggesting that the occurrence of multiple malignancies may be multifactorial in origin (20–23, 26). Further studies are warranted to investigate the hereditary contribution toward tumorigenesis in this subgroup.

Exposure to prior cancer treatment may lead to treatment intolerance in subsequent cancers. This affects the surgeons' selection of surgical methods and postoperative management. However, our results showed no differences in preoperative pulmonary reserve or intraoperative surgical margins in patients with and without previous extrapulmonary malignancies. Therefore, there was no need for extra consideration of surgical method selection, tumor approach, or preference for non-intubated airway management. Moreover, surgical blood loss, length of postoperative hospital stay, and chest tube duration did not differ between the two groups, indicating that no special care was needed. This result corresponds with those of several previous studies (23, 25).

Because of the undetermined interference caused by the previous cancer, whether to include patients with multiple primary malignancies in clinical trials remains controversial (37–40). Our results indicate that some previous extrapulmonary malignancies have a negative impact on survival. However, it is noteworthy that prior breast or thyroid cancer resulted in a better outcome. Higher performance status, lower CEA levels, well and moderately differentiated tumors, and early-stage cancers also served as favorable prognostic factors in the multivariate analysis. Broader inclusion of different subgroups of patients with lung cancer in future clinical trials is necessary to expand their authenticity and generalizability. The factors we identified may serve as the eligibility criteria to confirm equality between patients with and without previous extrapulmonary malignancies. Notably, in our study, the interval between the diagnoses of the two cancers was concentrated in the first 5 years and did not significantly impact survival trends. This calls into question the legitimacy of the current practice of excluding prior cancer within 5 years of enrollment and underscores the concerns of excluding specific groups of patients.

Breast cancer was the most common previous extrapulmonary malignancy reported by our and other studies (7, 8, 19, 20, 22, 24, 25). This may have accounted for the higher proportion of female patients in our group with lung cancer with previous extrapulmonary malignancies. According to the Taiwan Cancer Registry, breast and lung cancer have been among the top three most common cancers since 2003. The launch of a national screening program for breast cancer (41) and the recent advocation of low-dose CT (42) have been reported as factors contributing to this phenomenon, leading to greater discovery of both cancers.

Our results should be interpreted in light of several limitations. First, the study cohort only consisted of surgically treated patients. This may have underestimated the overall incidence of lung cancer in patients with previous extrapulmonary malignancies. Nevertheless, as the largest tertiary hospital in Taiwan, one-third of the early lung cancer resections in the country are performed at our institution, which provides an adequate number of samples. Second, as a single-center, retrospective study, our results may not be generalizable to the entire population. Although further studies are required in patients of different ethnic backgrounds, we reduce other possible bias by conducting our research over a short period of time and treat our patients under similar operative protocol. Third, because of the lack of data linkage between hospitals, we are incapable of knowing the status of previous malignancies, if they were evaluated and treated outside our hospital. However, by analyzing the existing documentation in the electronic medical record, we did make an effort to explore the additional relationships between previous cancer staging and lung cancer outcome.

In conclusion, lung cancer was more likely to develop in patients with previous breast, gastrointestinal, or thyroid cancer within 5 years after the first primary malignancy diagnosis. Although OS was lower in patients with previous extrapulmonary malignancies, previous breast or thyroid cancer did not increase mortality. Our findings may help surgeons to predict the prognosis in this subgroup of patients with primary lung cancer, and to arrange follow-up examinations more frequently.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

M-WL, H-HH, J-SC, and M-SH contributed to conception and design of the study. J-HC, H-YL, P-HC, and X-HC organized the database. K-CT, T-MT, and H-CL performed the statistical analysis. H-YL wrote the first draft of the manuscript. X-HC, P-HC, K-CT, and M-WL wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

The authors declare that this study received funding from the Ministry of Science and Technology, Taiwan [grant number: 107-2221-E-002-080-MY3], National Taiwan University Hospital, Taiwan [grant number: NTUH109-S4659] and Taiwan Lung Foundation. The funder had the following involvement with the study: English language editing and article processing fee. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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