Радиотерапия и повышенный риск возникновения второго первичного рака у выживших жертв рака молочной железы: эпидемиологическое и когортное исследование.

Background

Breast cancer (BC) stands as the foremost contributor to cancer-related illness, impairment, and fatality among women on a global scale [ 1 ]. Medical and surgical advancements in the past few decades have significantly improved the survival rates of BC patients. Subsequent malignancies in cancer survivors now make up 18 % of all cancer diagnoses in the US SEER cancer registries, ranking as the third most common type of cancer [ [2] , [3] ]. The findings revealed that by the 2022, the United States boasted over 4 million BC survivors, and this number is anticipated to continue its upward trend in the coming years [ 4 ]. With improved survival rates and the massive population base, BC survivors face a significant challenge of developing multiple primary malignancies inevitably, with a 17 % higher risk of developing second primary cancers compared to the general population [ 5 ]. The higher risks may be attributed to the delayed side effects of treatment, lifestyle and environment or shared etiological factors among various cancers [ [3] , [6] ].

Radiotherapy (RT) has been proven to effectively reduce local recurrence and improve prognosis for BC patients, while it does carry the risk of incidental irradiation of nearby healthy tissues. This unintended exposure may potentially increase the likelihood of developing a second cancer caused by radiation [ [3] , [7] ]. Multiple studies suggest that RT may increase the risk of developing multiple primary malignancies, including acute myeloid leukemia within two years of treatment, as well as cervical, ovarian, and thyroid cancers [ 7 ]. Existing studies have substantiated the notion that BC patients treated with RT encounter an elevated risk of developing second primary malignancies (SPCs) [ [3] , [7] ]. However, the issue of which specific SPCs exhibit an increased risk, the proportion of them associated with RT in BC patients, and the prognosis of SPCs related to RT and non-radiotherapy groups have not been adequately addressed.

Inspired by the research approach of tumor epidemiology [ [1] , [8] ], this study conducted a comprehensive analysis of the risk of 18 secondary primary cancers (SPCs) associated with radiotherapy (RT) and assessed the overall survival in breast cancer (BC) survivors. The dataset, encompassing a substantial population and spanning almost 30 years, facilitated a meticulous evaluation of long-term cancer risk patterns after RT. These findings may shed light on the incidence of SPCs, potential prognosis and treatment options associated with the connection between RT and SPCs in BC population.

Methods

Study cohort

The cohort was composed of female individuals aged 20–84 years who were diagnosed with primary BC at the localized and regional stage for the first time. Considering the typical latency period of a minimum of 5 years for radiation-induced SPCs to become clinically evident [ 9 ], these BC patients were reported between 1988 and 2013 and underwent follow-up from 1988 to 2018 at 9 registries (Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco–Oakland, Seattle–Puget Sound, and Utah) of the SEER (based on the November 2020 SEER data release). SPCs were defined as any system of cancer that occurred more than 5 years after the initial BC treatment. The follow-up for SPCs commenced five years after the diagnosis of BC and ceased upon the diagnosis of any SPCs, all-cause mortality, or completion of 30 years of follow-up. Inclusions were limited to participants pathologically confirmed with BC via positive histology. The exclusion criteria included patients with any SPCs diagnosed within 5 year after BC, patients who survived less than 5 years after BC diagnosis, patients who did not undergo surgery, and patients with missing data on race, survival status or follow-up information. This was an epidemiological and large cohort and the data presented was anonymous, so the informed consent from patients was waived. In line with the ethical guidelines of the London School of Economics and Political Science, this study, which involved secondary analysis of existing datasets, was deemed exempt from ethical approval and informed consent (London School of Economics and Political Science Research ethics: guidance on LSE research ethics, code of research conduct, and training. Updated April 23, 2020. Accessed March 26, 2019. https://info.lse.ac.uk/staff/divisions/research-and-innovation/research/research-policy/research-ethics ).

Study design

This study aimed to investigate the incidence of SPCs in BC survivors. BC patients were bifurcated into two groups based on the initial treatment modality involving RT. The RT group comprised of BC patients who underwent surgery and received external-beam RT, while the no-radiotherapy (NRT) group comprised of patients who received surgery alone. To obtain a comprehensive estimation of the risk of SPCs, we initially assessed the risk of developing various types of SPCs in BC survivors. According to reports, the majority of local recurrences in early-stage BC tend to occur within 5 years after BC surgery [ 10 , 11 ]. However, previous studies has primarily focused on treating contralateral BC as a SPC [ 5 , 12 , 13 ], inadvertently neglecting the risk of RT-related SPCs in the ipsilateral chest wall. Furthermore, the SEER program adheres to strict criteria when defining multiple primary neoplasms (SEER. 2007 Multiple primary and histology coding rules. 2018. https://seer.cancer.gov/tools/mphrules/ . Accessed February 28, 2018). Therefore, to the best of our knowledge, this study represents the first attempt to consider primary cancer in the ipsilateral breast as a targeted event associated with RT. In order to facilitate data analysis, our team conducted separate analyses based on CA statistics to assess the risk of developing second primary cancers (SPCs) in different human body systems [ 14 ]. These systems include oral cavity and pharynx, digestive system, respiratory system, bone and joints, soft tissue including heart, skin excluding basal and squamous, breast (including both contralateral and ipsilateral), female genital system, urinary system, eye and orbit, brain and other nervous system, endocrine system, all lymphatic and hematopoietic diseases, myeloma, leukemia, mesothelioma, kaposi sarcoma, and miscellaneous ( Fig. 1 A).

Statistical analysis

We employed Fine-Gray competing risk regression analysis to evaluate the cumulative incidence of SPCs. In this analysis, we considered death from any cause prior to SPC occurrence as competing event. Hazard ratios (HRs) and 95 % confidence intervals (CIs) were calculated to assess the occurrence of SPCs. The multivariable risk model was constructed using a backward selection procedure, wherein variables with a two-sided p-value less than 0.05 in univariable analyses were considered statistically significant and included in the multivariable analyses. Categorical data were compared using χ2 tests, or Fisher exact test. Mann-Whitney test was employed to analyze continuous variables, based on normal or non-normal distribution, respectively. The radiotherapy-related risk (RR) was calculated to compared the risk of SPCs in BC patients who received RT versus those who did not receive RT using Poisson regression analysis. Standardized incidence ratios (SIRs) were calculated using Poisson regression analysis to determine the ratio of observed SPC incidence among BC survivors to that in the general US population, with SEER∗Stat 8.4.0 used for calculation. Furthermore, to evaluate the dynamic risks and incidence of SPCs associated with RT, the RRs and SIRs were adjusted for latency time since BC diagnosis, age at BC diagnosis, and year of BC diagnosis. Additional details of the statistical methods can be found in Fig. S1 in the Supplement. We used the Kaplan-Meier method to calculate the overall survival rates for SPCs both in RT population and NRT population and SPC cohort and only BC cohort. The log-rank test was employed to determine if there were significant differences in survival, and p-values were calculated accordingly. Propensity score matching (PSM) was performed to minimize bias in survival comparisons. All analyses were conducted using R software (version 4.0.5).

Results

Patient characteristics and SPC trends in RT and NRT cohort

A total of 289121 patients diagnosed with BC were included in the study. After excluding patients with incomplete data, the final cohort consisted of 248268 patients ( Fig. 1 B). Among them, 205950 patients (83.0 %) were White, and the median age was 58 years (interquartile range (IQR), 49–68 years). The median follow-up time was 151 months (IQR, 100–218 months). The median latency of SPC in the overall patient population is 126 months. 29,236 survivors (11.8 %) developed second primary cancers, with higher incidences observed in breast cancer, and cancer of digestive system, respiratory system, and female genital system, accounting for 41 %, 15 %, 12 %, and 11 % respectively ( Fig. S2 ).

Of the patients in the cohort, 137471 (55.4 %) received RT, while 110797 (44.6 %) did not receive RT. Table 1 displays the baseline characteristics of BC patients according to their treatment modality. 16683 patients (12.1 %) in the RT group and 12553 patients (11.3 %) in the NRT group developed SPCs. The baseline characteristics of patients who developed SPCs are presented in Table S1 in the Supplement.

Overall, RT use increased markedly from 26.1 % to 64.4 % during 1988–2003 ( Fig. 1 C). However, the utilization rate stabilized in the subsequent years from 2004 to 2013, fluctuating between 60 % and 65 %. The SPC rate in the RT group consistently exceeds that in the NRT group throughout the entire follow-up period. This excess rate demonstrates an overall decreasing trend: among patients diagnosed in 1988–1989 and followed up for over 30 years, the RT group exhibited an SPC excess rate of at least 6.4 % compared to the NRT group. In the follow-up period ranging from 126 months to 360 months, the SPC rate in the RT group exceeded the NRT group by fluctuating between 0.3 % and 6.9 %. During the follow-up period of 60–126 months, the SPC rate in the RT group exceeded the NRT group by fluctuating between −0.1 % and 2.2 % ( Fig. 1 C).

Cumulative incidences of combined SPCs

The cumulative incidence of combined SPCs after diagnosing BC was 21.09 %. The incidences were 18.11 % in NRT group and 24.69 % in RT group (P < 0.001) ( Fig. 2 A). In system-specific analyses, the cumulative incidences of cancer in the breast, respiratory system, skin, leukemia, soft tissue cancer (including heart), and eye & orbit cancer were significantly higher in the RT group compared to the NRT group ( Fig. 2 B–E, G, H), while the incidence of myeloma was lower in the RT group (0.17 % vs 0.24 %; P = 0.040, Fig. 2 F). Higher incidences included BC (11.57 % vs. 6.30 %; P < 0.001), cancer in respiratory system (2.86 % vs 2.28 %; P < 0.001), skin cancer (0.69 % vs 0.56 %; P = 0.031), leukemia (0.54 % vs 0.42 %; P = 0.026), soft tissue cancer (including heart) (0.18 % vs 0.10 %; P < 0.001), and eye & orbit cancer (0.05 % vs 0.01 %; P = 0.047). However, no difference was observed in other cancers ( Figs. S3B–L ).

Risk of SPCs attributed to RT

All variables listed in Table 1 were included in the univariable competing risk regression analysis ( Tables S2–9 in the Supplement). In the multivariable analysis, it was found that RT was significantly associated with a higher risk of developing combined SPCs (adjusted HR, 1.29; 95 % CI, 1.26–1.33; P < 0.001), BC (adjusted HR, 1.58; 95 % CI, 1.52–1.64; P < 0.001), cancer in respiratory system (adjusted HR, 1.21; 95 % CI, 1.13–1.30; P = 0.013), skin cancer (adjusted HR, 1.26; 95 % CI, 1.10–1.44; P < 0.001), leukemia (adjusted HR, 1.30; 95 % CI,1.11–1.54; P = 0.001), and soft tissue cancer (including heart) (adjusted HR, 1.78; 95 % CI, 1.34–2.37; P < 0.001), and eye & orbit cancer (adjusted HR, 2.21; 95 % CI, 1.02–4.80; P = 0.044), but decreased risk for myeloma (adjusted HR, 0.76; 95 % CI, 0.61–0.97; P = 0.025).

To confirm the increased risk of SPCs attributable to RT, relative risks (RRs) were calculated. The adjusted RR for combined SPCs was 1.32 (95 % CI, 1.29–1.35; P < 0.001). Elevated risks were observed for BC (adjusted RR, 1.62; 95 % CI, 1.56–1.68; P < 0.001), cancer of respiratory system (adjusted RR,1.26; 95 % CI, 1.18–1.35; P < 0.001), skin cancer (adjusted RR, 1.31; 95 % CI, 1.14–1.49; P = 0.005), leukemia (adjusted RR, 1.45; 95 % CI,1.25–1.69; P < 0.001), soft tissue cancer (including heart) (adjusted RR, 1.83; 95 % CI, 1.37–2.46; P < 0.001) and eye & orbit cancer (adjusted RR, 2.34; 95 % CI, 1.12–5.22; P = 0.028), while a decreased risk was observed for myeloma (adjusted RR, 0.76; 95 % CI, 0.60–0.96; P = 0.021). The standardized incidence ratio (SIR) for combined SPCs was 1.30 (95 % CI, 1.28–1.32; P < 0.05) in patients who received RT. Specifically, higher SIRs were noted for BC (SIR, 2.03; 95 % CI, 1.98–2.08; P < 0 0.05), skin cancer (SIR, 1.09; 95 % CI, 1.01–1.19; P < 0.05), and cancer of soft tissue including heart (SIR, 2.11; 95 % CI, 1.78–2.50; P < 0.05) in patients who underwent RT, but the SIR for myeloma was lower for patients with RT (SIR, 0.72; 95 % CI, 0.60–0.85; P < 0.05) ( Table 2 ).

Dynamic risk and incidence evaluation of SPCs in BC population

To evaluate the potential risks of SPCs linked to RT, we constructed three dynamic RR plots based on age at BC diagnosis, time of BC diagnosis and latency period (see Tables S10–17 in the Supplement). The dynamic age-RR and diagnosis time-RR plot revealed that the highest RR of BC was observed in patients aged 20–49 and diagnosed with BC between 1988 and 1994. However, the RR exhibited a declining trend in older patients (adjusted RR: 20–49 years, 1.68; 50–69 years, 1.48; 70–84 years, 1.38) ( Fig. 3 A; Table S10 in the Supplement), and this trend persisted similarly across the years of BC diagnosis ( Fig. 3 B). During the short latency period, there was an observed increase in the RR of BC, with the risk gradually rising and reaching its peak during the long latency period (adjusted RR: 60–119 months, 1.46; 120–239 months, 1.58; 240–360 months, 2.00) ( Fig. 3 C). Notably, the RR trends for respiratory system cancer compared to BC were found to be significantly different ( Fig. 3 G–I; Table S11 in the Supplement). However, when examining the dynamic age-RR, diagnosis time-RR, and latency-RR plots, no increased risk was observed for the development of skin cancer, leukemia, myeloma, soft tissue cancer (including heart), and eye & orbit cancer across three different analyses in RT population ( Fig. 3 M–O and Fig. S4 , Tables S12–16 in the Supplement).

Furthermore, we conducted a thorough assessment of the dynamic SIRs in individuals who received RT and NRT. In the RT population, the incidence of BC was found to be higher compared to both NRT population and the general population in the United States. This observation was consistent across three analyses, with the incidence of BC being higher in NRT group than in the general population ( Fig. 3 D–F). However, our analysis demonstrated that there was no statistically significant rise in the SIRs of respiratory system cancer, skin (excluding basal & squamous) cancer, leukemia, myeloma, soft tissue (including heart), eye & orbit cancer among patients, irrespective of their receipt of radiation therapy, when compared to the general population ( Fig. 3J–L, Fig. 3 P–R and Fig. S5 ). Specially, we made a noteworthy observation: in the population of BC patients who did not receive RT, advanced age, early years' diagnosis, and an extended latency period were linked to significantly reduced SIRs for respiratory system cancer compared to the general population in the United States. Detailed information on the SIR values can be found in Tables S18–25 in the Supplement.

Prognosis of SPCs between RT and NRT cohort, and prognosis comparison of SPC after BC and only BC group

We conducted a comparison of 15-year OS between SPC patients with who received RT and those who did not. Our findings revealed that RT population who developed BC, cancer in respiratory system and leukemia after RT had a significantly higher 15-year OS compared to NRT population before PSM ( Fig. 4 A–B, G). However, PSM eliminated the previously identified statistical differences in survival rates between patients who underwent RT and those who did not. ( Fig. 4 D–E, J). In addition, no difference in survival of developing skin cancer, myeloma, soft tissue cancer and eye & orbit cancer was observed between patients who underwent RT and those who did not ( Fig. 4 C, F, H, I, K).

In the Kaplan-Meier survival analyses ( Fig. S6 ), the SPC group demonstrated significantly poorer 30-year OS compared to individuals with BC alone (with the onset of BC as the starting point for follow-up), with a decrease of more than 10 % among total population (30-year OS: 35.64 % vs 23.90 %; P < 0.001), NRT population (30-year OS: 31.94 % vs 20.86 %; P < 0.001) and RT population (30-year OS: 40.18 % vs 27.35 %; P < 0.001). This pattern started to emerge after the median latency period of 126 months, and it gradually became more noticeable during the subsequent follow-up period, even after PSM. Therefore, RT reduced OS by increasing the risk of SPC, while greatly impacting the quality of life for BC survivors.

Discussion

This is, to our knowledge, the first large population-based study to present the risk dynamics and prognosis of different types of SPCs after RT among BC survivors. In our study, the key findings are as follows. First, our results suggested that about 6.6 % of second solid cancers might be related to RT for the first cancer. RT was considered an important risk factor for the developing BC, cancer in respiratory system, skin cancer, leukemia, and soft tissue cancer (including heart), and eye & orbit cancer in BC survivors. However, RT seemed to be protective factors to develop myeloma in BC population. Second, the incidence of BC is higher in both RT population and NRT population, compared to the general population in the US. Third, the risks for developing BC after RT decreased with increasing age, decreased with diagnosis time, and increased with latency, but the almost opposite trends were observed for cancer in respiratory system. Fourth, while the OS for RT-associated SPCs is similar to that of patients without RT, SPC significantly decreased the 30-year OS in BC survivors by more than 10 %. Additionally, the increased risk of SPCs resulting from RT can negatively impact patients' quality of life and survival outcomes.

Despite extensive research on SPCs after RT [ 3 , 5 , 7 , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] ], the overall proportion and cumulative absolute risk of specific types of SPCs associated with RT in this population, classified according to different physiological and anatomical system classifications, are still not well understood. Unlike previous studies that proposed a one-year interval for second primary cancers after breast cancer [ 15 , 18 , 23 , 25 ], we strictly adhere to a minimum of five years as the standard for radiation-induced secondary cancers, which is consistent with several other studies [ 3 , 24 ]. Based on our findings, approximately 6.6 % of secondary solid tumors may be attributed to RT administered for primary cancer treatment. The ratio is consistent with previous studies, which estimated a range between 5 % and 8 % [ 3 , 13 , 22 ]. This study presented a investigation into the relationship between RT and the development of SPCs in different physiological systems among BC survivors. Consistent with previous similar studies, we found that RT was associated with significantly increased risks of developing BC [ 18 , 22 , 26 ], cancer in respiratory system [ [17] , [18] , [19] , [20] , [21] , 25 , 27 , 28 ], skin cancer [ 18 ], leukemia [ 15 , 29 ], and soft tissue cancer (including heart) [ [5] , [15] , [19] , [23] ] among BC survivors. In contrast to previous studies that primarily focused on contralateral BC as the second primary cancer and disregarded the increased risk of RT-related SPC in the ipsilateral chest wall, this study considered the occurrence of SPC in the ipsilateral breast as a second primary cancer. This approach aligned more closely with investigating the current status of SPCs in patients with BC, irrespective of their RT status. In this study, the incidence rates of contralateral second primary BC was 35.9 % in the left BC group and 35.2 % in the right BC group. This finding further confirmed that previous studies may have overlooked a considerable number of potential SPC events. Distinct from the previous case report [ 30 ], the current study revealed for the first time that RT may potentially elevate the incidence of eye and orbit cancer in BC patients. Due to the limited sample size in both the RT and NRT groups, with only 23 and 10 survivors respectively developing eye and orbit cancer, it is important to acknowledge that the results may be susceptible to the influence of random error. Meanwhile, the current study also indicated, for the first time, that RT appeared to reduce the risk of myeloma. A possible reason is that radiotherapy may have a certain degree of anti-tumor effect near the spinal bones or rib bones (the most common sites for developing myeloma) [ 31 ], which can eliminate potential myeloma cells or reduce their chances of development. Additionally, radiotherapy may also help regulate the function of the immune system [ [32] , [33] ], reducing the growth and spread of abnormal cells, thereby lowering the incidence of multiple myeloma. This may be attributed to the radiation targeting the chest region, which eliminates minor myeloma lesions, thus reducing the incidence of myeloma. The results could be affected by chance due to the limited number of survivors in both the RT and non-RT groups who developed myeloma, with only 161 and 131 cases, respectively. Although our results are inconsistent with the majority of previous studies suggesting an increased risk of thyroid cancer[ [25] , [28] ], our research indicates that there is no elevated risk of thyroid cancer after radiotherapy among overall breast cancer survivors, which is consistent with the findings of another recent large-scale study [ 5 ]. These findings contributed to the current body of knowledge in the field and warrant further investigation to better understand and minimize the potential risks associated with RT in BC patients.

In our analysis, we assessed the dynamic risk and incidence of each specific subtype of SPCs to offer a more comprehensive examination of the risk pattern. In line with prior research, our study revealed a gradual rise in the risk of skin cancer and soft tissue tumors with increasing age at diagnosis [ 23 ], while the risk of BC and leukemia exhibited a steady decline. Notably, among individuals diagnosed with BC aged 50–70, the relative risk (RR) reached its highest point for eye and orbit cancer, whereas it was lowest for respiratory system tumors, myeloma, and combined SPCs [ 22 ]. Further investigation is warranted to elucidate the underlying mechanisms. Generally, our findings indicated that the risks associated with RT were comparatively lower for women treated in more recent years (2005+). These reductions may be attributed to advancements in BC radiation therapy, improved local control, and the fact that the peak incidence of SPCs following BC diagnosis in more recent years has not been reached [ [34] , [35] ]. However, it is noteworthy that there has been a slight increase in the risk of respiratory system tumors among these survivors (from 1.20-fold to 1.33-fold). Potential explanations for this slight elevation may include the presence of common risk factors, such as advanced age and smoking, alongside the transient impacts of radiation therapy, and the fortuitous concurrence of an upsurge in lung cancer incidence within this timeframe.The risk of developing BC and eye and orbit cancer after RT was found to be highest after a latency of more than 20 years. In contrast, the highest risk for cancer of the respiratory system, skin cancer, myeloma, leukemia, soft tissue tumors, and combined SPCs was observed within 5–10 years. These findings suggested that extended monitoring may be required to identify occurrences of breast and eye cancers following RT. Conversely, prompt follow-up should be contemplated for respiratory system cancers, skin cancer, leukemia, and soft tissue tumors. The underlying mechanism responsible for these contrasting outcomes requires additional investigation.

Our research findings indicated that RT may potentially increase the likelihood of developing SPCs in specific systems, despite no observed difference in survival between RT-related and non-RT-related SPCs. The heightened occurrence of SPCs would negatively impact the quality of life for BC survivors, impose substantial financial burdens on individual treatments, and place strains on societal healthcare systems. It is worth noting that BC survivors who experienced SPCs exhibit a significantly poorer prognosis during long-term follow-up (after 12 years) compared to those without SPCs. This phenomenon could be ascribed to the genetic phenotypic variability and the concurrent impact of multiple tumors in SPC population, resulting in heightened treatment complexities and potentially inferior outcomes.

A notable strength of our study lies in the evaluation of RT-induced SPC in specific systems among BC survivors. The present investigation contributed to the identification and monitoring of these SPCs by considering the adoption of consistent diagnostic protocols for tumors within the same anatomical system. For instance, the utilization of chest CT and bronchoscopy is common in the evaluation of respiratory system tumors, whereas abdominal ultrasound and CT, as well as gastrointestinal endoscopy, are employed in the examination of tumors in the digestive system. Through our study, we were able to implement focused surveillance and facilitate the timely identification, diagnosis, and treatment of RT-related SPCs by utilizing pertinent information such as the initial age of breast cancer survivors, time of breast cancer diagnosis, and latency period for the development of SPCs. This approach has the potential to enhance the overall management of cancer survivors and improve the efficiency of detecting SPCs induced by RT. Another strength of this study is its extensive duration of follow-up, enabling the identification of potential subsequent SPCs over a longer timeframe. The large population of observed individuals with treatment exposure, as ascertained from the SEER database, bolstered the statistical robustness and generalizability of the study's findings.

While this study might provide valuable insights, it was important to acknowledge its limitations. Firstly, the lack of precise data regarding RT modality, dose, range in the SEER database posed challenges in accurately evaluating the correlations between these factors and the risk of SPCs. Consequently, this limitation may have resulted in an underestimation of the increased risk linked to RT. Specifically, in the case of a relatively small proportion of second cancers—such as those occurring in myeloma, soft tissue cancers, and eye & orbit cancers—the connection to RT might not be the predominant factor. Other factors, including chemotherapy and lifestyle choices such as smoking and obesity, and genetic background and adverse living or working environments, could also contribute to an elevated risk of SPCs [ [2] , [36] ]. Although attaining complete balance was challenging, we endeavored to mitigate potential biases by excluding incident SPCs within the initial 5-year follow-up period and breast cancer (BC) patients with less than 5 years of follow-up from the analysis, and employing a multivariable risk competing model to adjust for important confounding factors, such as chemotherapy status. Furthermore, it is worth noting that certain statistically significant associations observed in our study could potentially be attributed to random chance, particularly in the case of less common SPCs. Additionally, there may be variations in cancer survival across different regions, which means that the conclusions of our study may not be fully generalizable to other countries. However, this limitation is unlikely to affect our main conclusion.

Conclusions

In this cohort study, the present investigation was conducted to evaluate the heightened susceptibility to developing various types of secondary primary cancers (SPCs) in female breast cancer (BC) survivors who underwent radiotherapy (RT). Although the 15-year survival prognosis was comparable between the RT and NRT groups, the presence of SPC significantly reduced the 30-year survival rate from 35.64 % to 23.90 %. The dynamic risks of SPCs were assessed using competing risk models, taking into account factors such as age, time of diagnosis, and latency. The findings of this study might offer valuable insights into the clinical surveillance and follow-up of BC patients after RT, providing potential strategies for the early detection, diagnosis, and treatment of SPCs within the BC population.

CRediT authorship contribution statement

Niuniu Hou: Writing – original draft, Methodology, Investigation, Formal analysis, Conceptualization. Zhe Wang: Writing – original draft, Formal analysis. Yuwei Ling: Software, Formal analysis. Guangdong Hou: Software, Formal analysis. Bo Zhang: Validation, Software, Formal analysis. Xue Zhang: Validation, Software, Formal analysis. Mei Shi: Writing – review & editing. Zhuling Chu: Writing – review & editing. Yaoling Wang: Writing – review & editing. Jun Hu: Project administration, Conceptualization. Chong Chen: Supervision, Methodology, Conceptualization. Rui Ling: Supervision, Project administration, Methodology, Conceptualization.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The current study involved secondary analysis of existing, anonymous datasets that were deemed exempt from ethical approval and informed consent.

Consent for publication

Not applicable.

Funding

This study was funded by Key Research and Development Program of Shaanxi Province (2022ZDLSF02-07).

Declaration of competing interest

The authors declare that they have no competing interests.

Acknowledgements

Also, special thanks to all members of the SEER research team, all fieldworkers, and every participants.

Footnotes

Supplementary data to this article can be found online at https://doi.org/10.1016/j.breast.2024.103824 .

Contributor Information

Niuniu Hou, Email: hou_neoniu@163.com.

Jun Hu, Email: hu000924@163.com.

Chong Chen, Email: ccsys@126.com.

Rui Ling, Email: lingrui0105@163.com.

Supplementary data

The following is the Supplementary data to this article:

Multimedia component 1

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Associated Data

Supplementary Materials

Multimedia component 1

Data Availability Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.