Risk Of Second Primary Cancer Research Articles

Abstract PO4-11-08: Risk of second malignancies in breast cancer patients. A population-based retrospective cohort study between 2010-2020

Abstract Introduction: Breast cancer survivors live longer due to early detection programs and therapeutic advances. Staging and molecular classification are important for prognosis and treatment. At the same time these patients are at increased risk for second primary cancers. Comprehensive evaluation of second cancer risk among patients treated in recent decade with early detection and prevention programs of other tumors lacking. This study aims to identify, characterize and associate breast cancers with second primary malignancies based on different variables. Methods: We identified 3487 females with a first primary breast cancer between 2010 and 2020 in medical records at University Hospital of A Coruña in Spain. Over a median follow-up of 8 years, one hundred patients (2,9%) develop second cancer. According National Cancer Institute, second primary tumor (SPT) was defined as an invasive primary cancer after a first primary cancer. In our case a breast carcinoma. Second cancer risk was evaluated for all cancers (excluding ipsilateral breast carcinoma) which were diagnosed at least 12 months after primary breast tumor. We analyzed breast cancer subtype, family history and pathogenic genetic variants, tobacco use and second primary tumor type. Results: Several clinical characteristics were evaluated, including breast cancer stage, histological type and subtype. The incidence of breast cancer and SPT was increased with age with peaks in the 60’s and 70’s, respectively. Only 13% had SPT between 40-49 years. Approximately 10 women a year, in our study, developed second cancer. 52% of SPT patients had cancer family history. Pathogenic variant study was carried in 25% of women with SPT, 46% of them no mutation were found, but in 17% was detected a germline BRCA1 deleterious variant. Other pathogenic variants were founded: 4% in BRCA2, and 33% in others genes (CHEK2, MSH2, MSH6, PMS2, CDH1, FANC1 y SMAD4) Regards tobacco use, active smokers were 13% and 12% of women had been smoking years ago. Of these 13 active smokers, 10 develop lung cancer (77%) an 5 of former smokers (42%). Luminal subtype was the most common breast cancer (33% Luminal A, 34% Luminal B Her2 negative, 10% Luminal B Her2 positive, 4% Her2-enriched, 10% Triple negative and 3% carcinoma in situ with estrogen and progesterone expression) and stage I and II were most frequent (80%). The most usual second primary neoplasms were lung, colorectal and pancreatic carcinoma (21%, 17% and 7% respectively), and only 2% contralateral breast cancer, with an average of approximately 4 years between breast cancer and the SPT. In 11% of patients were found more than 2 tumors. At the time of the analysis, 73% of these patients are free of disease. In SPT study population few recurrences were described, 2 relapses of breast cancer and 9 of SPT. The median between breast cancer diagnosis and the SPT diagnosis was 54 months [0,7 – 129]. The median to relapse of breast cancer was 73 months [68 – 77]. The median between SPT diagnosis and relapse was 39,25 months [1 - 134]. STP recurrences were observed in colorectal and lung cancer, mainly. Data on recurrences and mutations were not significative. Conclusion: In our breast cancer population the incidence of second primary tumors is around 3% over a 10 – year period. The diagnosis of the SPT arises several years after breast cancer and generally has a worse prognosis. Elevated risks of second cancer among breast cancer survivors treated in recent decade suggests that heightened surveillance is warranted and continued efforts to reduce second cancers are needed. It is mandatory make an effort and focusing in recommendations and advise about tobacco consumption, healthy lifestyle and adherence to Pap test and stool test in survivors. Citation Format: Guadalupe Rama, Maria-Eva Perez-Lopez, Silvia Antolin Novoa, Cristina Reboredo, Beatriz Alonso, Sofia Silva Diaz, Begoña Graña, Lourdes Calvo, Tomas Garcia-Caballero. Risk of second malignancies in breast cancer patients. A population-based retrospective cohort study between 2010-2020 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-11-08.

Abstract PO1-03-03: STEEP criteria v2.0 validation: A multi-trial analysis using GEICAM and TRIO adjuvant trials to evaluate surrogate endpoints for overall survival

Abstract Background: Standardized definitions of efficacy endpoints are needed to improve clinical trial designs, data reporting and interpretation of results, and to allow cross-trial comparisons. STEEP (Standardized Definitions for Efficacy Endpoints) criteria were proposed in 2007 by an expert panel from the National Cancer Institute (NCI) to provide common definitions for clinical trials in early breast cancer (BC). Invasive disease-free survival (IDFS) was selected as a candidate surrogate endpoint for overall survival (OS) in adjuvant trials and has been widely used in the last 15 years. Advances in BC systemic treatment led to review these criteria (STEEP v2.0), with the definition of a new modified endpoint: invasive BC-free survival (IBCFS). IBCFS excludes second primary non-breast invasive cancers from IDFS which may better detect efficacy effects when the toxicity profile of the intervention is well-known and the risk of second primary cancer is small. Methods: We proposed a multi-trial analysis of 8 adjuvant chemotherapy (CT) trials from GEICAM and TRIO to evaluate the different surrogate endpoints defined in the STEEP v2.0. Trial-level surrogacy was assessed through correlation between the ln hazard ratio (HR) of OS and the ln HR of the different studied endpoints across trials. The correlation was estimated by the weighted, by trial size, least squares regression (WLS) line and evaluated comparing the R2 values between OS and the corresponding endpoint tested. Primary analyses evaluated the correlation of OS with IDFS/IBCFS. Secondary analyses evaluated the correlation of OS with other STEEP v2.0 endpoints (distant disease-free survival [DDFS], distant relapse-free survival [DRFS], recurrence-free survival [RFS], recurrence-free interval [RFI] and distant recurrence-free interval [DRFI]) and explored the surrogacy between OS and all endpoints in specific groups of patients (pts) according to their risk of relapse: hormone receptors positive (HR+)/HER2-negative (HER2-) pts with intermediate/high and high-risk and triple negative (TN) pts. Results: A total of 14,473 pts were included. Median age was 50 years (range, 20–82). All were female, and 51.8% were postmenopausal. With a median follow-up of 115 months (range, 0.0–188) we found 2,504 OS events, 4,146 IDFS events (60.9% being distant recurrences) and 3,810 IBCFS events (62.4% being distant recurrences). For each trial, HR of OS, IDFS and IBCFS indicated same conclusions. If HR< 1 for OS, it was also for IDFS and IBCFS and the same was true when HR >1. R2 results of the weighted linear correlations between the ln HR of OS versus (vs) IDFS and OS vs IBCFS were 0.86 and 0.89, respectively. Confidence intervals (CI) at 95% were both overlapping. All other efficacy endpoints showed strong correlation with OS in the overall analysis. R2 values for HR+/HER2- intermediate/high and high-risk pts were 0.89 (OS vs IDFS) and 0.84 (OS vs IBCFS). For TN pts the correlations were weaker, being 0.63 (OS vs IDFS) and 0.73 (OS vs IBCFS). All WLS R2 values are described in the table. Conclusions: All tested STEEP v2.0 endpoints were strongly correlated with OS (R2 close to 1), meaning that their use as surrogate endpoints for adjuvant CT trials is appropriate. Notably, no differences were found between them in this multi-trial analysis. Therefore, none of them is more appropriate than other to discriminate the value of a new intervention vs comparator in adjuvant CT studies with mature data and long-term follow-up. Table: Citation Format: Sara López-Tarruella, Marina Pollan, Ander Urriticoechea, Eva Carrasco, Gonzalo Spera, Miguel Martín, Begoña Bermejo, Linnea Chap, Manuel Ruíz - Borrego, John Crown, Jose Angel García-Sáenz, Arlene Chan, Angel Guerrero, Valerie Bee, Lourdes Calvo, Rodrigo Fresco, Andrea Blasco, Andrés Hernando, Dennis Slamon. STEEP criteria v2.0 validation: A multi-trial analysis using GEICAM and TRIO adjuvant trials to evaluate surrogate endpoints for overall survival [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-03-03.

Abstract 2194: Association of metabolic syndrome conditions with risk of second primary cancer of any organ in breast cancer survivors

Abstract Purpose: Breast cancer survivors are at increased risk of developing second primary cancers; however, factors attributing to increased risk of second primary cancer in breast cancer survivors are under-studied. We evaluated the association of metabolic syndrome conditions with second primary cancer of any organ in breast cancer survivors. Methods: In this retrospective cohort study, we included 37,222 patients diagnosed with breast cancer between 2008-2020 at Kaiser Permanente Southern California (KPSC), an integrated healthcare system. We extracted data on cancer-related variables, sociodemographic and clinical variables from KPSC’s cancer registry and electronic health records. Among the metabolic conditions, we identified diabetes, hypertension, and dyslipidemia using ICD-10 diagnosis codes at or 1-year prior to breast cancer diagnosis; obesity was based on body mass index (BMI≥30kg/m2). We included metabolic syndrome as a categorical variable: 0, 1-2, and 3+ metabolic conditions. We followed patients electronically from breast cancer diagnosis until patients developed second primary cancer of any organ, died, disenrolled from the health plan, or reached study’s end (12/31/2021), whichever occurred first. Proportional hazards regression was used to report association [HR (95%CI)] between metabolic conditions and any second primary cancer. Results: During a median (IQR) follow-up of 5.17 (2.75-8.58) years, 1701 (4.6%) patients developed any second primary cancer. More than half (53.1%) of the breast cancer survivors had 1-2 metabolic conditions at baseline; 19.4% had 3+ metabolic conditions, and the rest 27.5% did not have any metabolic condition. Hypertension was the most common metabolic condition (45.5%), followed by obesity (38.9%), dyslipidemia (36.5%), and diabetes (19.0%). Survivors with 0 and 1-2 metabolic conditions were 35% and 19% less likely to develop any second primary cancer than survivors with 3+ metabolic conditions, respectively [crude HR (95%CI): 0.65 (0.57-0.75) and 0.81 (0.72-0.91), respectively]. Reduced risk in survivors with 1-2 metabolic conditions persisted adjusting for age, race and ethnicity, breast cancer diagnosis year, breast tumor SEER summary stage, breast tumor estrogen-progesterone status, smoking status, and breast tumor treatment [adjusted HR (95%CI): 0.87 (0.77-0.99)]. Conclusion: Risk of second primary cancer of any organ was elevated in breast cancer survivors with three or more metabolic conditions. Citation Format: Amrita Mukherjee, Zheng Gu, Lie Hong Chen, Arnold L. Potosky, Reina Haque. Association of metabolic syndrome conditions with risk of second primary cancer of any organ in breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2194.

257 risk of second primary cancer in HPV+ head and neck squamous cell carcinoma (HNSCC)

257 risk of second primary cancer in HPV+ head and neck squamous cell carcinoma (HNSCC)

Incidence of late recurrence and second primary cancers 5-10 years after non-metastatic colorectal cancer.

The fraction of patients who are cancer-free survivors 5 years after curative-intended surgery for colorectal cancer (CRC) is increasing, suggesting that extending surveillance beyond 5 years may be indicated. Here we estimate the incidence of late recurrence, metachronous CRC, and second primary cancers 5-10 years postoperative. All patients resected for UICC stage I-III CRC in Denmark through 2004-2013 were identified. Through individual-level linkage of nationwide health registry data, recurrence status was determined using a validated algorithm. Cancer-free survivors 5 years after surgery, were included. Cumulative incidence functions (CIF) of late recurrence, metachronous CRC, and second primary cancer 5-10 years postoperative were constructed. Subdistribution hazards ratios (sHR) were computed using Fine-Gray regression. Among 8883 patients, 370 developed late recurrence (5-10-year CIF = 4.1%, 95%CI: 3.7%-4.6%), 270 metachronous CRC (5-10-year CIF = 3.0%, 95%CI: 2.7%-3.4%), and 635 a second primary cancer (5-10-year CIF = 7.2%, 95%CI: 6.7%-7.7%). The risk of late recurrence was reduced for patients operated in 2009-2013 compared to 2004-2008 (2.9% vs. 5.6%, sHR = 0.52, 95% CI: 0.42-0.65). The risk of metachronous CRC was likewise reduced from 4.1% to 2.1% (sHR = 0.50, 95%CI: 0.39-0.65). While the risk of second primary cancer did not change between 2009-2013 and 2004-2008 (7.1% vs. 7.1%, sHR = 0.98, 95% CI: 0.84-1.15). Using nation-wide 10-year follow-up data, we document that the incidences of late recurrence and metachronous CRC are low and decreasing from 2004 to 2013. Thus, despite increasing numbers of long-term cancer survivors, the data do not advocate for extending CRC-specific surveillance beyond 5 years.

An Entirely Oral Regimen of Oral-Arsenic Trioxide/All-Trans Retinoic Acid/Ascorbic Acid in Newly-Diagnosed Acute Promyelocytic Leukaemia (APL): Updated Results of an Ongoing Multicentre Trial

Background: Pure oral arsenic trioxide (oral-ATO) solution (Arsenol ®) was first formulated in Hong Kong. It achieves a bioavailability comparable with that of intravenous ATO (i.v.-ATO). Oral-ATO combined with all-trans retinoic acid (ATRA) and ascorbic acid (the AAA regimen) combined with chemotherapy is highly efficacious in relapsed and newly-diagnosed APL. To reduce treatment-related toxicities and long-term risks of second primary cancers, a chemotherapy-free approach is increasingly favoured. Aims: The objectives of this prospective multicentre study in newly diagnosed APL patients were: 1. to evaluate the efficacy and safety of an entirely oral AAA-induction in a risk-adapted strategy; 2. to evaluate the molecular responses during oral-AAA-based induction/consolidation/maintenance. Methods: Newly-diagnosed APL patients were stratified by presentation leucocyte count into standard-risk (≤ 10 x 10 9/L) and high-risk (> 10 x 10 9/L) groups. Standard-risk patients and high-risk patients ≥ 65 years old received AAA induction comprising oral-ATO (Arsenol ®, Jacobson Pharma Corporation, Hong Kong) (10 mg/day, or 0.16 mg/kg in patients < 18 years old, days 1-42), ATRA (45 mg/m 2/day, or 25 mg/m 2/day in patients <18 years old, in 2 divided doses, days 1-42), and oral ascorbic acid (1 g/day, or 15mg/kg/day in patients <18 years old, days 1-42). High-risk patients < 65 years old received in addition daunorubicin (50 mg/m 2/day i.v. for 3 days). On reaching first complete remission (CR1), consolidation with AAA (days 1-14) every 28 days for 2 cycles was given, followed by maintenance with AAA (days 1-14) every 8 weeks for 12 cycles. Real-time quantitative polymerase chain reaction for PML:: RARA with a sensitivity of 10 -5 was performed (weekly during induction, every 4 weeks during consolidation, every 8 weeks during maintenance and thereafter every 12 weeks for 2 years). For molecular response, the normalized copy number ratio was defined as PML::RARA copy number/ ABL copy number. Primary outcomes were overall survival (OS, time from presentation to death or last follow-up), and relapse-free survival (RFS, time from CR1 to molecular or haematological relapse, death or last follow-up), and safety (according to the Common Toxicity Criteria for Adverse Events (AE) version 5.0). The secondary outcome was molecular response. Data were censored on July 22, 2023. Results: Between January 1, 2018 to July 22, 2023, 5 paediatric/adolescent patients (male, N=2; female, N=3) at a median age of 12 (3-15) years and 116 adult (> 18 years old) patients (male, N=47 ; female, N=69) at a median age of 49 (19-91) years were accrued (standard risk: paediatric/adolescent, N=3; adults, N=87; high-risk: paediatric/adolescent, N=2; adults, N=29). Seven patients (all high-risk adults) died at presentation before induction (intracranial haemorrhage, N=6; severe APL differentiation syndrome, DS, with leucocyte >100 x10 9/L, N=1). One-hundred and fourteen patients received oral-AAA-based induction (AAA alone, N=90; AAA+daunorubicin, N=24), all achieving CR1. For PML:: RARA normalized copy number, all treated patients at week 8 achieved a ratio of <0.01; and on completion of AAA maintenance, all evaluable patients (N=56) achieved a ratio of <0.0001. The median follow-up was 29 (IQR: 8-47) months, with 56 patients (49%) having completed 2 years of AAA maintenance. There was only one relapse, occurring in an adult patient 12 months after completion of AAA maintenance. Molecular analysis showed a PML B2 domain A216V mutation that conferred resistance to ATO. One adult patient died of an unrelated gastrointestinal bleeding while in CR1. The 3-year OS was 99.1% (paediatric/adolescent: 100%; adult: 99%). The 3-year RFS was 97.9% (paediatric/adolescent: 100%; adult: 97.9%). The most common non-haematological AEs (all grade 1-2) were transaminitis (N=54, 47.3%) and headache (N=32, 28%) Notably, no cardiotoxicity (arrhythmias/cardiac failure) was observed. APL-DS occurred in 67 patients (58.7%) after initiation of AAA, all responding fully to intravenous dexamethasone. There were no treatment discontinuations. Conclusion: The use of an entirely oral AAA-based induction in a risk-adapted strategy that minimized chemotherapy was highly effective and safe in newly-diagnosed APL of all risk categories and age groups. Early deaths remained an obstacle to realizing a cure-for-all in APL.

Risk of second primary cancers after a diagnosis of first primary cancer: A pan-cancer analysis and Mendelian randomization study.

The risk of second primary cancers (SPC) is increasing after the first primary cancers (FPC) are diagnosed and treated. The underlying causal relationship remains unclear. We conducted a pan-cancer association (26 cancers) study in the Surveillance, Epidemiology, and End Results (SEER) database (non-Hispanic whites). The standardized incidence ratio (SIR) was estimated as the risk of SPCs in cancer survivors based on the incidence in the general population. Furthermore, the causal effect was evaluated by two-sample Mendelian Randomization (MR, 13 FPCs) in the UK Biobank (UKB, n=459,136,, European whites) and robust analysis (radial MR and Causal Analysis Using Summary Effect estimates, CAUSE). We found 11 significant cross-correlations among different cancers after harmonizing SIR and MR results. Whereas only 4 of them were confirmed by MR to have a robust causal relationship. In particular, patients initially diagnosed with oral pharyngeal cancer would have an increased risk of non-Hodgkin lymphoma (SIRSEER = 1.18, 95%Confidence Interval [CI]:1.05-1.31, ORradial-MR=1.21, 95% CI:1.13-1.30, p=6.00 × 10-3; ORcause = 1.17, 95% CI:1.05-1.31, p=8.90 × 10-3). Meanwhile, ovary cancer was identified to be a risk factor for soft tissue cancer (SIRSEER = 1.72, 95%Confidence Interval [CI]:1.08-2.60, ORradial-MR=1.39, 95% CI:1.22-1.58, p=1.07 × 10-3; ORcause = 1.36, 95% CI:1.16-1.58, p=0.01). And kidney cancer was likely to cause the development of lung cancer (SIRSEER = 1.28, 95%Confidence Interval [CI]:1.22-1.35, ORradial-MR=1.17, 95% CI:1.08-1.27, p=6.60 × 10-3; ORcause = 1.16, 95% CI:1.02-1.31, p=0.05) and myeloma (SIRSEER = 1.54, 95%Confidence Interval [CI]:1.33-1.78, ORradial-MR=1.72, 95% CI:1.21-2.45, p=0.02; ORcause = 1.49, 95% CI:1.04-2.34, p=0.02). A certain type of primary cancer may cause another second primary cancer, and the profound mechanisms need to be studied in the future. This work was in supported by grants from National Natural Science Foundation of China (Grant No. 81972645), Innovative research team of high-level local universities in Shanghai, Shanghai Youth Talent Support Program, intramural grant of The University of Hong Kong to Dr. Rong Na, and Shanghai Sailing Program (22YF1440500) to Dr. Da Huang.

Nodular type but not vitamin D levels increases the risk of second primary cancers in melanoma patients: An observational study of 663 patients

BackgroundVitamin D deficiency associates with the risk of developing many diseases, including cancer. At the molecular level, vitamin D appears to have an antineoplastic effect. However, the role of vitamin D deficiency in cancer pathogenesis remains unelucidated and numerous studies have resulted in discordant results. This study aimed to determine whether vitamin D deficiency during melanoma diagnosis increases the risk of developing non-cutaneous second primary cancers (SPC). Materials and methodsA retrospective study on 663 patients diagnosed with melanoma between 1 January 2011 and 31 October 2022. The effect of each variable on the development of a subsequent non-cutaneous cancer was performed using Kaplan–Meier curves and differences were assessed by log-rank tests. Cox proportional hazard univariate and multivariate models were used to quantify the effect of each variable in the time to develop a non-cutaneous neoplasia. ResultsOut of 663 patients, 34 developed a non-cutaneous SPC. There was no statistically significant association between vitamin D levels and non-cutaneous SPC development (log-rank, p=0.761). Age>60 years, stage III/IV, and nodular melanoma subtype were significantly associated with the development of a SPC. After multivariate analysis, only age>60 years (HR 3.4; HR CI 95%: 1.5–7.6) and nodular melanoma subtype (HR 2.2; HR CI 95%: 1.0–4.8) were included in the final model. ConclusionsOur results suggest that vitamin D deficiency is not associated with an increased risk of developing non-cutaneous SPC in melanoma patients. However, age over 60 years and nodular melanoma subtype increase the risk for non-cutaneous SPC development.

Risk for second primary cancers among pediatric and young adult melanoma survivors.

Second primary cancers (SPCs) are a leading cause of morbidity and mortality among cancer survivors. In this study, we aimed to characterize the incidence of SPCs among pediatric and young adult survivors of CM. Using the Surveillance, Epidemiology, and End Results Program data spanning 2000-2018, we calculated standardized incidence ratios (SIR) to assess SPC risk in all pediatric (0-18 years) and young adult (19-29 years) patients with a first primary cancer diagnosis of CM. Of 7,169 total CM survivors, 632 (8.82%) developed a SPC, corresponding to a 5-fold increased risk (standardized incidence ratio [SIR] 4.98; 95% confidence interval [CI] 4.60-5.38) compared to the general population. There was a highly elevated risk for second primary melanoma across all age groups (SIR 32.5; 95% CI 29.7-35.6), constituting the majority of SPC diagnoses (N = 485). Infants diagnosed with CM before 1 year of age had the highest risk for any SPC (SIR 164; 95% CI 19.8-592) and young adults diagnosed at 25-29 years had the lowest risk (SIR 4.64; 95% CI 4.19-5.13). SPC incidence was highest within the first year of CM diagnosis (SIR 27.5; 95% CI 23.7-31.6) and progressively decreased with time. Variation exists in the incidence and type of SPC according to age among pediatric and young adult survivors of CM.

Impact of thyroid hormone replacement on the risk of second cancer after thyroidectomy: a Korean National Cohort Study

We aimed to investigate the effect of thyroid hormone administration on the risk of second primary cancer in patients who underwent thyroidectomy for differentiated thyroid cancer. Data were extracted from the medical billing data of the Health Insurance Review and Assessment Service in South Korea. Patients between 19 and 80 years old who underwent thyroid surgery at least once between January 2009 and June 2020 were included. Data of patients with second primary cancer and control patients with matched age, sex, operation date, and follow-up duration were extracted at a ratio of 1:4. A nested case–control analysis was performed to exclude length bias to confirm the correlation between the duration of thyroid hormone administration, dose, and incidence of second primary cancer. Of the 261,598 patients who underwent surgery for thyroid cancer included in the study, 11,790 with second primary cancer and 47,160 without second primary cancer were matched. The average dose of thyroid hormone increased the adjusted odds ratio (OR) for both low (≤ 50 μg, OR 1.29, confidence interval (CI) 1.12–1.48) and high (< 100 μg, OR 1.24, CI 1.12–1.37) doses. Analyzing over time, the adjusted OR of second primary cancer increased, especially in short (≤ 1 year) (OR 1.19; CI 1.06–1.34) and long (> 5 years) duration (OR 1.25; CI 1.10–1.41). In conclusion, insufficient and excessive thyroid hormone replacement might be linked to increased second primary cancer in patients who underwent thyroidectomy for differentiated thyroid cancer.

Risk of second primary cancers in patients with rectal neuroendocrine neoplasms: a surveillance, epidemiology, and end results analysis.

While an elevated risk of second primary cancers (SPCs) has been observed in many other cancers, risk of SPCs has not been quantified in patients with rectal neuroendocrine neoplasms (NENs). Survivors of primary rectal NENs diagnosed between 2000 and 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER)-18 registries. Relative risk of SPCs was estimated as the standardized incidence ratio (SIR), which was calculated using SEER*Stat software. Between 2000 and 2018, a total of 15836 patients diagnosed with rectal NENs, of whom 1436 (9.1%) received diagnosis of SPCs (SIR: 1.19, 95%CI: 1.13-1.26). The majority of patients were aged 50-69 and had their first cancer diagnosed at the localized stage. Male survivors had a higher propensity for developing SPCs overall, while female survivors exhibited higher risks of specific SPCs. Age at diagnosis of rectal NENs influenced the risk of SPCs, with younger patients having greater risks. A statistically significant increase in the incidence of SPCs was observed among patients aged 30-64 years. Black patients had higher relative risks of certain SPCs, while White patients had a lower risk of subsequent melanoma. Trend analysis revealed that the highest excess burden of SPCs was observed in the years 2000 to 2002. Risk of SPCs remained elevated within the first four years post-diagnosis for survivors of rectal NENs, but diminished thereafter. The study revealed that individuals who survived rectal NENs were at an elevated risk of developing SPCs compared to the general population. Our results hold important implications for the formulation of lifelong surveillance recommendations for cancer survivors.

Significant risk of second primary cancer among laryngeal squamous cell carcinoma patients even after 20 years

Background: Evidence on the risk of second primary cancer (SPC) following primary laryngeal squamous cell carcinoma (LSCC) is limited, especially in Europe. Methods: Patients diagnosed with primary LSCC from 1953–2018 were retrieved from the Finnish Cancer Registry. A total of 6241 LSCC patients were identified adding to 49,393 person-years (PY) of follow-up until the end of 2019. Only one patient emigrated and was lost to follow-up. Both standardized incidence ratios (SIR) and excess absolute risk (EAR) per 1000 person-years at risk (PYR) of second primary cancer (SPC) were calculated relative to the general population. Only non-laryngeal SPCs diagnosed six months after diagnosis of primary LSCC were included. Results: A SPC was diagnosed in 1244 LSCC patients (20% of all LSCC patients) over the 65-year period, predominantly in men (92%, n = 1170). Out of all SPCs, 34% were diagnosed within 0.5 to 5 years and 66% after 5 years from primary LSCC. Among male patients, the overall SIR for SPC at any location was 1.61 (95% CI: 1.52–1.71), corresponding to 9.49 excess SPCs per 1000 PYR (95% CI: 8.19–11). The corresponding SIR for women was 1.47 (95% CI: 1.15–1.84), yielding 4.82 excess SPCs per 1000 PYR (95% CI: 2.36–9.84). The risk remained significant even after 20 years of follow-up (SIR for all 1.73, 95% CI: 1.49–2.01 and EAR 16.8 per 1000 PY, 11.88–23.75). The risk for SPC was also significantly elevated in all age groups, except <40. The highest SIRs were for SPCs arising in the mouth/pharynx (SIR for all 3.08, 95% CI: 2.36–3.95 and EAR 0.80 per 1000 PY, 0.55–1.15) and lungs (3.02, 2.75-3.30 and 5.90 per 1000, 5.13–6.78). Conclusion: Patients with LSCC as primary cancer have a 60% excess risk for an SPC, especially for tobacco-associated cancers, remaining significantly elevated even decades after treatment.

Association of radiotherapy for stage I-III breast cancer survivors and second primary malignant cancers: a population-based study.

With life span extending, breast cancer survivors may face the possibility of developing second primary cancers (SPCs). The objective of this research is to investigate the risk factors, risk attribute to radiotherapy and the survivalship for SPCs. A total of 445 523 breast cancer patients were enrolled from Surveillance, Epidemiology, and End Results database in 2000-2018. The risk factors for SPCs development were confirmed by competing risk model, and then were integrated to the nomogram establishment. The cumulative incidence of SPCs including SBC (second breast cancer), SGC (second gynecological cancer), and SLC (second lung cancer) were estimated. The radiotherapy-associated risk for SPCs were evaluated by Poisson regression in radiotherapy and no-radiotherapy. Propensity score matching was used to reduce possible bias for survival comparison. There were 57.63% patients in radiotherapy. The risk factors for developing SPCs were age, year, race, tumor size, stage, radiotherapy, grade, surgery, and histology. The cumulative incidence of SPCs was 7.75% in no-radiotherapy and 10.33% in radiotherapy. SLC, SBC, and SGC also appeared the similar results. The increased risk of developing SPCs were associated with radiotherapy in majority subgroups. The dynamic radiotherapy-associated risk for SPCs by age slightly increased risk was observed. Regardless radiotherapy or no-radiotherapy, the 10-year overall survival for SBC (radiotherapy: 59.41%; no-radiotherapy: 55.53%) and SGC (radiotherapy: 48.61%; no-radiotherapy: 35.53%) were worse than that among matched patients with only primary cancers. Breast cancer survivors remained a high radiotherapy-associated risk for developing SPCs. The prognosis in radiotherapy was better than in no-radiotherapy for some specific SPCs. Largely attention should be paid to these patients.

Modelling the influence of radiosensitivity on development of second primary cancer in out-of-field organs following proton therapy for paediatric cranial cancer.

Radiobiological modelling the risks of second primary cancer (SPC) after proton therapy (PT) for childhood cranial cancer remains largely unknown. Organ-specific dose-response risk factors such as radiosensitivity require exploration. This study compared the influence of radiosensitivity data (slope of βEAR) on children's lifetime attributable risks (LAR) of SPC development in out-of-field organs following cranial scattering and scanning PT. Out-of-field radiosensitivity parameter estimates for organs (α/β and βEAR) were sourced from literature. Physical distances for 13 out-of-field organs were measured and input into Schneider's SPC model. Sensitivity analyses were performed as a function of radiosensitivity (α/β of 1-10 Gy) and initial slope (βEAR) from Japanese/UK data to estimate the influence on the risk of radiation-induced SPC following scattering and scanning PT. Models showed similar LAR of SPC estimates for age and sex-matched paediatric phantoms, however, for breast there was a significant increase using Japanese βEAR data. For most organs, scattering PT demonstrated a larger risk of LAR for SPC which increased with α/β. Breast tissue exhibited the highest susceptibility in calculated LAR risk, demonstrating the importance for accurate data input when estimating LAR of SPC. The findings of this study demonstrated younger female patients undergoing cranial proton therapy have a higher risk of developing second primary cancer of the breast tissue. Long-term multicenter registries are important to improve predictive radiobiological modelling studies of side effects.

Second Primary Cancer Among Patients With Papillary Thyroid Carcinoma Following the Chernobyl Disaster

To our knowledge, there are no complete population-based studies of the risks of developing second malignant tumors after papillary thyroid carcinoma (PTC) in patients following the Chernobyl nuclear accident. To study the risk of second primary cancers in patients with PTC after the Chernobyl disaster. This was a retrospective cohort study conducted in the Republic of Belarus over a 31-year time frame evaluating patients with primary PTC and second malignant tumors. Personal data from the Belarussian Cancer Registry were used in the investigation, and only second primary cancers were included in the analysis. Patients were observed from January 1, 1990, to December 31, 2021, for the establishment of second primary malignant tumors. For analysis, synchronous and metachronous tumors were grouped into 1 group (second primary cancer group). If the patient had more than 2 cancers, they were observed until development of a second tumor and, subsequently, the development of a third tumor. The starting point for calculating the number of person-years was the date of thyroid cancer diagnosis. The end point for calculating the number of person-years was the date of diagnosis of the second primary malignant tumor, the date of death, the date of the last visit of the patient, or December 31, 2021 (the end the of study period). The incidence of a second primary malignant tumor with PTC was calculated for the study groups using standardized incidence ratios. Of the 30 568 patients with a primary PTC included in this study, 2820 (9.2%) developed a second malignant tumor (2204 women and 616 men); the mean (SD) age of all patients at time of the primary cancer was 53.9 (12.6) years and at time of the secondary cancer was 61.5 (11.8) years. Overall, the standardized incidence ratio was statistically significant for all types of cancer (1.25; 95% CI, 1.21-1.30), including solid malignant tumors (1.20; 95% CI, 1.15-1.25) and all leukemias (1.61; 95% CI, 2.17-2.13). Cancers of the digestive system (466 cases [21.1%]), genital organs (376 cases [17.1%]), and breasts (603 cases [27.4%]) were the most prevalent second primary tumors in women following PTC. Second primary tumors of the gastrointestinal tract (146 cases [27.7%]), genitourinary system (139 cases [22.6%]), and urinary tract (139 cases [22.6%]) were the most prevalent in men. Urinary tract cancers (307 cases [10.9%]) and gastrointestinal tumors (612 cases [21.4%]) were the most prevalent second primary tumors overall. This cohort study reports the increased incidence of solid secondary tumors in men and women over a 31-year time frame after the Chernobyl disaster. Moreover, there was a statistically significant increased risk of second tumors of the breast, colon, rectum, mesothelium, eye, adnexa, meninges, and adrenal glands as well as Kaposi sarcoma. These data might have an effect on the follow-up of this cohort of patients to detect secondary malignant tumors at an early stage.

Particle radiotherapy for breast cancer.

Breast cancer is the most common malignant tumor in female patients. Along with surgery, radiotherapy is one of the most commonly prescribed treatments for breast cancer. Over the past few decades, breast cancer radiotherapy technology has significantly improved. Nevertheless, related posttherapy complications should not be overlooked. Common complications include dose-related coronary toxicity, radiation pneumonia, and the risk of second primary cancer of the contralateral breast. Particle radiotherapy with protons or carbon ions is widely attracting interest as a potential competitor to conventional photon radiotherapy because of its superior physical and biological characteristics. This article summarizes the results of clinical research on proton and carbon-ion radiotherapy for treating breast cancer.

Risk of second primary cancer in patients with head and neck squamous cell carcinoma: a systemic review and meta-analysis.

Second primary cancer is a common event in patients with head and neck squamous cell carcinoma. However, the incidence and relevant factors vary by studies. We conducted a systematic review and meta-analysis of observational studies to estimate the incidence and relevant risk factors. PubMed and Web of Science were searched for studies published between January 2000 and December 2020 that reported the incidence of SPC in HNSCC patients. Per 1000-person-year incidence and odds ratios were used to estimate the incidence and potential risk factors. Due to the high heterogeneity, random-effects models were used to estimate the incidence and 95% confidence interval. Seven thousand seven hundred thirteen articles were identified from the databases, in which 60 studies were included in this meta-analysis. The pooled incidence of the total, synchronous, and metachronous SPC in patients with HNSCC were 29.116 per 1000-person-year, 6.960 per 1000-person-year, and 26.025 per 1000-person-year, respectively. The head and neck region was the most common area where SPC occurred, followed by the lung (7.472 per 1000-person-year) and upper digestive tract (2.696 per 1000-person-year). Smoking, alcohol consumption, betel quid chewing, primary cancer of T1-2, and N0 were risk factors, while HPV infection (OR 0.47, 95% CI 0.30-0.72) was the protective factor. SPC is frequently observed in HNSCC patients and had great impact on the prognosis. The findings could promote a more individualized follow-up strategy for SPC in HNSCC patients. This systemic review and meta-analysis provide sufficient evidence for the establishment of the follow-up strategy for head and neck squamous cancer patients.

Second primary cancer among 217702 colorectal cancer survivors: An analysis of national German cancer registry data.

With improvements in survival after colorectal cancer (CRC), more survivors are at risk of developing a second cancer, particularly in younger populations where CRC incidence is increasing. We estimated the incidence of second primary cancer (SPC) in CRC survivors and its potential risk factors. We identified CRC cases diagnosed between 1990 and 2011 and SPCs until 2013 from nine German cancer registries. Standardized incidence ratios (SIR) and absolute excess risk (AER) per 10 000 person-years were calculated and were stratified by index site: colon cancer (CC) and rectal cancer (RC), age and sex. Cox regression assessed potential SPC risk factors, including primary tumor-related therapy considering death as a competing risk. We included 217 202 primary CRC cases. SPC occurred in 18 751 CRC survivors (8.6%; median age: 69 years). Risk of cancer was significantly higher in CRC survivors than in the general population (SIR males 1.14, 95% confidence interval [CI] 1.12-1.17, AER = 24.7; SIR females 1.20, 95% CI 1.17-1.23, AER = 22.8). Increased risks of SPCs were observed for the digestive system, urinary system and female and male reproductive organs. CRC incidence increased in younger persons (<50 years) and SPC incidence was 4-fold in this group (SIR males 4.51, 95% CI 4.04-5.01, AER = 64.2; SIR females 4.03, 95% CI 3.62-4.48, AER = 77.0). Primary tumor-related factors associated with SPC risk were right-sided cancer and smaller primary tumor size. Treatment and risk of SPC differed for CC (no effect) and RC (lower risk after chemotherapy). CRC survivors have excess risk of developing SPC, with particular characteristics that could guide targeted surveillance.

Risk of second primary cancer from proton arc therapy of pediatric brain tumors.

Proton arc therapy (PAT) is currently explored for clinical implementation, despite its associated low-dose bath. This study therefore aimed at evaluating the risk of radiation-induced second primary cancer (SPC) for PAT in pediatric brain tumor patients. Two brain-specific models for SPC induction were applied in five cases to compare volumetric modulated arc therapy (VMAT), intensity modulated proton therapy (IMPT) and PAT surrogate plans. The PAT integral dose was reduced by a median of 29% compared to VMAT, and 17% compared to IMPT. For both models, the estimated SPC risks were consistently the lowest for PAT.

Pre-diagnostic cigarette smoking and risk of second primary cancer: The Melbourne Collaborative Cohort Study

Enhanced survival following a diagnosis of cancer has led to a steep rise in the number of individuals diagnosed with a second primary cancer. We examined the association between pre-cancer cigarette smoking and risk of second cancer in 9785 participants diagnosed with first invasive cancer after enrolment in the Melbourne Collaborative Cohort Study. Follow-up was from date of first invasive cancer until diagnosis of second primary invasive cancer, death, or 31 July 2019, whichever came first. Data on cigarette smoking was collected at enrolment (1990–94) along with information on other lifestyle factors including body size, alcohol intake and diet. We estimated hazard ratios (HR) and 95 % confidence intervals (CI) for incident second cancer with several smoking measures, adjusted for potential confounders. After a mean follow-up of 7.3 years, 1658 second cancers were identified. All measures of smoking were associated with increased risk of second cancer. We observed a 44 % higher risk of second cancer for smokers of ≥ 20 cigarettes/day (HR=1.44, 95 % CI: 1.18–1.76), compared with never smokers. We also observed dose-dependent associations with number of cigarettes smoked (HR=1.05 per 10 cigarettes/day, 95 % CI: 1.01–1.09) and duration of smoking (HR=1.07 per 10 years, 95 % CI: 1.03–1.10). The risk of second cancer increased by 4 % per 10 pack-years of smoking (HR=1.04, 95 % CI: 1.02–1.06; p < 0.001). There was suggestive evidence of stronger associations with number of cigarettes smoked and pack-years of smoking for women (pinteraction<0.05), particularly for the highest risk categories of both variables. These associations with pre-diagnostic smoking were markedly stronger for second cancers known to be smoking-related than for others (phomogeneity<0.001). Our findings for pre-diagnostic cigarette smoking indicated increased risk of second primary cancer for cancer sites considered smoking-related, highlighting the importance of assessing smoking habits in cancer survivors.