Second cancer is the leading cause of death in long-term survivors of Hodgkin disease (HD), with exceptionally high risks of breast cancer among women treated at a young age. Quantitative associations between radiotherapy dose delivered to the breast and administered chemotherapy have not been reported to date in large series, nor has the influence of ovarian exposures on subsequent risk.
Objective
To quantify the long-term risk of breast cancer associated with use of radiotherapy and chemotherapy to treat young women with HD.
Design, Setting, and Subjects
Matched case-control study of breast cancer within a cohort of 3817 female 1-year survivors of HD diagnosed at age 30 years or younger, between January 1, 1965, and December 31, 1994, and within 6 population-based cancer registries. The study was conducted March 1, 1996, through September 30, 1998.
Main Outcome Measures
Relative risk (RR) of breast cancer associated with radiation dose delivered to site of breast cancer or to ovaries and with cumulative dose of alkylating agents.
Results
Breast cancer occurred in 105 patients with HD who were matched to 266 patients with HD but without breast cancer. A radiation dose of 4 Gy or more delivered to the breast was associated with a 3.2-fold (95% confidence interval [CI], 1.4-8.2) increased risk, compared with the risk in patients who received lower doses and no alkylating agents. Risk increased to 8-fold (95% CI, 2.6-26.4) with a dose of more than 40 Gy (P<.001 for trend). Radiation risk did not vary appreciably by age at exposure or reproductive history. Increased risks persisted for 25 or more years following radiotherapy (RR, 2.3; 95% CI, 0.5-16.5;P= .03 for trend with dose). Treatment with alkylating agents alone resulted in a reduced risk (RR, 0.6; 95% CI, 0.2-2.0) of breast cancer, and combined alkylating agents and radiotherapy in a 1.4-fold (95% CI, 0.6-3.5) increased risk. Risk of breast cancer decreased with increasing number of alkylating agent cycles (P= .003 for trend). Risk also was low (RR, 0.4; 95% CI, 0.1-1.1) among women who received 5 Gy or more delivered to ovaries compared with those who received lower doses.
Conclusions
Hormonal stimulation appears important for the development of radiation-induced breast cancer, as evidenced by the reduced risk associated with ovarian damage from alkylating agents or radiation. The high radiation-related risk, which did not diminish at the highest doses or the longest follow-up, however, suggests the need for lifetime surveillance and programs of patient and public awareness.
Abstract In a previous registry‐based survey of 999 patients injected with α‐emitting 232 ThO 2 (Thorotrast), we identified elevated risks for lung carcinoma and malignant mesothelioma. Since injected Thorotrast is retained lifelong mostly in liver, spleen and lymph nodes, the mesothelial surfaces of these organs are constantly irradiated. Thorotrast‐administered patients also perpetually exhale 220 Rn, a 232 Th‐daughter. Study of Thorotrast‐exposed patients may, therefore, provide data with regard to carcinogenicity of radon exposure, a current public health concern, as well as the pathogenesis of malignant mesothelioma. The incidence and histologic types of lung carcinoma and malignant mesothelioma within the cohort were examined by review of available histopathologic material and medical records. Further, mutations of the p53 gene were analyzed whenever possible as it has previously been suggested that radon‐associated lung carcinomas exhibit specific mutational patterns. The cumulative risk for lung carcinoma reached 11.0% based on 20 confirmed cases. Nine were small cell lung cancer (SCLC), whereas the expected frequency was 18%. The risk for malignant mesothelioma reached 2.5% based on 7 cases. The actuarial risk of malignant mesothelioma for patients given more than 20 ml Thorotrast was 7.8% compared to 1.4% for patients administered smaller amounts. Seven lung carcinomas and 5 malignant mesotheliomas were analyzed for p53 mutations; only 1 (in a lung adenocarcinoma) was detected. A possible association between Thorotrast and SCLC is suggested. In addition, a possible dose‐response gradient exists for Thorotrast and malignant mesothelioma.
The purpose was to investigate the treatment flow of patients with HER2-positive metastatic breast cancer (mBC), progression-free survival (PFS) and overall survival (OS) across treatment lines and adherence to guidelines (defined as trastuzumab, pertuzumab and chemotherapy first line, where 85% received vinorelbine as backbone and T-DM1 second line). Furthermore, we identified clinical markers to predict the risk of developing brain metastases. Patients with HER2-positive mBC, diagnosed between 01.01.2014–31.12.2019, registered in the database of the Danish Breast Cancer Group were included in this real-word study. Clinical follow-up was assessed until 01.10.2020 and complete follow-up for overall survival until 01.10.2021. Survival data were analyzed using the Kaplan-Meier method with guidelines adherence analyzed as a time-varying covariate, and the risk of CNS metastasis was estimated by the cumulative incidence function. 631 patients were included. 329 (52%) patients followed the guidelines. The median OS for all patients was 42.3 months (95% Cl, 38.2–48.4), and significantly higher for the patients who followed guidelines; NA (95% CI, 78.2–NA). The median PFS for all patients was 13.4 months (95% Cl, 12.1–14.8), 6.6 (95% Cl, 5.8–7.6) and 5.8 (95% Cl, 4.9–6.9) for first, second and third line of treatment, respectively. Patients with ER-negative mBC had a higher risk of developing brain metastases and patients with high tumor burden had a higher risk of developing brain metastases with an adjusted HR of 0.69 (95% CI, 0.49–0.98), p = 0.047 and 2.69 (95% CI, 1.45–5.00), p = 0.002, respectively. We found that only half of the patients with HER2-positive mBC, received first and second-line treatment according to national guidelines. Patients receiving treatment according to guidelines had a significantly higher median OS compared to patients who did not. We also found that patients with ER-negative disease or high tumor burden had a significantly higher risk of developing brain metastases.
Abdominal radiotherapy for testicular cancer (TC) increases risk for second stomach cancer, although data on the radiation dose-response relationship are sparse.
577 Background: Increasingly, HER2-positive early breast cancer (EBC) is treated by NACT combined with trastuzumab and pertuzumab followed by surgery. Ontruzant is registered as a biosimilar trastuzumab based on the totality of evidence including a randomized phase III study of NACT+Herceptin versus NACT+Ontruzant demonstrating similar pCR-rates (Pivot et al. J Clin Oncol 2018;36:968). However, no data exist for the efficacy of the combination of NACT with pertuzumab+Ontruzant (p+O). This investigator-initiated study was conducted to assess real world efficacy in HER2-positive EBC patients treated with NACT+p+O based on data from DBCG. DBCG has since 1977 provided guidelines for treatment of breast cancer and collected data from Danish hospital departments of surgery, pathology, and oncology prospectively on NACT, date and type of surgery and patho-anatomic findings. Methods: From the DBCG database, information was extracted for consecutive patients with unilateral early HER2-positive breast cancer registered to have received NACT+p+O from September 1, 2018 to August 31, 2019. pCR was defined as absence of residual invasive tumor in the breast and axillary lymph nodes (ypT0/Tis ypN0(i-)). Results: 215 patients received NACT+p+O. Median age was 54.8 years (range 24-81). NACT used, in combination with concurrent p+O, was cyclophosphamide+epirubicin followed by paclitaxel (62% on 6 cycles and 35% on 8 cycles) or other chemotherapy followed by paclitaxel (3%). Overall, 56% of patients achieved a pCR (Table). 68% of node-positive patients before receiving NACT+p+O had tumor-free axillary nodes after completing NACT+p+O. Conclusions: Real-world data from a nationwide population based study demonstrated a pCR-rate with NACT+p+O comparable to that seen in clinical studies with NACT+p+Herceptin (Chen et al. BMC Cancer 2019;19:973). pCR-rate was highly dependent on estrogen receptor (ER)-status and malignancy grade but not on clinical nodal status and tumor size. 68% of patients with cN+ converted to ypN0(i-). [Table: see text]
