Second cancer risk after Hodgkin lymphoma, testicular cancer, breast cancer and childhood cancer

Now that curative treatment is available for a substantial group of cancer patients, it is increasingly important to evaluate to which extent the occurrence of late complications of treatment affects their long-term survival. In close collaboration with the Departments of Radiation Oncology and Medical Oncology we aim to assess the risk of second cancers, cardiovascular disease and other comorbidities after radiotherapy (RT) and chemotherapy (CT) for Hodgkin’s lymphoma (HL), testicular cancer, breast cancer and childhood cancer. These malignancies were chosen because they have excellent cure rates and occur at relatively young ages. We have established large patient cohorts with information on radiation fields and CT regimens. The nationwide HL and testicular cancer cohorts include 10,500 patients treated 1965-2009 and 8,500 patients treated 1966-2009, respectively. For breast cancer we have constructed 4-regions cohort of 90,000 breast cancer patients (1989-2004); we also built a 2-hospital cohort of breast cancer patients treated 1970-2009 (N=21,000) for whom we also collected cardiovascular risk factors. These cohorts are linked with the Netherlands Cancer Registry (NCR) and cardiovascular disease registries, but also actively followed through general practitioners. Dose-response relationships, influence of lifestyle and genetic susceptibility are investigated in case-control studies.

We recently reported on long-term second cancer risk in al HL cohort (Schaapveld et al, NEJM 2015). We observed that risk of solid cancers was still elevated 35 years or more after treatment (SIR 3.9). The cumulative incidence of second solid cancers did not differ according to study period (1965–1976, 1977–1988, or 1989–2000). We also confirmed our earlier findings that HL patients treated with CT in addition to RT had a 60-80% decreased risk of breast cancer, attributable to CT-induced premature menopause. The substantial risk reduction associated with early menopause indicates that ovarian hormones are a crucial factor to promote carcinogenesis once radiation has produced an initiating event.

We also examined the risk of other solid cancers. We showed that not only RT but also CT, especially the agent procarbazine, can increase the risk of solid malignancy after treatment for HL. In 2009 we observed an 1.8-fold increased risk of stomach cancer after CT and, for the first time, an increased risk (5.4-fold) after high doses of procarbazine. Subsequently, together with the U.S. National Cancer Institute, we led a large international case-control analysis of stomach cancer after HL (Morton et al, J Clin Oncol 2013; 31(27):3369). Stomach cancer risk significantly increased with increasing radiation dose to the stomach but also with increasing number of procarbazine-containing CT cycles. Patients who received both ≥25 Gy radiation to the stomach and high-dose procarbazine had strikingly elevated stomach cancer risk. Recent analyses in our large Dutch cohort of HL patients show that procarbazine also increases risks of colorectal cancer (Schaapveld et al, NEJM 2015; Van Eggermond et al, Br J Cancer 2017).

In our large cohort of testicular cancer survivors we recently showed, for the first time, that cisplatin is associated with a dose-dependent 3- to 5-fold increased risk of colorectal cancer and other gastrointestinal cancers (Groot et al, J Clin Oncol 2018). We recently reported that genetic susceptibility also contributes to the high risk of RT-induced breast cancer after HL (Opstal-van Winden et al, Blood 2019). In an international case-case analysis including >300 breast cancer patients after chest RT for HL and nearly 5,000 first primary breast cancer patients, we observed nine SNPs showing statistically significant interaction with RT on breast cancer risk. A case-control analysis (including ~500 chest-irradiated HL patients without breast cancer) showed that patients in the highest tertile of the RT-interaction- polygenic risk score (PRS) had a 1.6-fold higher BC risk than those in the lowest tertile. Remarkably, we observed a 4-fold increased RT-induced risk in the highest compared with the lowest decile of the general population BC-PRS, similar to the effect size found in the general population.

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