Breast cancer risk after radiotherapy for heritable and non-heritable retinoblastoma: a US–UK study

Abstract

Background:Retinoblastoma is a rare childhood eye cancer caused by germline or somatic mutations in the RB1 gene. Previous studies observed elevated breast cancer risk among retinoblastoma survivors. However, there has been no research on breast cancer risk in relation to radiation (primarily scatter radiation from the primary treatment) and genetic susceptibility of retinoblastoma survivors.Methods:Two groups of retinoblastoma survivors from the US and UK were selected, and breast cancer risk analysed using a case–control methodology, nesting within the respective cohorts, matching on heritability (that is to say, having bilateral retinoblastoma or being unilateral cases with at least one relative with retinoblastoma), and using exact statistical methods. There were a total of 31 cases and 77 controls.Results:Overall there was no significant variation of breast cancer risk with dose (P>0.5). However, there was a pronounced and significant (P=0.047) increase in the risk of breast cancer with increasing radiation dose for non-heritable retinoblastoma patients and a slight and borderline significant (P=0.072) decrease in risk of breast cancer with increasing radiation dose for heritable retinoblastoma patients, implying significant (P=0.024) heterogeneity in radiation risk between the heritable and non-heritable retinoblastoma groups; this was unaffected by the blindness status. There was no significant effect of any type of alkylating-agent chemotherapy on breast cancer risk (P>0.5).Conclusions:There is significant radiation-related risk of breast cancer for non-heritable retinoblastoma survivors but no excess risk for heritable retinoblastoma survivors, and no significant risk overall. However, these results are based on very small numbers of cases; therefore, they must be interpreted with caution.

Recent Advances in Retinoblastoma Treatment

“…Radiation is a known risk factor for breast cancer, but lower increased risks were noted for hereditary survivors who received radiotherapy (SIR = 3.89, 95 % CI 2.3-6.1) compared to those without radiotherapy (SIR = 8.72,, whereas the opposite pattern was noted in non-hereditary survivors, with a higher risk of breast cancer (SIR = 6.19, 95 % CI 2.0-14) in irradiated compared to non-irradiated survivors (SIR = 2.09, 95 % CI = 1.00-3.84) (Little et al 2014 ). Radiation is a known risk factor for breast cancer, but lower increased risks were noted for hereditary survivors who received radiotherapy (SIR = 3.89, 95 % CI 2.3-6.1) compared to those without radiotherapy (SIR = 8.72,, whereas the opposite pattern was noted in non-hereditary survivors, with a higher risk of breast cancer (SIR = 6.19, 95 % CI 2.0-14) in irradiated compared to non-irradiated survivors (SIR = 2.09, 95 % CI = 1.00-3.84) (Little et al 2014 ).…”

Risk factors for subsequent endocrine-related cancer in childhood cancer survivors

“…This supports the idea that factors other than treatment exposures, like genetic determinants, may also contribute to secondary breast cancer development in Hodgkin lymphoma survivors. Although Maule and coworkers did not observe a significantly increased risk for secondary breast cancer in survivors of soft-tissue sarcoma, retinoblastoma, nephroblastoma, neuroblastoma, germ cell tumors and non-Hodgkin lymphoma, other studies did (Kenney et al 2004, Guibout et al 2005, Inskip & Curtis 2007, Marees et al 2008, Reulen et al 2011, Lange et al 2014, Little et al 2014. The increased risk for secondary breast cancer in survivors of sarcoma might also be partly related to genetic factors.…”

“…In addition, a positive family history for sarcoma was associated with an increased secondary breast cancer risk (RR 5.3 (95% CI: 1.3-21.5)) (Kenney et al 2004). The increased risk for secondary breast cancer after retinoblastoma is observed in both heritable and nonheritable retinoblastoma survivors (Little et al 2014), and seems to become apparent after ≥40 years of follow-up since primary cancer diagnosis in heritable retinoblastoma survivors (Marees et al 2008).…”

“…Chemotherapy Most studies in cohorts of solely childhood cancer survivors and childhood-and adult-onset cancer survivors combined did not observe a relationship between chemotherapy and secondary breast cancer risk (Guibout et al 2005, Reulen et al 2008, Alm El-Din et al 2009, Little et al 2014, or observed a protective effect of certain chemotherapeutic agents on the development of radiation-related breast cancer , Travis et al 2003, 2005, De Bruin et al 2009, Swerdlow et al 2012, Schaapveld et al 2015. However, two studies reported an increased risk for secondary breast cancer attributable to chemotherapy (Hancock et al 1993, Henderson et al 2015.…”

“…Follow-up durations since childhood cancer are generally too short to assess the risk for secondary malignant neoplasms in aging childhood cancer survivors. Average follow-up durations since childhood cancer vary between 6.3 and 27.3 years in studies assessing secondary breast cancer risk (Hancock et al 1993, Metayer et al 2000, Ng et al 2002, Bhatia et al 2003, Gold et al 2003, Guibout et al 2005, Inskip & Curtis 2007, Constine et al 2008, Friedman et al 2008, Marees et al 2008, Alm El-Din et al 2009, De Bruin et al 2009, Maule et al 2011, Reulen et al 2011, Cooke et al 2013, Danner-Koptik et al 2013, Little et al 2014, Dorffel et al 2015, Schaapveld et al 2015, and 5.1-27 years in studies investigating secondary thyroid carcinoma risk (Crom et al 1997, Bhatia et al 2002, Cohen et al 2007, Inskip & Curtis 2007, Constine et al 2008, Taylor et al 2009, van Beek et al 2009, Friedman et al 2010, Maule et al 2011, Vivanco et al 2012, Danner-Koptik et al 2013, Caglar et al 2014, Clement et al 2015, de Vathaire et al 2015, Dorffel et al 2015, Brignardello et al 2016. Specific subtypes of secondary malignant neoplasms and potential risk-modifying factors yet unknown may become apparent at an adv...…”