Lisa B. Kenney

Breast Cancer after Childhood Cancer: A Report from the Childhood Cancer Survivor Study

Context Adult survivors of childhood cancer are at risk for developing breast cancer and other secondary cancer. Knowing the risk factors for breast cancer in these women may help to formulate screening policies for them. Contribution Among 6068 women who survived childhood cancer, 95 developed breast cancer at a median age of 35 years. Childhood sarcoma, chest irradiation, family history of breast cancer, and personal history of thyroid disease increased the risk for breast cancer. Implications Women who survived childhood cancer and had sarcoma, chest irradiation, family history of breast cancer, or personal history of thyroid disease should consider early, vigilant screening for breast cancer. The Editors Women treated with chest radiation therapy for childhood and adolescent Hodgkin disease are at increased risk for developing breast cancer at a young age (1-12). However, case reports and preliminary studies indicate that survivors of childhood cancer other than Hodgkin disease may also be at risk for secondary breast cancer (1, 13, 14). Practitioners caring for the growing population of young female survivors of childhood cancer are challenged with assessing breast cancer risk in order to recommend screening and preventive strategies. Although recent studies have shown that the risk for radiation-induced breast cancer is directly related to dose of chest radiation, specific details of previous treatment are not always available to clinicians and may not affect screening decisions (11, 12). In addition, whether primary cancer diagnosis, previous treatment other than chest radiation, or other well-established breast cancer risk factors contribute to a childhood cancer survivors risk for breast cancer is unknown. Studies of Hodgkin disease survivors have shown that clinical examination and screening mammography can detect early-stage secondary breast cancer in young women (15-17), and although treatment options may be limited by previous therapy, early-stage secondary breast cancer is curable (16, 17). Thus, identifying specific groups of childhood cancer survivors who would benefit from early mammographic screening might reduce the morbidity and mortality of breast cancer in these young women. In this study, we analyzed a large series of women with secondary breast cancer from a cohort of childhood cancer survivors, the Childhood Cancer Survivor Study (CCSS), to describe clinical and pathologic features of breast cancer and to determine breast cancer risk relative to the general population. We hypothesized that breast cancer risk would be modified by previous treatment and factors unrelated to treatment. Thus, in this large cohort of women, we assessed the influence of primary cancer, previous treatment, family cancer history, and menstrual and reproductive history on breast cancer risk. Methods Study Sample: Childhood Cancer Survivors Study The CCSS is a follow-up study of childhood cancer survivors established in 1994. Eligibility criteria included diagnosis at an age younger than 21 years with leukemia, brain tumor, Hodgkin disease, non-Hodgkin lymphoma, renal tumor, neuroblastoma, or soft-tissue or bone sarcoma and survival of at least 5 years after diagnosis. The 20276 eligible participants received a diagnosis from 1 January 1970 to 31 December 1986 at 1 of 25 collaborating institutions (Appendix). Participants (n= 14054) completed a self-report questionnaire, providing information about their medical history, family medical history, reproductive history, and socioeconomic status. Follow-up questionnaires were sent to patients reporting second cancer diagnoses. Information on the cohort was updated in 2000. We used data available as of May 2002 for this analysis. No men in the CCSS reported breast cancer by that date; thus, this analysis was restricted to women. Detailed information on the study methods and cohort characteristics has been reported (18). The human subjects committee at each participating institution approved the CCSS protocol. Clinical Data We abstracted treatment data from medical records, including chemotherapeutic agents and dose, and radiation therapy dose, and site for primary cancer and relapses. We asked participants who self-reported breast cancer to sign a medical release to confirm the diagnosis. We confirmed all cases of breast cancer in this report and obtained the tumor size, histologic characteristics, hormone receptor status, involvement of axillary nodes, and metastatic sites from pathology records. Statistical Analysis We compared survivors who had breast cancer with those who did not have breast cancer with respect to primary cancer diagnosis, age at diagnosis, years of follow-up, and therapy for the primary cancer. We calculated standardized incidence ratios for breast cancer by using age-, sex-, and calendar-yearspecific incidence rates of the general population (Surveillance, Epidemiology, and End Results Program [SEER], National Cancer Institute, Bethesda, Maryland [19]). We considered survivors to be at risk for breast cancer from 5 years after the childhood cancer diagnosis until 1 of the following 3 events: death, breast cancer diagnosis, or completion of the CCSS questionnaire. To make the definition of incidence comparable in the calculation of the observed and expected numbers, we included only the first primary breast cancer diagnosis. We calculated cumulative incidences of breast cancer by attained age (20). We used Poisson multiple regression models for standardized incidence ratios to assess the modification of risk for developing breast cancer by several variables chosen a priori (21). We considered the following risk factors for breast cancer: age at and years since primary cancer diagnosis; age at menarche (<12 years or 12 years); age at first live birth (never, <20 years, 20 to 24 years, or 25 years), as queried in the CCSS questionnaire; history of breast cancer in first-degree female relatives (yes or no); exposure to chest radiation (yes or no); exposure to pelvic radiation (yes or no); family history of sarcoma (yes or no); history of thyroid disease (thyroid nodules, overactive or underactive thyroid, or enlarged thyroid); and exposure to an alkylating agent (alkylating agent score, measured as previously described, accounted for several drug exposures and dose) (22). The Poisson multiple regression incorporated all time-dependent factors by splitting each survivors follow-up period into several time intervals, wherein each factor was assumed constant. We initially evaluated the relative rate of developing breast cancer for each risk factor, adjusting for the exposure to chest radiation (yes or no). We then stratified the analysis by the exposure to chest radiation and assessed the modification of risk with age at and years since primary cancer diagnosis, family history of breast cancer or sarcoma, history of thyroid disease, and exposure to pelvic radiation. The years since primary cancer diagnosis variable was the baseline time factor of the model for which we obtained fitted standardized incidence ratios relative to SEER data. For other variables, we calculated relative rates by comparing standardized incidence ratios across categories of each variable. All significance tests were 2-sided. We used SAS software, version 8 (SAS Institute Inc., Cary, North Carolina), and S-PLUS software, version 6 (Insightful Corp.), for this analysis. Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Cohort Characteristics Of the 20276 survivors eligible for the CCSS cohort, 9062 were women. Of those, 6498 women participated, 6068 of whom had signed medical record release to be eligible for this analysis. Of the 6068 eligible women, 95 women had 111 confirmed cases of breast cancer. Primary cancer diagnosis and age at treatment were similar between participants and nonparticipants (Table 1). Survivors with breast cancer were older at diagnosis of primary cancer and at follow-up than those without breast cancer. As expected, a large proportion of the women with breast cancer (65 of 95 [68%] women) were Hodgkin disease survivors, and all but 2 of the 65 women were known to have received chest radiation therapy. However, 30 of 95 (32%) women with breast cancer were survivors of other childhood cancer, and 20 of 95 (21%) women did not receive chest radiation therapy. The proportion of patients exposed to alkylating agents was similar in both groups (49.5% vs. 49.2%) (Table 1). Table 1. Characteristics of Women Who Did and Did Not Develop Breast Cancer and of Eligible Nonparticipants Since the oldest survivors in this cohort were 51 years of age, all cases of breast cancer were diagnosed in relatively young women (median age at diagnosis, 35 years [range, 20 to 49 years]) (Table 2). However, 19% (18 of 95 women) of the breast cancer cases occurred in women 20 to 29 years of age and 64% (61 of 95 women) of cases occurred in women 30 to 39 years of age. Median time from childhood cancer diagnosis to breast cancer diagnosis was 19 years; however, the range extended from 6 years to 29 years after primary cancer diagnosis (Table 2). Table 2. Clinical and Pathologic Characteristics of Breast Cancer Cases Of the 111 cases of breast cancer, 21 cases were ductal carcinoma in situ (Table 2). Of those 21 cases, 19 were diagnosed in Hodgkin disease survivors and 2 in soft-tissue sarcoma survivors. Table 2 shows the distribution of histologic characteristics in the invasive cases. We determined the stage in 66 of 90 (73%) invasive cases from pathology reports (Table 2). Twenty-six (29%) cases involved axillary lymph nodes, and 5 (6%) cases involved distant metastatic disease. Estrogen receptor status was available in 37 cases, and 76% of those were positive. There was no predominant laterality. Sixteen cases (17%) were bilateral, 5 were syn

Radiation Dose and Breast Cancer Risk in the Childhood Cancer Survivor Study

PURPOSE The purpose of this study was to quantify the risk of breast cancer in relation to radiation dose and chemotherapy among survivors of childhood cancer. METHODS We conducted a case-control study of breast cancer in a cohort of 6,647 women who were 5-year survivors of childhood cancer and who were treated during 1970 through 1986. One hundred twenty patients with histologically confirmed breast cancer were identified and were individually matched to four selected controls on age at initial cancer and time since initial cancer. Medical physicists estimated radiation dose to the breast tumor site and ovaries on the basis of medical records. RESULTS The odds ratio for breast cancer increased linearly with radiation dose, and it reached 11-fold for local breast doses of approximately 40 Gy relative to no radiation (P for trend < .0001). Risk associated with breast irradiation was sharply reduced among women who received 5 Gy or more to the ovaries (P = .002). The excess odds ratio per Gy was 0.36 for those who received ovarian doses less than 5 Gy and was 0.06 for those who received higher doses. Radiation-related risk did not vary significantly by age at exposure. Borderline significantly elevated risks were seen for doxorubicin, dactinomycin, dacarbazine, and carmustine. CONCLUSION Results confirm the radiation sensitivity of the breast in girls age 10 to 20 years but do not demonstrate a strong effect of age at exposure within this range. Irradiation of the ovaries at doses greater than 5 Gy seems to lessen the carcinogenic effects of breast irradiation, most likely by reducing exposure of radiation-damaged breast cells to stimulating effects of ovarian hormones.

Female Reproductive Health After Childhood, Adolescent, and Young Adult Cancers: Guidelines for the Assessment and Management of Female Reproductive Complications

PURPOSE As more young female patients with cancer survive their primary disease, concerns about reproductive health related to primary therapy gain relevance. Cancer therapy can often affect reproductive organs, leading to impaired pubertal development, hormonal regulation, fertility, and sexual function, affecting quality of life. METHODS The Childrens Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer (COG-LTFU Guidelines) are evidence-based recommendations for screening and management of late effects of therapeutic exposures. The guidelines are updated every 2 years by a multidisciplinary panel based on current literature review and expert consensus. RESULTS This review summarizes the current task force recommendations for the assessment and management of female reproductive complications after treatment for childhood, adolescent, and young adult cancers. Experimental pretreatment as well as post-treatment fertility preservation strategies, including barriers and ethical considerations, which are not included in the COG-LTFU Guidelines, are also discussed. CONCLUSION Ongoing research will continue to inform COG-LTFU Guideline recommendations for follow-up care of female survivors of childhood cancer to improve their health and quality of life.

Breast Cancer After Chest Radiation Therapy for Childhood Cancer

PURPOSE The risk of breast cancer is high in women treated for a childhood cancer with chest irradiation. We sought to examine variations in risk resulting from irradiation field and radiation dose. PATIENTS AND METHODS We evaluated cumulative breast cancer risk in 1,230 female childhood cancer survivors treated with chest irradiation who were participants in the CCSS (Childhood Cancer Survivor Study). RESULTS Childhood cancer survivors treated with lower delivered doses of radiation (median, 14 Gy; range, 2 to 20 Gy) to a large volume (whole-lung field) had a high risk of breast cancer (standardized incidence ratio [SIR], 43.6; 95% CI, 27.2 to 70.3), as did survivors treated with high doses of delivered radiation (median, 40 Gy) to the mantle field (SIR, 24.2; 95% CI, 20.7 to 28.3). The cumulative incidence of breast cancer by age 50 years was 30% (95% CI, 25 to 34), with a 35% incidence among Hodgkin lymphoma survivors (95% CI, 29 to 40). Breast cancer-specific mortality at 5 and 10 years was 12% (95% CI, 8 to 18) and 19% (95% CI, 13 to 25), respectively. CONCLUSION Among women treated for childhood cancer with chest radiation therapy, those treated with whole-lung irradiation have a greater risk of breast cancer than previously recognized, demonstrating the importance of radiation volume. Importantly, mortality associated with breast cancer after childhood cancer is substantial.

Male Reproductive Health After Childhood, Adolescent, and Young Adult Cancers: A Report From the Children's Oncology Group

The majority of children, adolescents, and young adults diagnosed with cancer will become long-term survivors. Although cancer therapy is associated with many adverse effects, one of the primary concerns of young male cancer survivors is reproductive health. Future fertility is often the focus of concern; however, it must be recognized that all aspects of male health, including pubertal development, testosterone production, and sexual function, can be impaired by cancer therapy. Although pretreatment strategies to preserve reproductive health have been beneficial to some male patients, many survivors remain at risk for long-term reproductive complications. Understanding risk factors and monitoring the reproductive health of young male survivors are important aspects of follow-up care. The Childrens Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer (COG-LTFU Guidelines) were created by the COG to provide recommendations for follow-up care of survivors at risk for long-term complications. The male health task force of the COG-LTFU Guidelines, composed of pediatric oncologists, endocrinologists, nurse practitioners, a urologist, and a radiation oncologist, is responsible for updating the COG-LTFU Guidelines every 2 years based on literature review and expert consensus. This review summarizes current task force recommendations for the assessment and management of male reproductive complications after treatment for childhood, adolescent, and young adult cancers. Issues related to male health that are being investigated, but currently not included in the COG-LTFU Guidelines, are also discussed. Ongoing investigation will inform future COG-LTFU Guideline recommendations for follow-up care to improve health and quality of life for male survivors.

Secondary malignancies across the age spectrum

Development of a second malignancy is one of the most serious late effects in survivors of both childhood and adult-onset cancers. Patterns of second malignancy risk across the age spectrum can differ in terms of the types of second malignancies observed, magnitude of the risks, the latency period, associated risk factors, and modifying influences. Potential explanations for the varying risk patterns by age include differences in susceptibility of individual tissue/organ to carcinogenesis based on stage of development and level of tissue maturity, microenvironment, attained age, and lifestyle factors. A thorough understanding of these differences is essential when considering treatment modifications in newly diagnosed cancer patients who are aimed at reducing the risk of second malignancy and other late effects without compromising cure. Moreover, an understanding of the variations in second cancer risk according to age at treatment is important in customizing patient follow-up.

Pregnancy after chemotherapy in male and female survivors of childhood cancer treated between 1970 and 1999: a report from the Childhood Cancer Survivor Study cohort

BACKGROUND The effect of many contemporary chemotherapeutic drugs on pregnancy and livebirth is not well established. We aimed to establish the effects of these drugs on pregnancy in male and female survivors of childhood cancer not exposed to pelvic or cranial radiotherapy. METHODS We used data from a subset of the Childhood Cancer Survivor Study cohort, which followed 5-year survivors of the most common types of childhood cancer who were diagnosed before age 21 years and treated at 27 institutions in the USA and Canada between 1970 and 1999. We extracted doses of 14 alkylating and similar DNA interstrand crosslinking drugs from medical records. We used sex-specific Cox models to establish the independent effects of each drug and the cumulative cyclophosphamide equivalent dose of all drugs in relation to pregnancies and livebirths occurring between ages 15 years and 44 years. We included siblings of survivors as a comparison group. FINDINGS We included 10 938 survivors and 3949 siblings. After a median follow-up of 8 years (IQR 4-12) from cohort entry or at age 15 years, whichever was later, 4149 (38%) survivors reported having or siring a pregnancy, of whom 3453 (83%) individuals reported at least one livebirth. After a median follow-up of 10 years (IQR 6-15), 2445 (62%) siblings reported having or siring a pregnancy, of whom 2201 (90%) individuals reported at least one livebirth. In multivariable analysis, survivors had a decreased likelihood of siring or having a pregnancy versus siblings (male survivors: hazard ratio [HR] 0·63, 95% CI 0·58-0·68; p<0·0001; female survivors: 0·87, 0·81-0·94; p<0·0001) or of having a livebirth (male survivors: 0·63, 0·58-0·69; p<0·0001; female survivors: 0·82, 0·76-0·89; p<0·0001). In male survivors, reduced likelihood of pregnancy was associated with upper tertile doses of cyclophosphamide (HR 0·60, 95% CI 0·51-0·71; p<0·0001), ifosfamide (0·42, 0·23-0·79; p=0·0069), procarbazine (0·30, 0·20-0·46; p<0·0001) and cisplatin (0·56, 0·39-0·82; p=0·0023). Cyclophosphamide equivalent dose in male survivors was significantly associated with a decreased likelihood of siring a pregnancy (per 5000 mg/m(2) increments: HR 0·82, 95% CI 0·79-0·86; p<0·0001). However, in female survivors, only busulfan (<450 mg/m(2) HR 0·22, 95% CI 0·06-0·79; p=0·020; ≥450 mg/m(2) 0·14, 0·03-0·55; p=0·0051) and doses of lomustine equal to or greater than 411 mg/m(2) (0·41, 0·17-0·98; p=0·046) were significantly associated with reduced pregnancy; cyclophosphamide equivalent dose was associated with risk only at the highest doses in analyses categorised by quartile (upper quartile vs no exposure: HR 0·85, 95% CI 0·74-0·98; p=0·023). Results for livebirth were similar to those for pregnancy. INTERPRETATION Greater doses of contemporary alkylating drugs and cisplatin were associated with a decreased likelihood of siring a pregnancy in male survivors of childhood cancer. However, our findings should provide reassurance to most female survivors treated with chemotherapy without radiotherapy to the pelvis or brain, given that chemotherapy-specific effects on pregnancy were generally few. Nevertheless, consideration of fertility preservation before cancer treatment remains important to maximise the reproductive potential of all adolescents newly diagnosed with cancer. FUNDING National Cancer Institute, National Institutes of Health, and the American Lebanese-Syrian Associated Charities.

Increased incidence of cancer in infants in the U. S.: 1980-1990†

During the decade between 1980‐1990, the rate of cancer in children in the U.S. increased. It is unknown whether cancer in infancy, which is biologically and clinically different from cancer in older children, also increased.

Sexual Function in Childhood Cancer Survivors: A Report from Project REACH

INTRODUCTION Of the approximately 12,000 children and adolescents that will be diagnosed with cancer in 2013, it is expected that over 80% of them will become long-term adult survivors of childhood cancer. Although it has been well established that cancer treatment often has profound negative impact on sexual functioning, sexual functioning in adult survivors of childhood cancer is not well understood. AIM The aim of the current study was to examine the report of sexual function in adult survivors of childhood cancer in relationship to both physical and emotional functioning. METHODS Two hundred ninety-one participants enrolled in Project REACH, a longitudinal study of childhood cancer survivors, completed questionnaires as part of an annual health survey. MAIN OUTCOME MEASURE Primary outcome measures included the sexual functioning subscale of the Swedish Health-Related Quality of Life Survey, the SF-12, and the BSI-18. RESULTS Results indicate that 29% of young adult survivors reported two or more discrete symptoms of sexual dysfunction. Females were twice as likely to report sexual problems. Sexual problems were not related to specific types of childhood cancer treatments such as type of chemotherapy or radiation. Young adults with sexual dysfunction did report poorer functioning across the range of SF-12 subscales including physical functioning, general health, fatigue, and mental health. CONCLUSIONS Significant sexual dysfunction is common in adult survivors of childhood cancer. A greater understanding of the particular relationship between sexual dysfunction and both physical and emotional well-being in this relatively young population is needed. Even when long-term cancer survivors are young adults and report generally good health, results underscore the need for clinicians to specifically assess sexual functioning.

Health status of the oldest adult survivors of cancer during childhood

Young adult survivors of childhood cancer have an increased risk for treatment‐related morbidity and mortality. In this study, the authors assessed how treatment for childhood cancer affects older‐adult health and health practices.