Julie Najita

Infertility, infertility treatment, and achievement of pregnancy in female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort

BACKGROUND Previous studies have shown decreased pregnancy rates and early menopause in female cancer survivors; however, infertility rates and reproductive interventions have not been studied. We investigated infertility and time to pregnancy in female childhood cancer survivors, and analysed treatment characteristics associated with infertility and subsequent pregnancy. METHODS The Childhood Cancer Survivor Study (CCSS) is a cohort study including 5 year cancer survivors from 26 Canadian and US institutions who were younger than 21 years at the time of diagnosis between Jan 1, 1970, and Dec 31, 1986, and a sibling control group. We included women aged 18-39 years who had ever been sexually active. We gathered demographic, medical, and reproductive data via a baseline questionnaire, and quantified exposure to alkylating agents and radiation therapy. Self-reported infertility, medical treatment for infertility, time to first pregnancy in survivors and siblings, and the risk of infertility in survivors by demographic, disease, and treatment variables were analysed. FINDINGS 3531 survivors and 1366 female sibling controls who enrolled between Nov 3, 1992, and April 4, 2004, were included. Compared with their siblings, survivors had an increased risk (relative risk [RR] 1·48 [95% CI 1·23-1·78]; p<0·0001) of clinical infertility (ie, >1 year of attempts at conception without success), which was most pronounced at early reproductive ages (RR 2·92 [95% CI 1·18-7·20], p=0·020, in participants ≤24 years; 1·61 [1·05-2·48], p=0·029, in those aged 25-29 years; and 1·37 [1·11-1·69], p=0·0035, in those aged 30-40 years). Despite being equally likely to seek treatment for infertility, survivors were less likely than were their siblings to be prescribed drugs for treatment of infertility (0·57 [95% CI 0·46-0·70], p<0·0001). Increasing doses of uterine radiation and alkylating agent chemotherapy were strongly associated with infertility. Although survivors had an increased time to pregnancy compared with their siblings (p=0·032), 292 (64%) of 455 participants with self-reported clinical infertility achieved a pregnancy. INTERPRETATION A more comprehensive understanding of infertility after cancer is crucial for counselling and decision making about future conception attempts and fertility preservation. FUNDING National Cancer Institute, American Lebanese Syrian Associated Charities, Swim Across America.

Suicide Ideation in Adult Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study

PURPOSE To evaluate risk of suicide ideation (SI) after childhood cancer, prevalence of SI in a cohort of adult survivors of pediatric cancers was compared with prevalence in a sibling comparison group. The relationship of SI to cancer treatment and current health was examined, and the hypothesis that poor physical health is significantly associated with suicidality, after adjusting for depression, was specifically tested. METHODS Nine thousand one hundred twenty-six adult survivors of childhood cancer and 2,968 siblings enrolled onto the Childhood Cancer Survivor Study completed a survey describing their demographics and medical and psychological functioning, including SI in the prior week. RESULTS Of survivors, 7.8% reported SI compared with 4.6% of controls (odds ratio = 1.79; 95% CI, 1.4 to 2.4). Suicidality was unrelated to age, age at diagnosis, sex, cancer therapy, recurrence, time since diagnosis, or second malignancy. SI was associated with primary CNS cancer diagnosis, depression, and poor health outcomes including chronic conditions, pain, and poor global health rating. A logistic regression analysis showed that poor current physical health was significantly associated with SI even after adjusting for cancer diagnosis and depression. CONCLUSION Adult survivors of childhood cancers are at increased risk for SI. Risk of SI is related to cancer diagnosis and post-treatment mental and physical health, even many years after completion of therapy. The association of suicidal symptoms with physical health problems is important because these may be treatable conditions for which survivors seek follow-up care and underscores the need for a multidisciplinary approach to survivor care.

Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the post-trastuzumab era.

BACKGROUND Trastuzumab is associated with improvements in overall survival (OS) among patients with HER2-positive metastatic breast cancer (MBC); however disease course and patterns of care in individual patients are highly variable. METHODS 113 HER2-positive patients diagnosed with MBC from 1999 to 2005 who received trastuzumab-based therapy were retrospectively identified to allow for a minimum of 5 years of follow-up time. Median OS and median duration of therapy were determined using Kaplan-Meier methodology and group comparisons were based on the log-rank test. Hazard ratios (HR) were obtained using a Cox proportional hazards model. RESULTS Median OS was 3.5 years (95% CI 3.0-4.4) from time of initiation of first therapy in the metastatic setting. On univariate analysis, central nervous system (CNS) disease at first recurrence was associated with a shorter OS compared with liver and/or lung metastases or other sites (CNS: 1.9 years CI 0.1-5.9, liver/lung: 3.2 years CI 2.5-4.2, other: 4.6 years CI 2.7-8.0; p = 0.05), however, this was not predictive of survival outcome in multivariate analysis. CNS metastases developed in 62 (55%) patients by the time of death or last follow-up. Median duration of therapy was similar up to 6 lines of treatment, and ranged from 5.2 months to 7.2 months. CONCLUSIONS The natural history of HER2-positive MBC has evolved with trastuzumab-based therapy with median OS now exceeding 3 years. CNS disease is a major problem with continued risk of CNS progression over time. Patients demonstrate clinical benefit to multiple lines of HER2-directed therapy.

Oncologists' and Cancer Patients' Views on Whole-Exome Sequencing and Incidental Findings: Results from The CanSeq Study

Purpose:Although targeted sequencing improves outcomes for many cancer patients, it remains uncertain how somatic and germ-line whole-exome sequencing (WES) will integrate into care.Methods:We conducted surveys and interviews within a study of WES integration at an academic center to determine oncologists’ attitudes about WES and to identify lung and colorectal cancer patients’ preferences for learning WES findings.Results:One-hundred sixty-seven patients (85% white, 58% female, mean age 60) and 27 oncologists (22% female) participated. Although oncologists had extensive experience ordering somatic tests (median 100/year), they had little experience ordering germ-line tests. Oncologists intended to disclose most WES results to patients but anticipated numerous challenges in using WES. Patients had moderately low levels of genetic knowledge (mean 4 correct out of 7). Most patients chose to learn results that could help select a clinical trial, pharmacogenetic and positive prognostic results, and results suggesting inherited predisposition to cancer and treatable noncancer conditions (all ≥95%). Fewer chose to receive negative prognostic results (84%) and results suggesting predisposition to untreatable noncancer conditions (85%).Conclusion:The majority of patients want most cancer-related and incidental WES results. Patients’ low levels of genetic knowledge and oncologists’ inexperience with large-scale sequencing present challenges to implementing paired WES in practice.Genet Med 18 10, 1011–1019.

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.

Responses to subsequent anti-HER2 therapy after treatment with trastuzumab-DM1 in women with HER2-positive metastatic breast cancer

BACKGROUND Women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) can respond to multiple lines of anti-HER2 therapy. It is unknown whether these patients will derive further clinical benefit following treatment with trastuzumab-MCC-DM1 (T-DM1). PATIENTS AND METHODS We retrospectively identified HER2-positive MBC patients treated with T-DM1 and characterized outcomes during subsequent lines of anti-HER2 therapy. Response was determined by a blinded radiology review. Time-dependent analyses were carried out using Kaplan-Meier estimates. RESULTS We identified 23 patients treated with single-agent T-DM1 and report on the 20 patients who discontinued protocol therapy. All patients received trastuzumab-based metastatic therapy before initiation of T-DM1 [median 7 regimens (range 3-14)]. Of these 20 patients, 75% (15 of 20) received further therapy with or without anti-HER2 agents after discontinuing T-DM1. Partial response to either first- or second-subsequent line(s) of therapy was seen in 5 of 15 (33%) treated patients, including 33% (4 of 12) who received a regimen containing trastuzumab and/or lapatinib. Median durations of therapy to first- and second-subsequent regimens after T-DM1 were 5.5 and 6.4 months, respectively. CONCLUSIONS In heavily pretreated HER2-positive MBC patients, prior exposure to T-DM1 does not exhaust the potential benefit of ongoing anti-HER2 therapy with trastuzumab- and/or lapatinib-based regimens.BACKGROUND Women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) can respond to multiple lines of anti-HER2 therapy. It is unknown whether these patients will derive further clinical benefit following treatment with trastuzumab-MCC-DM1 (T-DM1). PATIENTS AND METHODS We retrospectively identified HER2-positive MBC patients treated with T-DM1 and characterized outcomes during subsequent lines of anti-HER2 therapy. Response was determined by a blinded radiology review. Time-dependent analyses were carried out using Kaplan-Meier estimates. RESULTS We identified 23 patients treated with single-agent T-DM1 and report on the 20 patients who discontinued protocol therapy. All patients received trastuzumab-based metastatic therapy before initiation of T-DM1 [median 7 regimens (range 3-14)]. Of these 20 patients, 75% (15 of 20) received further therapy with or without anti-HER2 agents after discontinuing T-DM1. Partial response to either first- or second-subsequent line(s) of therapy was seen in 5 of 15 (33%) treated patients, including 33% (4 of 12) who received a regimen containing trastuzumab and/or lapatinib. Median durations of therapy to first- and second-subsequent regimens after T-DM1 were 5.5 and 6.4 months, respectively. CONCLUSIONS In heavily pretreated HER2-positive MBC patients, prior exposure to T-DM1 does not exhaust the potential benefit of ongoing anti-HER2 therapy with trastuzumab- and/or lapatinib-based regimens.

Lymphopenia Associated with Adjuvant Anthracycline/ Taxane Regimens

BACKGROUND We observed 2 cases of Pneumocystis carinii pneumonia (PCP) occurring in HIV-negative patients during treatment with dose-dense chemotherapy with doxorubicin/cyclophosphamide (AC) followed by paclitaxel (T). These represent the first case reports of PCP occurring during dose-dense chemotherapy for breast cancer. Because lymphocyte depletion is thought to predispose patients to PCP, we explored whether the shortened intervals between cycles during dose-dense chemotherapy might place patients at risk for lymphocyte depletion and thereby a potentially increased risk of opportunistic infection. PATIENTS AND METHODS Three cohorts of patients were analyzed. Cohort 1 involved 135 patients receiving dose-dense AC --> T on a phase II study. Cohort 2 included 64 patients who received treatment with dose-dense AC --> albumin-bound paclitaxel on a phase II clinical trial. Cohort 3 consisted of 59 patients who received AC --> T given every 3 weeks who were identified from the Clinical Research Information System database at Dana-Farber Cancer Institute. For cohorts 1 and 3, the electronic medical record was reviewed to determine absolute lymphocyte counts (ALCs) and absolute neutrophil counts (ANCs) for day 1 of each of the 8 cycles of treatment. For cohort 2, data was prospectively collected and entered into an electronic database. The lowest ALC obtained by each patient on day 1 of any cycle was termed the nadir. RESULTS Patients experienced grade 3 (ALC < 500 cells/mm3) or grade 4 (ALC < 200 cells/mm3) lymphopenia in all 3 cohorts: 63% with dose-dense AC -->T, 23.4% in dosedense AC --> albumin-bound paclitaxel, and 69% with dose-dense AC --> T every 3 weeks. Patients experienced their lowest median ALC count at cycle 5 of treatment in all 3 cohorts, with a median nadir of 400 cells/mm3 in cohort 1, 690 cells/mm3 in cohort 2, and 400 cells/mm3 in cohort 3. CONCLUSION The majority of patients receiving AC --> T every 2 or 3 weeks experience grade 3/4 lymphopenia. Median lymphocyte counts appear to be lowest around cycle 5, the point at which we observed 2 cases of PCP. Lymphocyte counts appear to be reaching a low enough level to place patients at risk for opportunistic infection during treatment with dosedense AC --> T and with AC --> T given every 3 weeks.

Phase II Study of Lapatinib in Combination With Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer: Clinical Outcomes and Predictive Value of Early [18F]Fluorodeoxyglucose Positron Emission Tomography Imaging (TBCRC 003)

PURPOSE Lapatinib plus trastuzumab improves outcomes relative to lapatinib alone in heavily pretreated, human epidermal growth factor receptor 2-positive metastatic breast cancer (MBC). We tested the combination in the earlier-line setting and explored the predictive value of [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) for clinical outcomes. PATIENTS AND METHODS Two cohorts were enrolled (cohort 1: no prior trastuzumab for MBC and ≥ 1 year from adjuvant trastuzumab, if given; cohort 2: one to two lines of chemotherapy including trastuzumab for MBC and/or recurrence < 1 year from adjuvant trastuzumab). The primary end point was objective response rate by RECIST v1.0; secondary end points included clinical benefit rate (complete response plus partial response plus stable disease ≥ 24 weeks) and progression-free survival. [(18)F]FDG-PET scans were acquired at baseline, week 1, and week 8. Associations between metabolic response and clinical outcomes were explored. RESULTS Eighty-seven patients were registered (85 were evaluable for efficacy). The confirmed objective response rate was 50.0% (95% CI, 33.8% to 66.2%) in cohort 1 and 22.2% (95% CI, 11.3% to 37.3%) in cohort 2. Clinical benefit rate was 57.5% (95% CI, 40.9% to 73.0%) in cohort 1 and 40.0% (95% CI, 25.7% to 55.7%) in cohort 2. Median progression-free survival was 7.4 and 5.3 months, respectively. Lack of week-1 [(18)F]FDG-PET/computed tomography ([(18)F]FDG-PET/CT) response was associated with failure to achieve an objective response by RECIST (negative predictive value, 91% [95% CI, 74% to 100%] for cohort 1 and 91% [95% CI, 79% to 100%] for cohort 2). CONCLUSION Early use of lapatinib and trastuzumab is active in human epidermal growth factor receptor 2-positive MBC. Week-1 [(18)F]FDG-PET/CT may allow selection of patients who can be treated with targeted regimens and spared the toxicity of chemotherapy.

A phase II study of ixabepilone plus trastuzumab for metastatic HER2-positive breast cancer.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #3137 Background: The epitholones are a new class of antineoplastic agents which are microtubule inhibitors with low susceptibility to several mechanisms of drug resistance. Ixabepilone (BMS-247550, aza-epothilone B) has demonstrated efficacy as monotherapy or in combination with capecitabine (in anthracycline- and taxane-pretreated metastatic breast cancer) and has recently been approved for use in refractory breast cancer. A multicenter NCI-sponsored study was conducted to analyze the safety and efficacy of the combination of ixabepilone with trastuzumab in patients with metastatic HER2-positive breast cancer. Methods : This phase II nonrandomized study enrolled two cohorts of patients. Cohort 1 received no prior chemotherapy or trastuzumab for metastatic disease and cohort two received one or two prior trastuzumab-containing regimens for metastatic disease. Patients in each cohort received the same treatment regimen of ixabepilone and trastuzumab. Patients received ixabepilone 40 mg/m2 as a 3-hour continuous infusion on day 1 of a 21-day cycle plus trastuzumab once every 21 days. For the initial treatment of trastuzumab, patients received 8 mg/kg IV, and for all subsequent trastuzumab treatments 6 mg/kg. Treatment was continued until disease progression or unacceptable toxicity. Endpoints included response rate (RR), time to progression (TTP), toxicity, and predictive biomarkers. Results : 39 women entered the study (median age 51, range 29-74) with 15 patients in cohort 1 and 24 patients in cohort 2. A median of 7 cycles of therapy were administered in each cohort. In cohort 1, there were 12 partial responses (PR), and 1 patient with stable disease for 5 months (SD). In cohort 2, there were 8 PRs and 9 patients with SD. Across both cohorts, the overall RR was 51%, with a clinical benefit rate (CR + PR + SD for at least 6 months) of 56%. Treatment-related toxicities included neuropathy (grade ≥2, 55%), myalgias (grade ≥2, 20%), anemia (grade ≥2, 18%), neutropenia (grade ≥2, 23%), and elevated transaminases (grade ≥2, 10%). There were no episodes of grade 2 or higher cardiac toxicity. Biomarker data will be presented. Conclusion : This represents the first study of the combination of ixabepilone with trastuzumab for the treatment of metastatic HER2-positive breast cancer. These results suggest that the combination has an encouraging response rate as first- and subsequent- line therapy for metastatic breast cancer. Clinically significant neuropathy was the major toxicity, and appeared to be cumulative. Based on these results, further evaluation of ixabepilone plus trastuzumab is warranted. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3137.

Breastfeeding in survivors of Hodgkin lymphoma treated with chest radiotherapy

Female survivors of therapeutic chest radiation often question whether they will have difficulty with breast feeding, given their prior exposure to breast radiation. In the current study, the rates of successful breastfeeding in long‐term survivors who received chest radiotherapy (CXRT) as a treatment for Hodgkin lymphoma (HL) were examined.