Biomedical subjects

Lois B Travis

Publications and source records attributed to Lois B Travis.

9 recordsLinked to original sources

PubMed2003

An intron splice acceptor polymorphism in hMSH2 and risk of leukemia after treatment with chemotherapeutic alkylating agents.

PURPOSE: We sought to determine whether the -6 exon 13 T>C polymorphism in the DNA mismatch repair gene hMSH2 modulates susceptibility to acute myeloid leukemia after therapy and particularly after O(6)-guanine alkylating chemotherapy. We also determined the extent of microsatellite instability (MSI) in therapy-related acute myeloid leukemia (t-AML) as a marker of dysfunctional DNA mismatch repair. EXPERIMENTAL DESIGN: Using a novel restriction fragment length polymorphism, verified by direct sequencing, we have genotyped 91 t-AML cases, 420 de novo acute myeloid leukemia cases, and 837 controls for the hMSH2 -6 exon 13 polymorphism. MSI was evaluated in presentation bone marrow from 34 cases using the mononucleotide microsatellite markers BAT16, BAT25, and BAT26. RESULTS: Distribution of the hMSH2 -6 exon 13 polymorphism was not significantly different between de novo acute myeloid leukemia cases and controls, with heterozygotes and homozygotes for the variant (C) allele representing 12.2 and 1.6%, respectively, of the control population. However, the variant (C) hMSH2 allele was significantly overrepresented in t-AML cases that had previously been treated with O(6)-guanine alkylating agents, including cyclophosphamide and procarbazine, compared with controls (odds ratio, 4.02; 95% confidence interval, 1.40-11.37). Thirteen of 34 (38%) t-AML cases were MSI positive, and 2 of these 13 cases were homozygous for the variant (C) allele, a frequency substantially higher than in the control population. CONCLUSIONS: Association of the hMSH2 -6 exon 13 variant (C) allele with leukemia after O(6)-guanine alkylating agents implicates this allele in conferring a nondisabling DNA mismatch repair defect with concomitant moderate alkylation tolerance, which predisposes to the development of t-AML via the induction of DNA mismatch repair-disabling mutations and high-grade MSI. Homozygosity for the hMSH2 variant in 2 of 13 MSI-positive t-AML cases provides some support for this model.

Adolescent↗

PubMed2003

Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease.

CONTEXT: 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.

Adolescent↗

PubMed2003

Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin's disease.

BACKGROUND: Female survivors of Hodgkin's disease (HD) have a strongly elevated risk of breast cancer, but factors responsible for the increased risk are not well known. METHODS: We investigated the effects of radiation dose, chemotherapy (CT), and reproductive factors on breast cancer risk in a nested case-control study in The Netherlands in a cohort of 770 female patients who had been diagnosed with HD before age 41. Detailed treatment information and data on reproductive factors were collected for 48 case patients who developed breast cancer 5 or more years after diagnosis of HD and 175 matched control subjects. The radiation dose was estimated to the area of the breast where the case patient's tumor had developed and to a comparable location in matched control subjects. Relative risks (RRs) of breast cancer were calculated by conditional logistic regression. Statistical tests were two-sided. RESULTS: The risk of breast cancer increased statistically significantly with radiation dose (P(trend) =.01); patients who received 38.5 Gy or more had an RR of 4.5 (95% confidence interval [CI] = 1.3 to 16) times that of patients who received less than 4 Gy. Patients who received both CT and radiotherapy (RT) had a statistically significantly lower risk than those treated with RT alone (RR = 0.45, 95% CI = 0.22 to 0.91). Breast cancer risk increased with increasing radiation dose among patients who received RT only (RR = 12.7, 95% CI = 1.8 to 86, for patients receiving > or =38.5 Gy) but not among patients treated with CT and RT. Sixty-nine percent of control subjects treated with RT and more than six cycles of CT, but only 9% of those who received RT alone, reached menopause before age 41. Reaching menopause before age 36 was associated with a strongly reduced risk of breast cancer (RR = 0.06, 95% CI = 0.01 to 0.45). CONCLUSION: Breast cancer risk increases with increasing radiation dose up to at least 40 Gy. The substantial risk reduction associated with CT may reflect its effect on menopausal age, suggesting that ovarian hormones promote tumorigenesis after radiation has produced an initiating event.

Adult↗

PubMed2002

Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: a multicenter case-control study.

Although numerous reports indicate that patients receiving autotransplants for lymphoma are at increased risk for myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), the separate contributions of pretransplantation- and transplantation-related therapy are not well characterized. We conducted a case-control study of 56 patients with MDS/AML and 168 matched controls within a cohort of 2 739 patients receiving autotransplants for Hodgkin disease or non-Hodgkin lymphoma at 12 institutions (1989-1995). Detailed abstraction of medical records was undertaken to determine all pre- and posttransplantation therapy, and transplantation-related procedures. In multivariate analyses, risks of MDS/AML significantly increased with the intensity of pretransplantation chemotherapy with mechlorethamine (relative risks [RRs] = 2.0 and 4.3 for cumulative doses < 50 mg/m2 and > or = 50 mg/m,2 respectively; trend over dose categories, P =.04) or chlorambucil (RRs = 3.8 and 8.4 for duration < 10 months or > or = 10 months, respectively; trend, P =.009), compared with cyclophosphamide-based therapy. Transplantation-conditioning regimens including total-body irradiation (TBI) at doses 12 Gy or less did not appear to elevate leukemia risk (RR = 1.3; P =.48) compared with non-TBI regimens; however, a statistically significant increased risk was found for TBI doses of 13.2 Gy (RR = 4.6; P =.03). Peripheral blood stem cells were associated with a nonsignificant increased risk of MDS/AML (RR = 1.8; P =.12) compared with bone marrow grafts. Our data show that type and intensity of pretransplantation chemotherapy with alkylating agents are important risk factors of MDS/AML following autotransplantation. Transplantation-related factors may also modulate this risk; however, the apparent contribution of high-dose TBI requires confirmation.

Acute Disease↗

PubMed2002

Second malignant neoplasms among long-term survivors of Hodgkin's disease: a population-based evaluation over 25 years.

PURPOSE: To quantify the relative and absolute excess risks (AER) of site-specific second cancers, in particular solid tumors, among long-term survivors of Hodgkin's disease (HD) and to assess risks according to age at HD diagnosis, attained age, and time since initial treatment. PATIENTS AND METHODS: Data from 32,591 HD patients (1,111 25-year survivors) reported to 16 population-based cancer registries in North America and Europe (1935 to 1994) were analyzed. RESULTS: Two thousand one hundred fifty-three second cancers (observed-to-expected ratio [O/E] = 2.3; 95% confidence interval [CI] = 2.2 to 2.4), including 1,726 solid tumors (O/E = 2.0; 95% CI, 1.9 to 2.0) were reported. Cancers of the lung (observed [Obs] = 377; O/E = 2.9), digestive tract (Obs = 376; O/E = 1.7), and female breast (Obs = 234; O/E = 2.0) accounted for the largest number of subsequent malignancies. Twenty-five years after HD diagnosis, the actuarial risk of developing a solid tumor was 21.9%. The relative risk of solid neoplasms decreased with increasing age at HD diagnosis, however, patients aged 51 to 60 years at HD diagnosis sustained the highest cancer burden (AER = 79.2/10,000 patients/year). After a progressive rise in relative risk and AER of all solid tumors over time, there was an apparent downturn in risk at 25 years. Temporal trends and treatment group distribution for cancers of the esophagus, stomach, rectum, female breast, bladder, thyroid, and bone/connective tissue were suggestive of a radiogenic effect. CONCLUSION: Significantly increased risks of second cancers were observed in all HD age groups. Although significantly elevated risks of stomach, female breast, and uterine cervix cancers persisted for 25 years, an apparent decrease in relative risk and AER of solid tumors at other sites is suggested.

Actuarial Analysis↗

PubMed2002

Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease.

BACKGROUND: Lung cancer is a frequent cause of death in patients cured of Hodgkin's disease, but the contributions of chemotherapy, radiotherapy, and smoking are not well described. We quantified the risk of treatment-associated lung cancer, taking into account tobacco use. METHODS: Within a population-based cohort of 19 046 Hodgkin's disease patients (diagnosed from 1965 through 1994), a case-control study of lung cancer was conducted. The cumulative amount of cytotoxic drugs, the radiation dose to the specific location in the lung where cancer developed, and tobacco use were compared for 222 patients who developed lung cancer and for 444 matched control patients. All statistical tests were two-sided. RESULTS: Treatment with alkylating agents without radiotherapy was associated with increased lung cancer risk (relative risk [RR] = 4.2; 95% confidence interval [CI] = 2.1 to 8.8), as was radiation dose of 5 Gy or more without alkylating agents (RR = 5.9; 95% CI = 2.7 to 13.5). Risk increased with both increasing number of cycles of alkylating agents and increasing radiation dose (P for trend <.001). Among patients treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), risk increased with cumulative amounts of mechlorethamine and procarbazine (P<.001) when evaluated separately. Statistically significantly elevated risks of lung cancer were apparent within 1-4 years after treatment with alkylating agents, whereas excess risk after radiotherapy began 5 years after treatment and persisted for more than 20 years. Risk after treatment with alkylating agents and radiotherapy together was as expected if individual excess risks were summed. Tobacco use increased lung cancer risk more than 20-fold; risks from smoking appeared to multiply risks from treatment. CONCLUSIONS: Past treatments with alkylating agents and radiation therapy for Hodgkin's disease were associated with an increased risk of lung cancer in a dose-dependent and additive fashion. The precise risk estimates, however, should be interpreted cautiously, given the possible residual and enhancing effects of tobacco.

Adolescent↗

PubMed2002

Therapy-associated solid tumors.

As survival after a diagnosis of cancer improves, characterization of the late sequelae of treatment becomes critical. The development of second malignant neoplasms represents one of the most serious side effects of treatment with radiation and chemotherapy. Although secondary leukemia was the first reported carcinogenic effect resulting from cancer treatment, solid tumors now comprise the largest second tumor burden in some populations of survivors. It should be recognized, however, that solid cancers do not necessarily represent an adverse effect of therapy, but may also reflect the operation of shared etiologic factors, host determinants, gene-environment interactions, and other influences. Quantification of second cancer risk is important in terms of patient management, enabling clinicians to make informed decisions with regard to optimal treatment of the initial cancer, balancing efficacy against acute and chronic sequelae. This article focuses on selected highlights and recent developments in treatment-associated solid malignancies, with emphasis on radiotherapy and chemotherapy in adults, and summarizes areas for future research. Although cancer therapy represents a double-edged sword, it should always be recognized that it is advances in treatment that are largely responsible for the tremendous improvement in patient survival. Thus, the benefit derived from many cancer therapies far outweighs any risk of developing a second cancer.

Antineoplastic Agents↗

PubMed2002

Cancer incidence among Swedish patients exposed to radioactive thorotrast: a forty-year follow-up survey.

Thorotrast is an alpha-particle-emitting radiological contrast medium that caused chronic exposure to internal alpha-particle radiation when it was administered systemically. Cancer incidence in 432 Swedish patients exposed to Thorotrast was evaluated by computerized linkage of the cohort with the Swedish Cancer Register. Standardized incidence ratios (SIRs) were calculated as the ratio of observed cases in the cohort to expected cases in the general population. A total of 170 cancers occurring in 152 individuals were reported, whereas only 57 cases were expected. The SIR was significantly increased for cancer at all sites (3.0), with the largest excesses noted for primary liver and gallbladder cancer (SIR = 39.2). Other significantly elevated risks were observed for liver cancer not specified as primary, small intestine cancer, stomach cancer, leukemia, kidney cancer, CNS tumors, and pancreatic cancer. Among women, there was a significantly increased risk for lung cancer, based on a small number. Our results show that cumulative radiation exposure is directly related to carcinogenesis in the liver and gallbladder, which is consistent with earlier findings. In addition, there may be a relationship between radiation exposure and the development of other solid tumors.

Adolescent↗

PubMed2002

p53 mutations in leukemia and myelodysplastic syndrome after ovarian cancer.

PURPOSE: Although p53 mutations occur in alkylating agent-related leukemias, their frequency and spectrum in leukemias after ovarian cancer have not been addressed. The purpose of this study was to examine p53 mutations in leukemias after ovarian cancer, for which treatment with platinum analogues was widely used. EXPERIMENTAL DESIGN: Adequate leukemic or dysplastic cells were available in 17 of 82 cases of leukemia or myelodysplastic syndrome that occurred in a multicenter, population-based cohort of 23,170 women with ovarian cancer. Eleven of the 17 received platinum compounds and other alkylating agents with or without DNA topoisomerase II inhibitors and/or radiation. Six received other alkylating agents, in one case, with radiation. Genomic DNA was extracted and p53 exons 5, 6, 7, and 8 were amplified by PCR. Mutations and loss of heterozygosity were analyzed on the WAVE instrument (Transgenomic) followed by selected analysis by sequencing. RESULTS: Eleven p53 mutations involving all four exons studied and one polymorphism were identified. Genomic DNA analyses were consistent with loss of heterozygosity for four of the mutations. The 11 mutations occurred in 9 cases, such that 6 of 11 leukemias after platinum-based regimens (55%) and 3 of 6 leukemias after other treatments (50%) contained p53 mutations. Two leukemias that occurred after treatment with platinum analogues contained two mutations. Among eight mutations in leukemias after treatment with platinum analogues, there were four G-to-A transitions and one G-to-C transversion. CONCLUSIONS: p53 mutations are common in leukemia and myelodysplastic syndrome after multiagent therapy for ovarian cancer. The propensity for G-to-A transitions may reflect specific DNA damage in leukemias after treatment with platinum analogues.

Adult↗