Breast Cancer Following Radiotherapy and Chemotherapy Among Young Women With Hodgkin Disease

Travis, Lois B.; Hill, Deirdre A.; Dores, Graça M.; Gospodarowicz, Mary K.; Leeuwen, Flora E. van; Holowaty, Eric J.; Glimelius, Bengt; Andersson, Michael; Wıklund, Tom; Lynch, Charles F.; Veer, M. B. Van't; Glimelius, Ingrid; Storm, Hans H.; Pukkala, Eero; Stovall, Marilyn; Curtis, Rochelle E.; Boice, John D.; Gilbert, Ethel S.

doi:10.1001/jama.290.4.465

Cited by 601 publications

(518 citation statements)

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“…One (Travis et al, 2003) was a matched case-control study within a cohort of 3817 female 1-year survivors of Hodgkin disease diagnosed at age 30 years or younger, between January 1, 1965, and December 31, 1994, and within 6 population-based cancer registries. Record-linkage techniques were used to identify women who developed a second primary breast cancer.…”

Section: Data Sets and Analysismentioning

confidence: 99%

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Second cancers after fractionated radiotherapy: Stochastic population dynamics effects

Sachs

Shuryak

Brenner

et al. 2007

Journal of Theoretical Biology

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When ionizing radiation is used in cancer therapy it can induce second cancers in nearby organs. Mainly due to longer patient survival times, these second cancers have become of increasing concern. Estimating the risk of solid second cancers involves modeling: because of long latency times, available data is usually for older, obsolescent treatment regimens. Moreover, modeling second cancers gives unique insights into human carcinogenesis, since the therapy involves administering well characterized doses of a well studied carcinogen, followed by long-term monitoring.In addition to putative radiation initiation that produces pre-malignant cells, inactivation (i.e. cell killing), and subsequent cell repopulation by proliferation can be important at the doses relevant to second cancer situations. A recent initiation/inactivation/proliferation (IIP) model characterized quantitatively the observed occurrence of second breast and lung cancers, using a deterministic cell population dynamics approach. To analyze if radiation-initiated pre-malignant clones become extinct before full repopulation can occur, we here give a stochastic version of this IIP model. Combining Monte Carlo simulations with standard solutions for time-inhomogeneous birth-death equations, we show that repeated cycles of inactivation and repopulation, as occur during fractionated radiation therapy, can lead to distributions of pre-malignant cells per patient with variance ≫ mean, even when pre-malignant clones are Poisson-distributed. Thus fewer patients would be affected, but with a higher probability, than a deterministic model, tracking average pre-malignant cell numbers, would predict. Our results are applied to data on breast cancers after radiotherapy for Hodgkin disease. The stochastic IIP analysis, unlike the deterministic one, indicates: a) initiated, pre-malignant cells can have a growth advantage during repopulation, not just during the longer tumor latency period that follows; b) weekend treatment gaps during radiotherapy, apart from decreasing the probability of eradicating the primary cancer, substantially increase the risk of later second cancers.

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Section: Data Sets and Analysismentioning

confidence: 99%

“…The data sets used, set 1 (Travis et al, 2003) and set 2 ( van Leeuwen et al, 2003), are described in the Methods section. The figure shows predictions, all of which use K=25 acute dosefractions, starting on a Monday and continuing daily except for Saturdays and Sundays.…”

Section: Fig 5 Comparing Different Models With Data On Second Breasmentioning

confidence: 99%

Second cancers after fractionated radiotherapy: Stochastic population dynamics effects

Sachs

Shuryak

Brenner

et al. 2007

Journal of Theoretical Biology

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“…Reaching menopause before age 36 years was associated with a greatly reduced risk of breast cancer (RR 0.06, 95% CI 0.01 -0.45) and risk increased steeply with number of premenopausal years after treatment: relative risks were 0.15, 0.24 and 0.91 for o5, 5 -14, and X15 premenopausal years, respectively. Travis et al (2003) found that breast cancer risk decreased significantly (P ¼ 0.003) with increasing number of alkylating agent cycles and decreased, although the trend was not significant, with younger age at menopause. Thus ovarian hormones may be critical to carcinogenesis after radiation initiation.…”

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confidence: 95%

“…Analyses of patients treated with both chemotherapy and radiotherapy have in several studies (Gervais-Fagnou et al, 1999;Swerdlow et al, 2000;van Leeuwen et al, 2000Travis et al, 2003) but not all (Hancock et al, 1993;Aisenberg et al, 1997) suggested a reduced risk compared with that after radiotherapy alone. In the British cohort, the relative risk for patients treated at less than 25 years of age was 14.4 after radiotherapy alone and 4.6 after radiotherapy plus chemotherapy (Swerdlow et al, 2000).…”

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confidence: 99%

Second primary breast cancer after Hodgkin's disease

Horwich

Swerdlow

2004

Br J Cancer

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Although the potential carcinogenic risk of radiotherapy is well known, it has become clear that there is a particularly high risk of radiation-induced breast cancer in women treated for Hodgkin's disease at young ages. Thankfully, death from breast cancer in this population is uncommon, but it is important to understand factors contributing to the risk, including treatment parameters, and to develop a logical and efficient method for medical management of those at risk. In this minireview, we examine the evidence which should inform such a management policy. The prognosis of patients with Hodgkin's disease has been improved dramatically over the last 40 years by the development of extended field radiotherapy techniques and then by combination chemotherapy (DeVita et al, 1980;Rosenberg and Kaplan, 1985). However, long-term follow-up of survivors has demonstrated that a price of this success has been an increased risk of second cancers. Acute leukaemia frequently occurs in the first decade after treatment, mainly as a consequence of chemotherapy regimens that included an alkylating agent (Tucker et al, 1988;Kaldor et al, 1990;Swerdlow et al, 2000). In the long term, however, the absolute excess risks of a second solid cancer are higher (Swerdlow et al, 2000;Ng et al, 2002b; and are linked mainly with radiotherapy, although for some sites, such as lung cancer, there may be a substantial risk also from chemotherapy (Swerdlow et al, 2000;Travis et al, 2002). Recent reports from The Netherlands and from an international consortium of cancer registries have refined our understanding of how therapy may affect breast cancer risk.The relative risks of many cancers are higher if patients have been treated for Hodgkin's disease at a younger age (Swerdlow et al, 2000;van Leeuwen et al, 2000;Dores et al, 2002). Thus, although the risk of breast cancer is only about 50% increased in most all-age studies of women with Hodgkin's disease (van Leeuwen et al, 1999), relative risks are far larger than this in patients treated at young ages, especially those treated in childhood and adolescence (Hancock et al, 1993;Bhatia et al, 1996b); for them this is one of the main long-term sequelae of radiotherapy. This effect of age is unsurprising, as similar gradients are seen in other cohorts of radiation-exposed women (United Nations Scientific Committee on the Effects of Atomic Radiation, 1994).The size of risk of breast cancer found in Hodgkin's disease patients has varied between studies. For patients treated under age 21 years relative risks have generally been around 15 -25 (Hancock et al, 1993;Sankila et al, 1996;Wolden et al, 1998;Metayer et al, 2000;van Leeuwen et al, 2000;Dores et al, 2002), although they have been less raised (Neglia et al, 2001) or more raised (Mauch et al, 1996;Bhatia et al, 1996b;Aisenberg et al, 1997;Ng et al, 2002b) than this in a few studies; absolute excess risks have generally been of the order of 20 -40 per 10 000 per annum. Relative risks have been greater for patients treated at ages 10 -16 than at...

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“…There is significant evidence, derived from diverse populations, that ionising radiation can cause breast cancer. Some examples are patients who received therapeutic radiation to the chest early in life for Hodgkin's disease (HD), patients who were treated with radiation for mastitis and other benign breast diseases, patients who received thymic irradiation, patients who underwent frequent fluoroscopies for pulmonary disease, and atomic bomb survivors (Behrens et al, 2000;Clemons et al, 2000;Gaffney et al, 2001;Land et al, 2003;Travis et al, 2003). Among these, the best-studied group are women who developed breast cancer after treatment for HD.…”

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confidence: 99%

Array comparative genomic hybridisation (aCGH) analysis of premenopausal breast cancers from a nuclear fallout area and matched cases from Western New York

Varma

Huang

et al. 2005

Br J Cancer

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High-resolution array comparative genomic hybridisation (aCGH) analysis of DNA copy number aberrations (CNAs) was performed on breast carcinomas in premenopausal women from Western New York (WNY) and from Gomel, Belarus, an area exposed to fallout from the 1986 Chernobyl nuclear accident. Genomic DNA was isolated from 47 frozen tumour specimens from 42 patients and hybridised to arrays spotted with more than 3000 BAC clones. In all, 20 samples were from WNY and 27 were from Belarus. In total, 34 samples were primary tumours and 13 were lymph node metastases, including five matched pairs from Gomel. The average number of total CNAs per sample was 76 (range 35 -134). We identified 152 CNAs (92 gains and 60 losses) occurring in more than 10% of the samples. The most common amplifications included gains at 8q13.2 (49%), at 1p21.1 (36%), and at 8q24.21 (36%). The most common deletions were at 1p36.22 (26%), at 17p13.2 (26%), and at 8p23.3 (23%). Belarussian tumours had more amplifications and fewer deletions than WNY breast cancers. HER2/neu negativity and younger age were also associated with a higher number of gains and fewer losses. In the five paired samples, we observed more discordant than concordant DNA changes. Unsupervised hierarchical cluster analysis revealed two distinct groups of tumours: one comprised predominantly of Belarussian carcinomas and the other largely consisting of WNY cases. In total, 50 CNAs occurred significantly more commonly in one cohort vs the other, and these included some candidate signature amplifications in the breast cancers in women exposed to significant radiation. In conclusion, our high-density aCGH study has revealed a large number of genetic aberrations in individual premenopausal breast cancer specimens, some of which had not been reported before. We identified a distinct CNA profile for carcinomas from a nuclear fallout area, suggesting a possible molecular fingerprint of radiation-associated breast cancer.

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Breast Cancer Following Radiotherapy and Chemotherapy Among Young Women With Hodgkin Disease

Cited by 601 publications

References 53 publications

Second cancers after fractionated radiotherapy: Stochastic population dynamics effects

Second cancers after fractionated radiotherapy: Stochastic population dynamics effects

Second primary breast cancer after Hodgkin's disease

Array comparative genomic hybridisation (aCGH) analysis of premenopausal breast cancers from a nuclear fallout area and matched cases from Western New York

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