Cardiac Structure Injury After Radiotherapy for Breast Cancer: Cross-Sectional Study With Individual Patient Data.

Purpose Incidental cardiac irradiation can cause cardiac injury, but little is known about the effect of radiation on specific cardiac segments. Methods For 456 women who received breast cancer radiotherapy between 1958 and 2001 and then later experienced a major coronary event, information was obtained on the radiotherapy regimen they received and on the location of their cardiac injury. For 414 women, all with documented location of left ventricular (LV) injury, doses to five LV segments were estimated. For 133 women, all with documented location of coronary artery disease with ≥ 70% stenosis, doses to six coronary artery segments were estimated. For each segment, numbers of women with left-sided and right-sided breast cancer were compared. Results Of women with LV injury, 243 had left-sided breast cancer and 171 had right-sided breast cancer (ratio of left v right, 1.42; 95% CI, 1.17 to 1.73), reflecting the higher typical LV radiation doses in left-sided cancer (average dose left-sided, 8.3 Gy; average dose right-sided, 0.6 Gy; left minus right dose difference, 7.7 Gy). For individual LV segments, the ratios of women with left- versus right-sided radiotherapy were as follows: inferior, 0.94 (95% CI, 0.70 to 1.25); lateral, 1.42 (95% CI, 1.04 to 1.95); septal, 2.09 (95% CI, 1.37 to 3.19); anterior, 1.85 (95% CI, 1.39 to 2.46); and apex, 4.64 (95% CI, 2.42 to 8.90); corresponding left-minus-right dose differences for these segments were 2.7, 4.9, 7.2, 10.4, and 21.6 Gy, respectively ( Ptrend < .001). For women with coronary artery disease, the ratios of women with left- versus right-radiotherapy for individual coronary artery segments were as follows: right coronary artery proximal, 0.48 (95% CI, 0.26 to 0.91); right coronary artery mid or distal, 1.69 (95% CI, 0.85 to 3.36); circumflex proximal, 1.46 (95% CI, 0.72 to 2.96); circumflex distal, 1.11 (95% CI, 0.45 to 2.73); left anterior descending proximal, 1.89 (95% CI, 1.07 to 3.34); and left anterior descending mid or distal, 2.33 (95% CI, 1.19 to 4.59); corresponding left-minus-right dose differences for these segements were -5.0, -2.5, 1.6, 3.5, 9.5, and 38.8 Gy ( Ptrend = .002). Conclusion For individual LV and coronary artery segments, higher radiation doses were strongly associated with more frequent injury, suggesting that all segments are sensitive to radiation and that doses to all segments should be minimized.

Estimating the Risks of Breast Cancer Radiotherapy: Evidence From Modern Radiation Doses to the Lungs and Heart and From Previous Randomized Trials.

Purpose Radiotherapy reduces the absolute risk of breast cancer mortality by a few percentage points in suitable women but can cause a second cancer or heart disease decades later. We estimated the absolute long-term risks of modern breast cancer radiotherapy. Methods First, a systematic literature review was performed of lung and heart doses in breast cancer regimens published during 2010 to 2015. Second, individual patient data meta-analyses of 40,781 women randomly assigned to breast cancer radiotherapy versus no radiotherapy in 75 trials yielded rate ratios (RRs) for second primary cancers and cause-specific mortality and excess RRs (ERRs) per Gy for incident lung cancer and cardiac mortality. Smoking status was unavailable. Third, the lung or heart ERRs per Gy in the trials and the 2010 to 2015 doses were combined and applied to current smoker and nonsmoker lung cancer and cardiac mortality rates in population-based data. Results Average doses from 647 regimens published during 2010 to 2015 were 5.7 Gy for whole lung and 4.4 Gy for whole heart. The median year of irradiation was 2010 (interquartile range [IQR], 2008 to 2011). Meta-analyses yielded lung cancer incidence ≥ 10 years after radiotherapy RR of 2.10 (95% CI, 1.48 to 2.98; P < .001) on the basis of 134 cancers, indicating 0.11 (95% CI, 0.05 to 0.20) ERR per Gy whole-lung dose. For cardiac mortality, RR was 1.30 (95% CI, 1.15 to 1.46; P < .001) on the basis of 1,253 cardiac deaths. Detailed analyses indicated 0.04 (95% CI, 0.02 to 0.06) ERR per Gy whole-heart dose. Estimated absolute risks from modern radiotherapy were as follows: lung cancer, approximately 4% for long-term continuing smokers and 0.3% for nonsmokers; and cardiac mortality, approximately 1% for smokers and 0.3% for nonsmokers. Conclusion For long-term smokers, the absolute risks of modern radiotherapy may outweigh the benefits, yet for most nonsmokers (and ex-smokers), the benefits of radiotherapy far outweigh the risks. Hence, smoking can determine the net effect of radiotherapy on mortality, but smoking cessation substantially reduces radiotherapy risk.

Accelerated Partial Breast Irradiation: Executive summary for the update of an ASTRO Evidence-Based Consensus Statement.

PURPOSE: To update the accelerated partial breast irradiation Consensus Statement published in 2009 and provide guidance on use of intraoperative radiation therapy (IORT) for partial breast irradiation in early-stage breast cancer, based on published evidence complemented by expert opinion. METHODS AND MATERIALS: A systematic PubMed search using the same terms as the original Consensus Statement yielded 419 articles; 44 articles were selected. The authors synthesized the published evidence and, through a series of conference calls and e-mails, reached consensus regarding the recommendations. RESULTS: The new recommendations include lowering the age in the "suitability group" from 60 to 50 years and in the "cautionary group" to 40 years for patients who meet all other elements of suitability (Table 1). Patients with low-risk ductal carcinoma in situ, as per Radiation Therapy Oncology Group 9804 criteria, were categorized in the "suitable" group. The task force agreed to maintain the current criteria based on margin status. Recommendations for the use of IORT for breast cancer patients include: counseling patients regarding the higher risk of ipsilateral breast tumor recurrence with IORT compared with whole breast irradiation; the need for prospective monitoring of long-term local control and toxicity with low-energy radiograph IORT given limited follow-up; and restriction of IORT to women with invasive cancer considered "suitable." CONCLUSION: These recommendations will provide updated clinical guidance regarding use of accelerated partial breast irradiation for radiation oncologists and other specialists participating in the care of breast cancer patients.

Altered fractionation schedules in radiation treatment: a review.

Conventionally fractionated radiotherapy is delivered in 1.8- to 2.0-Gy fractions. With increases in understanding of radiation and tumor biology, various alterations of radiotherapy schedules have been tested in clinical trials and are now regarded by some as standard treatment options. Hyperfractionation is delivered through a greater number of smaller treatment doses. Accelerated fractionation decreases the amount of time over which radiotherapy is delivered typically by increasing the number of treatments per day. Hypofractionation decreases the number of fractions delivered by increasing daily treatment doses. Furthermore, many of these schedules have been tested with concurrent chemotherapy regimens. In this review, we summarize the major clinical studies that have been conducted on altered fractionation in various disease sites.

Impact of radiation treatment parameters and adjuvant systemic therapy on cosmetic outcomes after accelerated partial breast irradiation using 3-dimensional conformal radiation therapy technique.

PURPOSE: There are concerns regarding cosmetic outcomes of 3-dimensional conformal accelerated partial breast radiation therapy (3DCRT APBI). Associations between cosmetic outcomes and treatment parameters or receipt of adjuvant systemic therapy were sought to guide 3DCRT APBI. METHODS AND MATERIALS: An analysis of cosmetic outcomes among patients treated with 3DCRT APBI at Moffitt Cancer Center was performed. Overall cosmesis was evaluated using modified Harvard criteria and toxicity outcomes were graded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Patients were treated to 38.5 Gy in 3.85 Gy twice daily fractions per dose-volume objectives specified in the National Surgical Adjuvant Breast and Bowel B-39/Radiation Therapy Oncology Group 0413 (NSABP B-39/RTOG 0413) trial. RESULTS: At least 1 evaluation was available for 97 treated breasts (94 women) with median follow-up of 17.2 months (range, 1-60 months). Most breasts (90.7%) had grade 1 to 2 (excellent to good) overall cosmesis. Nine breasts (9.3%) had grade 3 to 4 (fair to poor) overall cosmesis, secondary to >25% asymmetry in 5 patients, grade 3 fibrosis in 3 patients, and fat necrosis in 1 patient. Increasing percentage of ipsilateral breast volume receiving more than 50% of the prescription dose (V50%) correlated with less than excellent cosmesis (P < .001), with a threshold V50% of 40%. Telangiectasia formation (6%) correlated with increased evaluation planning target volume (P = .006) and V50% (P = .017). Grade 2+ fibrosis (18%) and grade 1+ induration (83%) were also correlated with increasing V50% (P = .006 and .002, respectively). Smaller ipsilateral breast volume correlated with worsening cosmesis (P = .048) and induration (P = .028). Two of 4 patients receiving chemotherapy developed grade 3 fibrosis (P = .004) and fair/poor cosmesis (P = .04). CONCLUSIONS: The current analysis implies that acceptable cosmetic results are achievable with 3DCRT APBI technique by adhering to optimal radiation therapy dose-volume constraints, particularly ipsilateral breast V50%.

Monte Carlo comparison of superficial dose between flattening filter free and flattened beams.

This study investigates the superficial dose from FFF beams in comparison with the conventional flattened ones using a Monte Carlo (MC) method. Published phase-space files which incorporated real geometry of a TrueBeam accelerator were used for the dose calculation in phantom and clinical cases. The photon fluence on the central axis is 3 times that of a flattened beam for a 6 MV FFF beam and 5 times for a 10 MV beam. The mean energy across the field in air at the phantom surface is 0.92-0.95 MeV for the 6 MV FFF beam and 1.18-1.30 MeV for the corresponding flattened beam. At 10 MV, the values are 1.52-1.72 and 2.15-2.87 MeV for the FFF and flattened beams, respectively. The phantom dose at the depth of 1 mm in the 6 MV FFF beam is 6% ± 2.5% (of the maximum dose) higher compared to the flattened beam for a 25 × 25 cm(2) field and 14.6% ± 1.9% for the 2 × 2 cm(2) field. For the 10 MV beam, the corresponding differences are 3.4% ± 1.5% and 10.7% ± 0.6%. The skin dose difference at selected points on the patient's surface between the plans using FFF and flattened beams in the head-and-neck case was 6.5% ± 2.3% (1SD), and for the breast case it was 6.4% ± 2.3%. The Monte Carlo simulations showed that due to the lower mean energy in the FFF beam, the clinical superficial dose is higher without the flattening filter compared to the flattened beam.

Risk of ischemic heart disease in women after radiotherapy for breast cancer.

BACKGROUND: Radiotherapy for breast cancer often involves some incidental exposure of the heart to ionizing radiation. The effect of this exposure on the subsequent risk of ischemic heart disease is uncertain. METHODS: We conducted a population-based case-control study of major coronary events (i.e., myocardial infarction, coronary revascularization, or death from ischemic heart disease) in 2168 women who underwent radiotherapy for breast cancer between 1958 and 2001 in Sweden and Denmark; the study included 963 women with major coronary events and 1205 controls. Individual patient information was obtained from hospital records. For each woman, the mean radiation doses to the whole heart and to the left anterior descending coronary artery were estimated from her radiotherapy chart. RESULTS: The overall average of the mean doses to the whole heart was 4.9 Gy (range, 0.03 to 27.72). Rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per gray (95% confidence interval, 2.9 to 14.5; P<0.001), with no apparent threshold. The increase started within the first 5 years after radiotherapy and continued into the third decade after radiotherapy. The proportional increase in the rate of major coronary events per gray was similar in women with and women without cardiac risk factors at the time of radiotherapy. CONCLUSIONS: Exposure of the heart to ionizing radiation during radiotherapy for breast cancer increases the subsequent rate of ischemic heart disease. The increase is proportional to the mean dose to the heart, begins within a few years after exposure, and continues for at least 20 years. Women with preexisting cardiac risk factors have greater absolute increases in risk from radiotherapy than other women. (Funded by Cancer Research UK and others.).

Optimization of Adjuvant Radiation in Breast Conservation Therapy: Can We Minimize without Compromise?

Adjuvant breast radiation therapy after breast conservation surgery is recommended as it yields significant reduction in the risk of local recurrence, and confers a potential overall survival benefit. Although the standard breast radiation regimen has historically been delivered over 5-7 weeks; more novel, shorter courses of breast radiation are currently being employed, offering the advantage of more convenience and less time-commitment. Herein, we review the recent literature substantiating these abbreviated radiation treatment approaches and the methods of delivery thereof. In addition, we discuss imaged guided techniques currently being utilized to further refine the delivery of adjuvant breast radiation therapy.

Fractionation for whole breast irradiation: an American Society for Radiation Oncology (ASTRO) evidence-based guideline.

PURPOSE: In patients with early-stage breast cancer treated with breast-conserving surgery, randomized trials have found little difference in local control and survival outcomes between patients treated with conventionally fractionated (CF-) whole breast irradiation (WBI) and those receiving hypofractionated (HF)-WBI. However, it remains controversial whether these results apply to all subgroups of patients. We therefore developed an evidence-based guideline to provide direction for clinical practice. METHODS AND MATERIALS: A task force authorized by the American Society for Radiation Oncology weighed evidence from a systematic literature review and produced the recommendations contained herein. RESULTS: The majority of patients in randomized trials were aged 50 years or older, had disease Stage pT1-2 pN0, did not receive chemotherapy, and were treated with a radiation dose homogeneity within ±7% in the central axis plane. Such patients experienced equivalent outcomes with either HF-WBI or CF-WBI. Patients not meeting these criteria were relatively underrepresented, and few of the trials reported subgroup analyses. For patients not receiving a radiation boost, the task force favored a dose schedule of 42.5 Gy in 16 fractions when HF-WBI is planned. The task force also recommended that the heart should be excluded from the primary treatment fields (when HF-WBI is used) due to lingering uncertainty regarding late effects of HF-WBI on cardiac function. The task force could not agree on the appropriateness of a tumor bed boost in patients treated with HF-WBI. CONCLUSION: Data were sufficient to support the use of HF-WBI for patients with early-stage breast cancer who met all the aforementioned criteria. For other patients, the task force could not reach agreement either for or against the use of HF-WBI, which nevertheless should not be interpreted as a contraindication to its use.

Radiation dose-volume effects in the heart.

The literature is reviewed to identify the main clinical and dose-volume predictors for acute and late radiation-induced heart disease. A clear quantitative dose and/or volume dependence for most cardiac toxicity has not yet been shown, primarily because of the scarcity of the data. Several clinical factors, such as age, comorbidities and doxorubicin use, appear to increase the risk of injury. The existing dose-volume data is presented, as well as suggestions for future investigations to better define radiation-induced cardiac injury.

Time to treatment in patients with stage III non-small cell lung cancer.

PURPOSE: To determine whether time to treatment (TTT) has an effect on overall survival (OS) in patients with unresectable or medically inoperable Stage III non-small cell lung cancer (NSCLC) and whether patient or treatment factors are associated with TTT. METHODS AND MATERIALS: Included in the study were 237 consecutive patients with Stage III NSCLC treated at University of Michigan Hospital (UM) or the Veterans Affairs Ann Arbor Healthcare System (VA). Patients were treated with either palliative or definitive radiotherapy and radiotherapy alone (n = 106) or either sequential (n = 69) or concurrent chemoradiation (n = 62). The primary endpoint was OS. RESULTS: Median follow-up was 69 months, and median TTT was 57 days. On univariate analysis, the risk of death did not increase significantly with longer TTT (p = 0.093). However, subset analysis showed that there was a higher risk of death with longer TTT in patients who survived >or= 5 years (p = 0.029). Younger age (p = 0.027), male sex (p = 0.013), lower Karnofsky Performance Score (KPS) (p = 0.002), and treatment at the VA (p = 0.001) were significantly associated with longer TTT. However, on multivariate analysis, only lower KPS remained significantly associated with longer TTT (p = 0.003). CONCLUSION: Time to treatment is significantly associated with OS in patients with Stage III NSCLC who lived longer than 5 years, although it is not a significant factor in Stage III patients as a whole. Lower KPS is associated with longer TTT.

The effect of radiation dose and chemotherapy on overall survival in 237 patients with Stage III non-small-cell lung cancer.

PURPOSE: To study the effects of radiation dose, chemotherapy, and their interaction in patients with unresectable or medically inoperable Stage III non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: A total of 237 consecutive Stage III NSCLC patients were evaluated. Median follow-up was 69.0 months. Patients were treated with radiation therapy (RT) alone (n = 106), sequential chemoradiation (n = 69), or concurrent chemoradiation (n = 62). The primary endpoint was overall survival (OS). Radiation dose ranged from 30 to 102.9 Gy (median 60 Gy), corresponding to a bioequivalent dose (BED) of 39 to 124.5 Gy (median 72 Gy). RESULTS: The median OS of the entire cohort was 12.6 months, and 2- and 5-year survival rates were 22.4% and 10.0%, respectively. Multivariable Cox regression model demonstrated that Karnofsky performance status (p = 0.020), weight loss < 5% (p = 0.017), chemotherapy (yes vs. no), sequence of chemoradiation (sequential vs. concurrent; p < 0.001), and BED (p < 0.001) were significant predictors of OS. For patients treated with RT alone, sequential chemoradiation, and concurrent chemoradiation, median survival was 7.4, 14.9, and 15.8 months, and 5-year OS was 3.3%, 7.5%, and 19.4%, respectively (p < 0.001). The effect of higher radiation doses on survival was independent of whether chemotherapy was given. CONCLUSION: Radiation dose and use of chemotherapy are independent predictors of OS in Stage III NSCLC, and concurrent chemoradiation is associated with the best survival. There is no interaction between RT dose and chemotherapy.

Cardiac morbidity and mortality after breast conservation treatment in patients with early-stage breast cancer and preexisting cardiac disease.

BACKGROUND: This study was undertaken to determine the risk of late cardiac morbidity and mortality in patients with preexisting cardiac disease treated with contemporary radiation techniques for early-stage breast cancer. PATIENTS AND METHODS: Medical records were reviewed for 41 patients with early-stage breast cancer and a history of myocardial infarction, congestive heart failure (CHF), and/or coronary artery disease before radiation therapy. Data were recorded on baseline cardiac disease and tumor characteristics, cardiac morbidity during and after treatment, and survival status of each patient. Patients were stratified for right- versus left-sided breast cancer and compared. RESULTS: There was no significant difference in overall survival (OS) between the right- and left-sided groups (log-rank test; P = .19). The left-sided group had a higher incidence of cardiac deaths (right side, 2 of 26 [9%]; left side, 4 of 15 [27%]; hazard ratio, 4.2; P = .08) 10 years after treatment, including deaths secondary to myocardial infarction, CHF, or coronary artery disease. On the other hand, the right-sided group had a higher proportion of deaths secondary to breast cancer (right, 8 of 26 [31%]; left, 2 of 15 [13%]) and non-breast cancer/noncardiac causes (right, 7 of 26 [27%]; left, 1 of 15 [7%]). CONCLUSION: Although OS was similar in both groups, radiation was associated with a higher incidence of cardiac death in patients with left-sided breast cancer. Efforts should be made to minimize cardiac exposure and also to promote more vigilant risk factor modification in this group of women.

Association between tangential beam treatment parameters and cardiac abnormalities after definitive radiation treatment for left-sided breast cancer.

PURPOSE: To examine the association between radiation treatment (RT) parameters, cardiac diagnostic test abnormalities, and clinical cardiovascular diagnoses among patients with left-sided breast cancer after breast conservation treatment with tangential beam RT. METHODS AND MATERIALS: The medical records of 416 patients treated between 1977 and 1995 with RT for primary left-sided breast cancer were reviewed for myocardial perfusion imaging and echocardiograms. Sixty-two patients (62/416, 15%) underwent these cardiac diagnostic tests for cardiovascular symptoms and were selected for further study. Central lung distance and maximum heart width and length in the treatment field were determined for each patient. Medical records were reviewed for cardiovascular diagnoses and evaluation of cardiac risk factors. RESULTS: At a median of 12 years post-RT the incidence of cardiac diagnostic test abnormalities among symptomatic left-sided irradiated women was significantly higher than the predicted incidence of cardiovascular disease in the patient population, 6/62 (9%) predicted vs. 24/62 (39%) observed, p = 0.001. As compared with patients with normal tests, patients with cardiac diagnostic test abnormalities had a larger median central lung distance (2.6 cm vs. 2.2 cm, p = 0.01). Similarly, patients with vs. without congestive heart failure had a larger median central lung distance (2.8 cm vs. 2.3 cm, p = 0.008). CONCLUSIONS: Contemporary RT for early breast cancer may be associated with a small, but potentially avoidable, risk of cardiovascular morbidity that is associated with treatment technique.

Coronary artery findings after left-sided compared with right-sided radiation treatment for early-stage breast cancer.

PURPOSE: To compare the incidence and distribution of coronary artery disease after left-sided versus right-sided irradiation in patients treated with breast conservation for early-stage breast cancer who subsequently underwent cardiac stress testing and/or catheterization for cardiovascular symptoms. PATIENTS AND METHODS: The medical records of 961 stage I-II breast cancer patients treated from 1977 to 1995 at the University of Pennsylvania with conventional tangential beam radiation treatment (RT) were screened for cardiac stress tests and catheterizations performed after RT. The results of these tests were analyzed by laterality of RT and compared with baseline cardiovascular risk. RESULTS: At diagnosis, patients with left-sided and right-sided breast cancer had the same estimated 10-year risk (both 7%) of developing coronary artery disease. At a median time of 12 years post-RT (range, 2 to 24 years), 46 patients with left-sided and 36 patients with right-sided breast cancer (total, N = 82) had undergone cardiac stress testing. A statistically significant higher prevalence of stress test abnormalities was found among left (27 of 46; 59%) versus right-side irradiated patients (three of 36; 8%; P = .001). Furthermore, 19 of 27 of left-sided abnormalities (70%) were in the left anterior descending artery territory. Thirteen left-side irradiated patients also underwent cardiac catheterization revealing 12 of 13 with coronary stenoses (92%) and eight of 13 with coronary stenoses (62%) solely in the left anterior descending artery. CONCLUSION: Patients treated with left-sided radiation as a component of breast conservation have an increased risk of late, radiation-associated coronary damage. Treatment with modern radiation techniques may reduce the risk of cardiac injury.

Late cardiac mortality and morbidity in early-stage breast cancer patients after breast-conservation treatment.

PURPOSE: Several studies have reported increased cardiac mortality related to the use of left-sided breast or chest-wall irradiation. This study was undertaken as a comprehensive examination of the long-term cardiac mortality and morbidity after breast irradiation using contemporary irradiation techniques. METHODS: The medical records of 961 consecutive patients presenting between 1977 and 1994 with stage I or II breast cancer treated with breast conservation treatment were reviewed. Data was recorded on baseline pretreatment patient, tumor and treatment characteristics and on subsequent cancer or cardiac related events. The median follow-up time was 12 years. RESULTS: There was no difference in overall mortality from any cardiac cause (P = .25). Death from any cardiac cause occurred in 2% of right-sided patients and 3.5% of left-sided patients. However, in the second decade after treatment, there was a higher rate of cardiac deaths in left-sided patients, with a cumulative risk of 6.4% (95% CI, 3.5% to 11.5%) for left-sided compared with 3.6% (95% CI, 1.8% to 7.2%) for right-sided patients at 20 years. There were statistically higher rates of chest pain, coronary artery disease, and myocardial infarction diagnosed in left-sided patients (all P < or = .002). The presence of hypertension was associated with a higher risk of coronary artery disease in left-sided patients. CONCLUSION: Irradiation to the left breast is not associated with a higher risk of cardiac death up to 20 years after treatment, but is associated with an increased rate of diagnoses of coronary artery disease and myocardial infarction compared with right breast treatment.

Genetic variation in radiation-induced expression phenotypes.

Studies have demonstrated that natural variation in the expression level of genes at baseline is extensive, and the determinants of this variation can be mapped by a genetic-linkage approach. In this study, we used lymphoblastoid cells to explore the variation in radiation-induced transcriptional changes. We found that, among normal individuals, there is extensive variation in transcriptional response to radiation exposure. By studying monozygotic twins, we demonstrated that there is evidence of a heritable component to this variation. The postradiation variation in the expression level of several genes, including the ferredoxin reductase gene (FDXR) and the cyclin-dependent kinase inhibitor 1A gene (CDKN1A), is significantly greater (P<.001) among twin pairs than within twin pairs. The induction of FDXR by radiation showed a bimodal distribution. Our findings have important implications for understanding the genetic basis of radiation response, which has remained largely unknown due to the lack of family material needed for genetic studies. Our approach, which uses expression phenotypes in cell lines, allows us to expose cells from family members to radiation. Similar study design can be applied to dissect the genetic basis of other complex human traits.