Risk Of Inflammatory Breast Cancer Research Articles

Abstract P1-24-06: Risk factor modeled microenvironment effects lymphatics activity and IBC invasiveness and progression

Abstract Background. Lymphovascular invasion (LVI) and breast tumor emboli within dermal and breast lymphatic vessels are prognostic for metastatic spread and poor outcomes, and are abundant in Inflammatory breast cancer (IBC). IBC is an aggressive breast cancer that presents suddenly with breast swelling and redness due to tumor emboli in lymphatics. Lack of breast-feeding and obesity are IBC risk factors. We sought to demonstrate the combinatorial effects of a high-fat diet and nursing on lymphatic function and compare these to IBC tumor induced changes in lymphatic function. We hypothesize that risk factors for aggressive breast cancer may alter lymphatic function in the normal gland prior to tumor initiation. Methods. Following two rounds of pregnancy in 20 multiparous SCID Beige immunocompromised mice, half of the mice were force weaned while half nursed pups. Prior to forced weaning, half of each of these groups were fed a high fat diet (HFD: 60 Kcal %, N = 10) while the other half received a low-fat diet (LFD: 10 Kcal %, N = 10). Consecutive dynamic near-infrared fluorescence (NIRF) lymphatic imaging was performed at 6-7 months (covid interruption) and 14 months after initiating the diet by injecting a near-IR fluorophore into the mammary fatpad and recording lymphatic pulsing over 8 minutes using V++. Matlab and ImageJ were used to quantify pulsing rates on the ventral lymphatics in each animal. Fatpads were subsequently inoculated with SUM149 IBC cells and imaging was repeated 16 months post diet initiation. Lymphatic imaging over time by HFD vs LFD was further studied in nulliparous animals. Tissues were collected for further analyses. ResultsData analysis prior to tumor injection, demonstrated lymphatic pulsing (pulses/4 minutes) increased over time in HFD force weaned (HFFW) and HFD nursing (HFN) animals only (65.5 vs 72.6, P=0.059; 60.1 vs 76.6, P=0.0099, respectively). Comparing HFFW and HFN to matched LFD groups (LFFW and LFN), at 14 weeks HFD was associated with increased pumping after forced weaning (62.3 vs. 72.6, P=0.074), and nursing (62.5 vs 76.6, P=0.0023). There was an increase in pulsing after tumor initiation (16 months after initiation of diet) in all groups (80.1, 84.1, 83.2, 82.4, P > 0.05 all comparisons to initial timepoint). In a separate experiment examining HFD (N=5) vs LFD (N=5) in nulliparous mice, lymphatic contractile activity increased in all animals over. time, average ventral lymphatic contractile frequency for LFD and HFD at week 8,11 and 14 weeks after diet initiation were 5, 8.64, 15.9 pumps/4 mins vs 11.8, 18.5, 28.2 pumps/4 mins, (P = 0.01, 0.05, and 0.0005 respectively). ConclusionsHFD increased lymphatic pulsing rate over time to a significantly greater extent than LFD continuing over 14 months independent of reproductive and nursing status. Tumor initiation prompted further increased pulsing rates beyond that observed after HFD across all groups. The magnitude of the effect of HFD on lymphatic pulsing approached the rate after tumor initiation, while reproductive variables did not impact lymphatic pulsing. Further studies are warranted to demonstrate the relationship if any between lymphatic pumping pre-initiation and LVI after tumor initiation and examine the role of intervention on reducing LVI. Citation Format: Wintana Balema, Janelle Morton, Richard Larson, Fred C Velasquez, Eva Sevick-Muraca, Wendy A Woodward. Risk factor modeled microenvironment effects lymphatics activity and IBC invasiveness and progression [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-24-06.

Risk factors for inflammatory and non-inflammatory breast cancer in North Africa.

Studies of the etiology of inflammatory breast cancer (IBC), a rare but aggressive breast cancer, have been hampered by limited risk factor information. We extend previous studies by evaluating a broader range of risk factors. Between 2009 and 2015, we conducted a case-control study of IBC at six centers in Egypt, Tunisia, and Morocco; enrolled were 267 IBC cases and for comparison 274 non-IBC cases and 275 controls, both matched on age and geographic area to the IBC cases. We administered questionnaires and collected anthropometric measurements for all study subjects. We used multiple imputation methods to account for missing values and calculated odds ratios (ORs) and 95% confidence intervals (CIs) using polytomouslogistic regression comparing each of the two case groups to the controls, with statistical tests for the difference between the coefficients for the two case groups. After multivariable adjustment, a livebirth within the previous 2 years (OR 4.6; 95% CI 1.8 to 11.7) and diabetes (OR 1.8; 95% CI 1.1 to 3.0) were associated with increased risk of IBC, but not non-IBC (OR 0.9; 95% CI 0.3 to 2.5 and OR 0.9; 95% CI 0.5 to 1.6 for livebirth and diabetes, respectively). A family history of breast cancer, inflammatory-like breast problems, breast trauma, and low socioeconomic status were associated with increased risk of both tumor types. We identified novel risk factors for IBC and non-IBC, some of which preferentially increased risk of IBC compared to non-IBC. Upon confirmation, these findings could help illuminate the etiology and aid in prevention of this aggressive cancer.

Obesity and related conditions and risk of inflammatory breast cancer: a nested case-control study.

Inflammatory breast cancer (IBC) is a rare, poorly understood and aggressive tumor. We extended prior findings linking high body mass index (BMI) to substantial increased IBC risk by examining BMI associations before and after adjustment for well-characterized comorbidities using medical record data for diabetes, insulin resistance, and disturbances of cholesterol metabolism in a general community healthcare setting. We identified 247 incident IBC cases diagnosed at Kaiser Permanente Northern California between 2005 and 2017 and 2470 controls matched 10:1 on birth year and geographic area and with ≥ 13months of continuous enrollment prior to diagnosis/index date. We assessed exposures from 6years up to one year prior to the diagnosis/index date, using logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs). Before adjustment for comorbidities, ORs (95% CIs) for BMI of 25-< 30, 30-< 35, and ≥ 35 compared to < 25kg/m2 were 1.5 (0.9-2.3), 2.0 (1.2-3.1), and 2.5 (1.4-4.4), respectively. After adjustment for pre-diabetes/diabetes, HDL-C and triglyceride levels, and dyslipidemia, corresponding ORs were 1.3 (0.8-2.1), 1.6 (0.9-2.9), and 1.9 (1.0-3.5). The OR for HDL-C levels < 50mg/dL compared to ≥ 65mg/dL was 2.0 (1.2-3.3) in the adjusted model. In a separate model the OR for a triglyceride/HDL-C ratio ≥ 2.50 compared to < 1.62 was 1.7 (1.1-2.8) after adjustment for BMI, pre-diabetes/diabetes, and dyslipidemia. Results did not differ significantly by estrogen receptor status. Obesity and measures of insulin resistance independently increased IBC risk as did obesity and low HDL-C levels. These findings, if confirmed, have implications for IBC prevention.

Abstract A023: Results from a town hall meeting: Inflammatory breast cancer listening session led by KOMEN scholars

Abstract Introduction: Cancer is the leading cause of death in North Carolina. While the incidence rate of breast cancer (BC) is higher in White women, African American and Latino women are more likely to die from BC than White women. Moreover, inflammatory breast cancer (IBC) is a rare and aggressive form of BC, and African Americans are more likely to be diagnosed with IBC compared to whites, have poor BC outcomes, and generally are less likely to get life-saving information and resources to reduce cancer risks. Additionally, work is needed to improve diagnosis rates and decrease time to treatment for IBC patients. Translational research scientists do not get exposure to community engagement opportunities that can add to their knowledge of the research spectrum around a particular disease. Engaging new researchers in this arena can add to addressing cancer disparities research. Methods: An IBC listening session was conducted during the annual Women's Health Awareness Day conference sponsored by the National Institute of Environmental Health Sciences and North Carolina Central University. The session was developed by KOMEN translational health disparities researchers as part of their enhanced community engagement training program. Scholars created the marketing plan and listening session guide for the program with guidance and training from staff experts. Scholars were note takers, facilitators, and created summary reports that highlighted guiding questions for the session, which included the following questions: 1)What do you know about BC? 2) Are you aware of different types of breast cancers? 3) Have you heard of IBC? 4) How aware do you think people in your community are about BC and IBC? 5) Where do you get your information about BC and IBC? 6) What are ways we should educate the community with getting information on how to become aware about the signs and symptoms of IBC? Results: There were 49 African American and Latina participants. Only 15 of 49 attendees had heard of IBC. Most women were aware of causes and symptoms of breast cancer; however, there was a lack of awareness around IBC. Those aware of IBC learned about it from their coworkers, doctors, or had family members die from the disease. Participants recommended more one-on-one education, patient self-advocacy sessions, making education and awareness available online, changing breast cancer communication to include IBC symptoms, and letting people know that you can have breast cancer without the presence of lumps. Conclusion: Poor awareness, communication, and education around inflammatory breast cancer risk factors were substantial. There is significant need to raise awareness in diverse communities about inflammatory breast cancer risks, screening guidelines, diagnosis, and treatment options. Community-engaged research lead by under-represented researcher scholars in training can add to the translational research training experience. Citation Format: Maria Dixion, Kearston L. Ingraham, Seronda A. Robinson, Jodie M. Fleming, Gayathri R. Devi, Holly Hough, Hamzah Kharabsheh, Dana M. Austin, Tia A. Tate, Artis Woodard, Joshua Alexander, Joan P. Packenham, Nadine J. Barrett, Kevin P. Williams. Results from a town hall meeting: Inflammatory breast cancer listening session led by KOMEN scholars [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A023.

Abstract 4593: Genomic profiling of cell free DNA (cfDNA) from patients with inflammatory breast cancer (IBC)

Abstract Inflammatory breast cancer (IBC) currently accounts for 2% to 6% of all breast cancer cases in the United States and up to 20% of all breast cancer cases globally. IBC exhibits distinctively aggressive clinical features compared to all breast cancers, and accounts for a disproportionally high mortality rate—15% of breast cancer-related deaths in U.S. In addition, the survival rates between stage-matched IBC and non-IBC differ drastically. Therefore, we are in need of better understanding the molecular abnormalities driving IBC aggressive phenotype. We performed a study to evaluate the genomic alterations in cell free DNA (cfDNA) from plasma from 13 IBC patients, including 9 with triple-negative disease. In 6 patients, mutation analyses were also studied in tumor samples (tumor tissue or tumor cells from pleural effusions). Mutation analysis was performed by next-generation sequencing (NGS) using a unique molecular identifiers (UMI) assay and a panel of 93 breast cancer-related genes (Qiagen). The data were analyzed using the Qiagen's GeneGlobe portal and Biomedical Genomics Workbench and interpretation was performed with Qiagen's QCI. Somatic mutations detected in cfDNA samples were seen in: TP53 (7/13), RB1 (2/13), GEN1 (2/13) and EP300 (2/13); additional somatic mutations were found in PIK3CA (1/13), ERBB2 (1/13), PALB2 (1/13) and MUC16 (1/13). In 4 patients with plasma and tumor samples taken at the same time of the disease progression, complete concordance was not found in the somatic mutations detected in cfDNA and tumor cells DNA. Interestingly, in 12 of 13 IBC patients some variants were observed with high variant allele frequencies (VAF), ~50% or ~100% at a total coverage depth ≥230 reads, in the following genes: BRCA2 (1/13), RAD51D (2/13), PALB2 (1/13), RAD51C (1/13), AR (1/13) and MUTYH (1/13), which were classified as pathogenic or likely pathogenic, and BARD1 (3/13), SYNE1 (2/13), KMT2C (2/13), BRIP1 (1/13), XRCC3 (1/13), RET (1/13), APC (1/13), RAD50 (1/13) and MUC16 (1/13), classified as variants of uncertain significance. Moreover, 11 of these patients had a family history of different cancers including breast, colon, prostate, stomach, bladder, cervical cancers, and melanoma and myeloma. In the 6 patients where cfDNA and tumor samples were available, mutations with high VAF were found in both samples (100% concordance), suggesting that variants with high VAF are germline variants. These results suggest that the described germline variants could increase the risk of IBC and somatic mutation information obtained from cfDNA is complementary to that obtained from tissue samples. Studies on more samples are in progress. Citation Format: Jianming Pei, Jacqueline Talarchek, Jennifer S. Winn, Katherine Alpaugh, Massimo Cristofanilli, Sandra V. Fernandez. Genomic profiling of cell free DNA (cfDNA) from patients with inflammatory breast cancer (IBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4593.

Inflammatory breast cancer: High incidence of GCC haplotypes (-1082A/G, -819T/C, and -592A/C) in the interleukin-10 gene promoter correlates with over-expression of interleukin-10 in patients' carcinoma tissues.

Interleukin-10 is involved in carcinogenesis by supporting tumor escape from the immune response. The aim of this study was to assess the single nucleotide polymorphisms, -1082A/G, -819T/C and -592A/C, in interleukin-10 gene promoter in inflammatory breast cancer compared to non-inflammatory breast cancer and association of these polymorphisms with interleukin-10 gene expression. We enrolled 105 breast cancer tissue (72 non-inflammatory breast cancer and 33 inflammatory breast cancer) patients and we determined the three studied single nucleotide polymorphisms in all samples by polymerase chain reaction restriction fragment length polymorphism and investigated their association with the disease and with various prognostic factors. In addition, we assessed the expression of interleukin-10 gene by real-time quantitative reverse transcription polymerase chain reaction and the correlation between studied single nucleotide polymorphisms and interleukin-10 messenger RNA expression. We found co-dominant effect as the best inheritance model (in the three studied single nucleotide polymorphisms in non-inflammatory breast cancer and inflammatory breast cancer samples), and we didn't identify any association between single nucleotide polymorphisms genotypes and breast cancer prognostic factors. However, GCC haplotype was found highly associated with inflammatory breast cancer risk (p < 0.001, odds ratio = 43.05). Moreover, the expression of interleukin-10 messenger RNA was significantly higher (p < 0.001) by 5.28-fold and 8.95-fold than non-inflammatory breast cancer and healthy control, respectively, where GCC haplotype significantly increased interleukin-10 gene expression (r = 0.9, p < 0.001).

Diabetes, Abnormal Glucose, Dyslipidemia, Hypertension, and Risk of Inflammatory and Other Breast Cancer.

Background: Obesity has been associated with substantially higher risk of inflammatory breast cancer (IBC) than other breast cancer. Here, we assess whether comorbidities of obesity, namely diabetes, abnormal glucose, dyslipidemia, and hypertension, are differentially related to risk of IBC and other breast cancers by tumor stage at diagnosis (localized/regional/distant/unstaged).Methods: We used linked SEER-Medicare data, with female breast cancer cases ages 66+ years identified by SEER registries (years 1992-2011). We divided first breast cancers into IBC (N = 2,306), locally advanced non-IBC (LABC; N = 10,347), and other (N = 197,276). We selected female controls (N = 200,000) from a stratified 5% random sample of Medicare recipients alive and breast cancer free. We assessed exposures until 12 months before diagnosis/selection using Medicare claims data. We estimated odds ratios (OR) and 99.9% confidence intervals (CI) using unconditional logistic regression.Results: Diabetes was associated with increased risk of distant IBC (98.5% of IBC cases; OR 1.44; 99.9% CI 1.21-1.71), distant (OR 1.24; 99.9% CI, 1.09-1.40) and regional (OR 1.29 (99.9% CI, 1.14-1.45) LABC, and distant (OR 1.23; 99.9% CI, 1.10-1.39) and unstaged (OR 1.32; 99.9% CI, 1.18-1.47) other breast cancers. Dyslipidemia was associated with reduced risk of IBC (OR 0.80; 95% CI, 0.67-0.94) and other breast cancers except localized disease. Results were similar by tumor estrogen receptor status. Abnormal glucose levels and hypertension had little association with risk of any tumor type.Conclusions: Associations with diabetes and dyslipidemia were similar for distant stage IBC and other advanced tumors.Impact: If confirmed, such findings could suggest avenues for prevention. Cancer Epidemiol Biomarkers Prev; 26(6); 862-8. ©2017 AACR.

Epidemiological risk factors associated with inflammatory breast cancer subtypes.

In this single-institution case-control study, we identified risk factors associated with inflammatory breast cancer (IBC) subtypes based on staining of estrogen receptor (ER), progesterone receptor (PR) and expression of human epidermal growth factor 2 (HER2neu) to determine distinct etiologic pathways. We identified 224 women with IBC and 396 cancer-free women seen at the MD Anderson Cancer Center. Multinomial logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between breast cancer risk factors and the IBC tumor subtypes: luminal (ER+ and/or PR+/HER2neu-), HER2neu+ (any ER and PR, HER2neu+), and triple-negative (ER-/PR-/HER2neu-). In multivariable analysis, compared with women age ≥26 at first pregnancy, women age <26 had a higher risk of triple-negative IBC (OR 3.32, 95% CI 1.37-8.05). Women with a history of breast-feeding had a lower risk of triple-negative (OR 0.30; 95% CI 0.15-0.62) and luminal IBC (OR 0.35, 95% CI 0.18-0.68). A history of smoking was associated with an increased risk of luminal IBC (OR 2.37; 95% CI 1.24-4.52). Compared with normal-weight women, those who were overweight or obese (body mass index ≥25kg/m(2)) had a higher risk of all three tumor subtypes (p<0.01 for all subtypes). Overweight or obese status is important modifiable risk factor for IBC of any subtype. Modifiable risk factors, age at first pregnancy (≥26), breast-feeding, and smoking may be associated with specific IBC subtypes. These results highlight the importance of evaluating epidemiologic risk factors for IBC for the identification of subtype-specific prevention strategies.

Inflammatory breast cancer clusters: A hypothesis.

Cancer clusters have long been a focus of interest because of the possibility of identifying etiologic agents. Only on rare occasions, however, have such cluster investigations been successful. One major difficulty in cluster investigations, particularly in the area of breast cancer, is the long latent period. There have been a number of publications providing a discouraging picture regarding cancer cluster investigations. The possibility of learning from a cluster investigation, however, is greatly increased if the cancer involved is relatively rare and if it has a short latent period. Inflammatory breast cancer (IBC) fits these criteria and is worth pursuing because of the strong evidence that environmental factors play a major role. In this report we describe our experience with several clusters and the lessons learned which are now being utilized to improve investigation of future IBC clusters. The first IBC cluster that we evaluated was in 2000, when we were asked to investigate an apparent cluster of IBC in Castro Valley, California where three women in an office setting of 24 people were diagnosed with IBC in a ten month period from May 1999 to March 2000. Our investigation of this striking cluster did not yield a specific trigger for this cluster but it did indicate that the women involved all had at least two IBC risk factors that may well have made them susceptible to getting IBC. We are now investigating another apparent cluster in Texas and are aware of several others requiring careful consideration. We see a need for a consistent protocol for the evaluation of IBC clusters focusing on the laboratory investigation of environmental triggers, primarily infectious agents and chemical carcinogens.

Abstract P6-12-04: Risk factors for inflammatory breast cancer

Abstract Background: The 5-year survival rates for inflammatory breast cancer (IBC) are significantly lower than non-IBC, highlighting the importance of cancer prevention in IBC. We investigated the risk factors for IBC subtypes based on estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2neu) status to determine distinct etiological pathways. The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic at University of Texas MD Anderson Cancer Center (UTMDACC) treats the largest number of IBC patients in a single center. The center maintains a prospective, comprehensive epidemiology registry, through which we were able to conduct the largest single center case-control study on IBC. Methods: We identified 246 patients diagnosed with IBC using strict consensus criteria and 397 cancer free patients seen at the UTMDACC Dan L. Duncan Cancer prevention clinic. We used logistic regression to estimate the odds ratios (OR) and 95% confidence intervals (CI) for the associations between breast cancer reproductive and lifestyle risk factors and IBC tumor subtypes. The tumor subtypes of IBC patients were classified as ER-positive (ER+/PR+/Her2neu-), Her2neu-positive (Her2neu+) and triple negative (ER-/PR-/Her2neu-). Results: In age-adjusted univariate analysis, body mass index (BMI), history of smoking, number of children, age at first pregnancy, breastfeeding, menopausal status, and first degree family history of breast cancer were statistically significant associated with risk of IBC (p&amp;lt;0.05). In multivariable analysis of IBC tumor subtypes, compared to cancer free controls, patients with triple negative (OR = 3.73, 95% CI = 1.52 – 9.13) and Her2neu-positive (OR = 19.27, CI = 4.14 – 89.62) tumors were significantly more likely to have ≥ 2 vs 0-1 children. Patients with triple negative (OR = 0.19, 95% CI = 0.09 – 0.45) and ER-positive (OR = 0.42, CI = 0.19 – 0.88) tumors were significantly less likely to have a history of breastfeeding. Patients with ER-positive (OR = 5.02, CI = 2.29 – 10.99) tumors were also significantly more likely to have a history of smoking. Patients with triple negative (OR = 6.07, CI = 2.62 – 17.07), ER-positive (OR = 7.22, CI = 2.94 – 17.78) and Her2neu-positive (OR = 12.81, CI = 4.59 – 35.78) were more likely to be overweight or obese (BMI ≥ 25kg/m2). Conclusion: The associations identified suggest that overweight or obese status is an important modifiable risk factor for all IBC subtypes. Triple negative IBC share similar risk factors as non-IBC triple negative tumors with increasing number of children and lack of breastfeeding associated with increased risk. Interestingly lack of breastfeeding was also associated with ER-positive IBC tumors, and Her2neu-positive IBC tumors were associated with increasing number of children; two associations that have not been previously reported. Impact: These results highlight the importance of evaluating epidemiologic risk factors of IBC, which could lead to the identification of subtype specific prevention strategies. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-04.

Risk Factors for Inflammatory Breast Cancer and Other Invasive Breast Cancers

We investigated risk factors for inflammatory breast cancer (IBC), a rare, aggressive, and poorly understood breast cancer that is characterized by diffuse breast skin erythema and edema. We included 617 IBC case subjects in a nested case-control study from the Breast Cancer Surveillance Consortium database (1994-2009). We also included 1151 noninflammatory, locally advanced, invasive breast cancers with chest wall/breast skin involvement (LABC), 7600 noninflammatory invasive case subjects without chest wall/breast skin involvement (BC), and 93 654 control subjects matched to case subjects on age and year at diagnosis and mammography registry. We present estimates of rate ratios (RRs) and 95% confidence intervals (CI) from conditional logistic regression analyses for each case group vs control subjects based on multiply imputed datasets. First-degree family history of breast cancer and high mammographic breast density increased risk of IBC, LABC, and BC. High body mass index (BMI) increased IBC risk irrespective of menopausal status and estrogen receptor (ER) expression; rate ratios for BMI 30 and greater vs BMI less than 25 were 3.90 (95% CI = 1.50 to 10.14) in premenopausal women and 3.70 (95% CI = 1.98 to 6.94) in peri/postmenopausal women not currently using hormones. BMI 30 and greater slightly increased risk of ER-positive BC (RR = 1.40; 95% CI = 1.11 to 1.76). Statistically significant reductions in risk of ER-negative IBC with older age at first birth and of ER-positive IBC with higher education were not seen for LABC and BC of the same ER status. Different associations with BMI, age at first birth, and education between IBC and/or LABC and BC suggest a distinct etiology for IBC.

In Vitro Assessment of the Inflammatory Breast Cancer Cell Line SUM 149: Discovery of 2 Single Nucleotide Polymorphisms in the RNase L Gene

Background: Inflammatory breast cancer (IBC) is a rare, highly aggressive form of breast cancer. The mechanism of IBC carcinogenesis remains unknown. We sought to evaluate potential genetic risk factors for IBC and whether or not the IBC cell lines SUM149 and SUM190 demonstrated evidence of viral infection.Methods: We performed single nucleotide polymorphism (SNP) genotyping for 2 variants of the ribonuclease (RNase) L gene that have been correlated with the risk of prostate cancer due to a possible viral etiology. We evaluated dose-response to treatment with interferon-alpha (IFN-α); and assayed for evidence of the putative human mammary tumor virus (HMTV, which has been implicated in IBC) in SUM149 cells. A bioinformatic analysis was performed to evaluate expression of RNase L in IBC and non-IBC.Results: 2 of 2 IBC cell lines were homozygous for RNase L common missense variants 462 and 541; whereas 2 of 10 non-IBC cell lines were homozygous positive for the 462 variant (p= 0.09) and 0 of 10 non-IBC cell lines were homozygous positive for the 541 variant (p = 0.015). Our real-time polymerase chain reaction (RT-PCR) and Southern blot analysis for sequences of HMTV revealed no evidence of the putative viral genome.Conclusion: We discovered 2 SNPs in the RNase L gene that were homozygously present in IBC cell lines. The 462 variant was absent in non-IBC lines. Our discovery of these SNPs present in IBC cell lines suggests a possible biomarker for risk of IBC. We found no evidence of HMTV in SUM149 cells. A query of a panel of human IBC and non-IBC samples showed no difference in RNase L expression. Further studies of the RNase L 462 and 541 variants in IBC tissues are warranted to validate our in vitro findings.

8q24 Cancer Risk Allele Associated with Major Metastatic Risk in Inflammatory Breast Cancer

BackgroundAssociation studies have identified low penetrance alleles that participate to the risk of cancer development. The 8q24 chromosomal region contains several such loci involved in various cancers that have been recently studied for their propensity to influence the clinical outcome of prostate cancer. We investigated here two 8q24 breast and colon cancer risk alleles in the close vicinity of the MYC gene for their role in the occurrence of distant metastases.Methodology/Principal findingsA retrospective series of 449 patients affected with breast or colon adenocarcinoma was genotyped for the rs13281615 and/or rs6983267 SNPs. Statistical analyses were done using the survival package v2.30 in the R software v2.9.1. The two SNPs did not influence the development of distant metastases of colon cancer; rs6983267 showed a mild effect on breast cancer. However, this effect was greatly emphasized when considering inflammatory breast cancer (IBC) solely. Replicated on a larger and independent series of IBC the contribution of the genotype to the metastatic risk of IBC was found an independent predictor of outcome (p = 2e-4; OR 8.3, CI95∶2.6–33).Conclusions/SignificanceOur study shows first that the monitoring of this specific germline variation may add a substantial tool for IBC prognostication, an aggressive disease that evolves towards distant metastases much more frequently than non-IBC and for which no reliable prognostic factor is available in medical practice. Second, it more generally suggests that risk alleles, while associated with low susceptibility, could correlate with a high risk of metastasis.

Inflammatory breast cancer and body mass index.

No studies have investigated the etiology of inflammatory breast cancer (IBC), the most lethal form of breast cancer. Because high body mass index (BMI) is associated with decreased risk of premenopausal breast cancer but increased risk of postmenopausal breast cancer, we evaluated whether high BMI was a risk factor for IBC. In a case-comparison study, we matched by ethnicity and registration date 68 IBC patients treated at The University of Texas M.D. Anderson Cancer Center from 1985 to 1996 with 143 patients with non-IBC and 134 patients with cancer at sites other than the breast or reproductive tract (non-breast cancer). The non-breast cancer group was used in lieu of a population-based, healthy control group, which was not available. IBC patients were younger at menarche and the time of their first live birth than non-IBC and non-breast cancer patients. The proportion of premenopausal IBC patients was higher than the proportion of premenopausal women in the comparison groups, although differences were not significant. There were no differences in height, but IBC patients were heavier (77.6 kg) than non-IBC (70.0 kg) and non-breast cancer patients (68.0 kg). After adjusting for other factors, women in the highest BMI tertile (BMI > 26.65 kg/m2) relative to the lowest tertile (BMI < 22.27) had significantly increased IBC risk (IBC v non-IBC, odds ratio [OR] = 2.45, 95% confidence interval [CI] = 1.05 to 5.73; IBC v non-breast cancer, OR = 4.52, 95% CI = 1.85 to 11.04). This association was not significantly modified by menopausal status and was independent of age at menarche, family history of breast cancer, gravidity, smoking status, and alcohol use. Our investigation showed that high BMI was significantly associated with an increased risk of IBC. This association did not vary by menopausal status, although IBC patients were more likely to be premenopausal. Confirming our findings and identifying other IBC risk factors may provide directions for future research on the aggressive nature of IBC.