Summary An antimacrophage serum prepared in a rabbit injected with BALB/c mouse peritoneal macrophages detected a macrophage‐specific antigen on peritoneal macrophages and a second macrophage antigen shared with polymorphonuclear leucocytes and fibroblasts. The macrophage‐specific antigen was present in the four mouse strains examined, in one of three strains of rats and in guinea‐pigs The specific peritoneal macrophage antigen and the antigen shared with polymorphs were detectable only after culture of macrophages from bone marrow, spleen, Lung and pleural cavity, isolated Kupffer cells, whether cultured or otherwise, showed no reaction with the antisera. Ultrastructurally, the specific macrophage antigen was localized to the cell membrane as discrete electron‐dense deposits of 25‐40 nm, regularly distributed 30‐50 nm apart.
Background: Hereditary cancer gene panel testing can assess breast cancer risk for women with significant family histories. The Claus risk model is another method to determine which women qualify for annual breast MRIs based on family history, and can be used for those with BRCA negative status or for those who do not qualify for BRCA testing. In July 2014, Kaiser Permanente Southern California, a large integrated health plan, began using hereditary cancer panels comprised of moderate and high-risk breast cancer genes (GeneDx). At the time of implementation, no clinical management guidelines existed for patients with PV/LPV in moderate risk genes. In March 2015, the National Comprehensive Cancer Network (NCCN) amended the Genetic/Familial High Risk Assessment Breast and Ovarian guidelines to include breast cancer surveillance for patients with PV/LPV in moderate risk genes including ATM, CHEK2 and PALB2. Objective: To determine if the identification of PV/LPV in moderate risk genes versus Claus model calculation increases the number of women warranting breast MRI in a managed care setting. Methods: We performed a retrospective query of our gene panel results from 6/2014 to 5/2015 to identify patients with ATM, CHEK2 and PALB2 PV/LPV. Personal and family histories were obtained from the test requisitions. Patients with personal histories of breast cancer were excluded from analysis. We calculated the lifetime breast cancer risk using the Claus model for all eligible female patients with a moderate risk gene PV/LPV. To calculate the risk, the Claus model included family history of breast cancer in first and second-degree relatives. A lifetime breast cancer risk of >20% indicates "high" risk. Results: A total of 19 female patients without breast cancer had a PV/LPV detected in a moderate risk gene (ATM, CHEK2, and PALB2. Claus model calculation was feasible in 12 patients. Of these 12, 4 had a PV/LPV in ATM, 6 in CHEK2 and 2 in PALB2. Only one out of these 12 women was identified with >20% risk of breast cancer based on the Claus model, and was recommended a breast MRI. A review of electronic medical records (EMR) notes to date (June 1, 2015) revealed that breast MRI was recommended for 10 of the 12 patients above, and completed in 6. MRI identified a suspicious breast lesion in one patient. Follow-up tests and lumpectomy revealed atypical ductal hyperplasia and she will be followed with annual MRI and mammogram. The remaining 2 of12 women had no mention of MRI in their EMR, and will be flagged for follow-up to determine MRI status. Conclusions: Eleven out of 12 women with a PV/LVP in a moderate risk gene would not have been identified as having an increased breast cancer risk by the Claus model. In our small sample, utilization of a High/Moderate Risk Gene Panel identified more patients potentially warranting enhanced breast cancer surveillance with annual breast MRI than the Claus model. This finding suggests that the use of hereditary cancer gene panel testing may impact the medical management of women with a familial risk for breast cancer. Larger studies with outcome data are needed to determine optimal surveillance guidelines. Citation Format: Alvarado M, Tiller GE, Kershberg H, Solomon SR, Mullineaux L, Haque R. Women without significant claus model breast cancer risks may warrant breast MRI when a pathogenic/likely-pathogenic variant (PV/LPV) is detected in a hereditary cancer moderate risk gene. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-26.
BACKGROUND: Controversy exists whether women newly diagnosed with triple negative breast cancer (TNBC) should be referred to genetic counseling as they may be more likely to be BRCA carriers. However, prior studies included small numbers of carriers and their results have had limited influence on practice guidelines. The objective of this study was to determine the association of breast cancer molecular subtype and BRCA status in a large group of medically insured women. METHODS: We examined a cohort of 2,105 women with breast cancer history tested for BRCA mutations in a large California health plan from 1997–2011. BRCA test results were recorded in the health plan's clinical genetics registry. Of the 2,105 breast cancer patients, 249 were BRCA mutation carriers (143 BRCA1 carriers, and 106 BRCA2 carriers). We conducted data linkages of all patients with the health plan's NCI-SEER affiliated tumor registry and identified ER, PR, and HER2. HER2 status was also captured from pathology reports using natural language processing. ER, PR, and HER2 status were assessed by immunohistochemical or FISH techniques. Patients were classified into four main biologic subtypes: triple negative (ER−/PR−/HER2−); luminal A (ER+ and/or PR+/HER2−); luminal B (ER+ and/or PR+/HER2+); and HER2-enriched (HER2+/ER−). We examined the association between molecular subtypes (collapsed into TNBC vs. non TNBC categories) and BRCA1/2 mutation status using contingency table analyses. P-values (two-sided) were estimated using chi-square analysis. Multivariable logistic regression was used to estimated adjusted odds ratios (OR) and 95% confidence intervals. RESULTS: TNBC subtype was strongly associated with BRCA status (P < 0.0001). Women with TNBC tumors were five-fold more likely to be BRCA carriers than women who had non-TNBC breast tumors (OR = 5.6, 95% CI: 4.1–7.5). Specifically, the association of TNBC with BRCA1 was more robust (OR = 12.2, 95% CI: 8.3–17.9). Adjusting for age and stage of breast cancer diagnosis and race/ethnicity did not materially modify the association between TNBC and BRCA1 status. TNBC was not associated with BRCA2 status (OR = 1.6, 95% CI: 0.9–2.7). CONCLUSION: TNBC was strongly associated with BRCA1 status, but not with BRCA2 status. Statistically significant numbers of patients with BRCA mutations have a TNBC profile. These patients should therefore be referred to clinical genetics for further evaluation and possible testing. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-08-06.
Background: Next generation cancer gene panel testing is fairly new in clinical practice. Little is known about the diagnostic yield of multigene cancer panel testing in community based hospitals. Objective: To describe characteristics of a diverse cohort who underwent high/moderate risk multigene panel testing for either a personal or a family history of cancer in a large health plan, and report the proportion of pathogenic/likely pathogenic variants (PV/LPV) and variants of unknown clinical significance (VUS) by race/ethnicity. Methods: Subjects included all 586 female patients who were referred for genetic counseling and underwent multigene panel testing between July 2014 and January 2015. Based on a literature review, the custom-designed high/moderate risk gene panel included 20 cancer susceptibility genes (described below). All tests were performed by the same commercial laboratory (GeneDx). Results: Of the 586 women, 78 (13.3%) tested positive PV/LPV316 (53.9%) tested negative; and 192 (32.8%) carried one or more VUS. Age at testing ranged from 22-81 years (median 50 years). More women with PV/LPV results tended to be obese than those who tested negative (39.7% vs. 31.2%), and had greater comorbidity (Charlson Index of >3, 35.9% vs. 33.2%). Of 586 women, 305 (52.0%) had a cancer diagnosis, mainly first primary breast cancer (n=290, 95.1%), while some also had a second primary breast cancer (n=67, 11.4%). Of the 305 women with cancer, 131 (42.9%) were diagnosed prior to the multigene testing implementation (1987-2013), while 174 (57.1%) were diagnosed after implementation. The cohort was diverse in terms of race/ethnicity: Western/Northern European (31.2%), Latina/Caribbean (30.0%), Asian (14.8%), African-American (7.2%), Ashkenazi Jewish (6.3%), Native American (5.9%), and other (14.9%) (percent exceeds 100% due to mixed race/ethnicity). Of the 192 women who carried a VUS, 60.4% were Western/Northern European, and 46.4% were Latina/Caribbean. Pathogenic or likely pathogenic mutations were higher in Latina /Caribbean women (37.2%), followed by Western/Northern European (26.7%), and African (10.3%). We identified a total of 84 pathogenic mutations among the 78 women with PV/LPV in the following genes: BRCA1 (n=22), BRCA2 (n=17), MUTYH (n=16; all heterozygous), CHEK2 (n=9), ATM (n=4), PALB2 (n=4), PMS2 (n=3), MLH1 (n=2), VHL (n=2), and one mutation in each of the following genes: APC, CDH1, PTEN, TP53, and STK11. VUS were detected in 192 patients (32.7%) of the 586 tested. VUS in ATM (n=57), APC (n=32) and CHEK2 (n=25) comprised 59.4% of all VUS detected. Discussion: The large percent of VUS was surprising, given that our panel included only high/moderate risk cancer genes. The over-representation of BRCA1/2 among all mutations (45.1%) likely reflected a greater proportion of patients referred for genetic counseling with a personal and/or family breast cancer history. Given that 35% of our positive results were dominant-acting pathogenic or suspected pathogenic mutations, our results suggest that multigene cancer panel testing is an appropriate method for detecting germline mutations in a high-risk cohort in a managed care setting. Citation Format: Haque R, Alvarado M, Ahmed SA, Chung J, Tiller GE. Implementation of next generation cancer gene panel testing in a large HMO. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-04.
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