Women with BRCA1 or BRCA2 mutations have a high breast cancer (BC) risk. Breast density is an ind... more Women with BRCA1 or BRCA2 mutations have a high breast cancer (BC) risk. Breast density is an independent biomarker of BC risk. We demonstrated that deslorelin (D), a gonadotropin-releasing hormone agonist (GnRHA), reduced mammographic breast density among BRCA1 carriers (Weitzel, CCR 2007). We report here on correlative studies in a Phase II chemoprevention study of intranasal D plus low-dose add-back estradiol and testosterone for 10 months in 10 premenopausal high-risk women. Pre- and post-study measures included mammographic and MRI breast density; serum hormone levels; breast tissue gene expression by Affymetrix GeneChip Human Genome U133 Plus 2.0 Array; Q-PCR to validate the top genes; analysis of sera by 2D-PAGE and LC-MS/MS Mass Spectrometry, validated by a marker specific ELISA. Nine of 10 participants showed a mean reduction in MRI volumetric breast density of 17.3% (p=0.045), a mean reduction in MRI fibroglandular volume of 15.1% (p=0.041) and a mean reduction in mammogra...
BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To i... more BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854,
Background: Though germline TP53 pathogenic/likely pathogenic variants (PV) are associated with L... more Background: Though germline TP53 pathogenic/likely pathogenic variants (PV) are associated with Li–Fraumeni syndrome, many detected by multigene panels represent aberrant clonal expansion (ACE), most due to clonal hematopoiesis (CH). Discerning ACE/CH from germline variants and postzygotic mosaicism (PZM) is critically needed for risk assessment and management. Methods: Participants in the Li-Fraumeni & TP53 Understanding & Progress (LiFT UP) study with a TP53 PV were eligible. Demographics, personal/family cancer history, and clinical laboratory test reports were obtained. DNA from multiple tissues was analyzed using a custom QIAseq assay (ACE panel) that included TP53 and other CH-associated genes; the ACE panel and eyebrow follicles were assessed in a workflow to discern TP53 PV clinical categories. Results: Among 134 participants there was a significant difference for the age at diagnosis (P < 0.001), component cancers (P = 0.007), and clinical testing criteria (P < 0.001)...
Cancer Epidemiology, Biomarkers & Prevention, 2020
Background: The success of multisite collaborative research relies on effective data collection, ... more Background: The success of multisite collaborative research relies on effective data collection, harmonization, and aggregation strategies. Data Coordination Centers (DCC) serve to facilitate the implementation of these strategies. The utility of a DCC can be particularly relevant for research on rare diseases where collaboration from multiple sites to amass large aggregate datasets is essential. However, approaches to building a DCC have been scarcely documented. Methods: The Li-Fraumeni Exploration (LiFE) Consortium's DCC was created using multiple open source packages, including LAM/G Application (Linux, Apache, MySQL, Grails), Extraction-Transformation-Loading (ETL) Pentaho Data Integration Tool, and the Saiku-Mondrian client. This document serves as a resource for building a rare disease DCC for multi-institutional collaborative research. Results: The primary scientific and technological objective to create an online central repository into which data from all participating...
1514 Background: Germline TP53 mutations are associated with Li-Fraumeni syndrome (LFS). However,... more 1514 Background: Germline TP53 mutations are associated with Li-Fraumeni syndrome (LFS). However, approximately 20% of commercial laboratory multigene panel test (MGPT)-detected pathogenic TP53 variants represent aberrant clonal expansion (ACE), rather than a germline finding, and are often detected in individuals that lack classic features of LFS. Clonal hematopoiesis (CH) is a form of ACE, and in the absence of an abnormal hemogram is termed Clonal hematopoiesis of indeterminate potential (CHIP). CHIP is often associated with a pathogenic variant (PV) in hematopoietic pathway gene(s) at a variant allele frequency (VAF) less than expected for a heterozygous germline finding. The prevalence increases with age and exposure to chemotherapy. The presence of a skewed VAF is usually noted in a comment on a genetic test result, however, clinicians without genetic training often lack understanding of the comment and need strategies to discern the difference between germline findings, CHIP,...
e13030 Background: Older women with BC are less likely to undergo genetic cancer risk assessment ... more e13030 Background: Older women with BC are less likely to undergo genetic cancer risk assessment since a hallmark of hereditary BC is younger age at onset. Hence there are limited data regarding genetic risk assessment findings in older women with BC. We analyzed the clinical characteristics and germline variant profiles of women with history of BC referred for genetic counseling at age ≥ 65 years, enrolled in the Clinical Cancer Genomics Community Research Network registry. Methods: Women age ≥ 65 with a history of BC (invasive or ductal carcinoma in situ) who underwent genetic testing from 1997 to 2016 were included. The profile of those found to have BC-related pathogenic variants was analyzed. Demographic and clinical characteristics for those with and without germline variants were compared using Fisher’s test and x2statistics. Results: 1372 women age ≥ 65 with BC were identified. Genetic testing was performed in 75% (n = 1035), among whom 10.4% (n = 108) had a germline variant...
1518 Background: Eligibility for lung cancer screening is based largely on pack-years of smoking,... more 1518 Background: Eligibility for lung cancer screening is based largely on pack-years of smoking, missing many cases. To propose additional groups for screening, this observational study evaluated whether germline mutations associated with cancer risk accelerate onset of lung adenocarcinoma (LA) in ever- and never-smokers. Methods: Patients with LA and family history of cancer were recruited from our oncology clinic and the Clinical Cancer Genomics Community Research Network. With consent, blood samples were screened by large multi-gene panel for 4 categories of germline mutation [lung cancer-associated genes ( TP53, EGFR); BRCA2; other genes in Fanconi anemia (FA) pathway; other DNA repair genes]. Accelerated failure-time models of age at LA diagnosis, adjusted for sex, ethnicity, and packs per day, were constructed for never-smokers and ever-smokers. Statistical significance, at p<0.05 limited the False Discovery Rate to 5% across 8 hypotheses. Results: In never-smokers with LA...
Genetic Cancer Risk Assessment (GCRA) clinical referral and testing guidelines are limited for in... more Genetic Cancer Risk Assessment (GCRA) clinical referral and testing guidelines are limited for individuals and families with gastric cancer. In part, this is due to a lack of knowledge regarding hereditary gastric cancer susceptibility. The Clinical Cancer Genomics Community Research Network registry includes over 15,000 families seen for GCRA at City of Hope and 45 other collaborating sites. The purpose of this research was to identify variants conferring inherited gastric cancer susceptibility for individuals and families in our registry without previously known genetic predisposition. Adult research participants from our IRB-approved registry with a DNA sample and a personal history of gastric cancer were selected. Those with a previously identified genetic predisposition were excluded (n = 8). In families with more than one eligible individual, the individual with earliest onset of disease was selected. All histologies were included (i.e., intestinal and diffuse adenocarcinomas,...
Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2)... more Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. To identify mutation-specific cancer risks for carriers of BRCA1/2. Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. Mutations of BRCA1 or BRCA2. Breast and ovarian cancer risks. Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian c...
Journal of cancer education : the official journal of the American Association for Cancer Education, 2002
There is a gap in knowledge about hereditary cancer and genetic testing among primary care practi... more There is a gap in knowledge about hereditary cancer and genetic testing among primary care practitioners. Education is needed to enable identification and management of patients at high risk for cancer. A new cancer genetics curriculum was delivered through individual lectures and full-day conferences. Innovative marketing and conference organizational approaches were used to increase participation. The curriculum has been delivered to 7,400 health care professionals with diverse educational backgrounds. Conventional formats were successfully used to implement this new curriculum. CME evaluations indicated satisfaction with the programs and a clear need for and continued interest in cancer genetics applications.
Background-Prior studies have suggested that BRCA-related epithelial ovarian cancer (EOC) conveys... more Background-Prior studies have suggested that BRCA-related epithelial ovarian cancer (EOC) conveys improved survival compared to sporadic EOC, but few studies have studied differences between BRCA genotypes. We compared characteristics and outcome by genotype in BRCAassociated EOC. Methods-BRCA-associated EOC patients, between 01/30/1981 and 12/30/2008, were retrospectively identified through IRB-approved registry studies. Clinical characteristics, including event-free (EFS) and overall survival (OS), for BRCA1 vs. BRCA2 were examined. Results-197 cases were identified (148 BRCA1; 49 BRCA2); median follow-up was 63 months. BRCA2 patients were older (55.4 vs. 51.1 years; p<0.01) and had fewer poorlydifferentiated tumors (67% vs. 82%; p<0.05). No difference in EFS was observed. OS at 5-years was 75% in BRCA2 vs. 61% in BRCA1 patients; this was not statistically significant. A nonsignificant trend towards improved OS was observed in BRCA2 patients with advanced-stage disease (HR = 0.59, 95% CI 0.32-1.08).
Germline variants in the 3 0 untranslated region (3 0 UTR) of cancer genes disrupting microRNA (m... more Germline variants in the 3 0 untranslated region (3 0 UTR) of cancer genes disrupting microRNA (miRNA) regulation have recently been associated with cancer risk. A variant in the 3 0 UTR of the KRAS oncogene, referred to as the KRAS variant, is associated with both cancer risk and altered tumor biology. Here, we test the hypothesis that the KRAS variant can act as a biomarker of outcome in epithelial ovarian cancer (EOC), and investigate the cause of altered outcome in KRAS variant-positive EOC patients. As this variant seems to be associated with tumor biology, we additionally test the hypothesis that this variant can be directly targeted to impact cell survival. EOC patients with complete clinical data were genotyped for the KRAS variant and analyzed for outcome (n ¼ 536), response to neoadjuvant chemotherapy (n ¼ 125) and platinum resistance (n ¼ 306). Outcome was separately analyzed for women with known BRCA mutations (n ¼ 79). Gene expression was analyzed on a subset of tumors with available tissue. Cell lines were used to confirm altered sensitivity to chemotherapy associated with the KRAS variant. Finally, the KRAS variant was directly targeted through small-interfering RNA/miRNA oligonucleotides in cell lines and survival was measured. Postmenopausal EOC patients with the KRAS variant were significantly more likely to die of ovarian cancer by multivariate analysis (hazard ratio ¼ 1.67, 95% confidence interval: 1.09-2.57, P ¼ 0.019, n ¼ 279). Perhaps explaining this finding, EOC patients with the KRAS variant were significantly more likely to be platinum resistant (odds ratio ¼ 3.18, confidence interval: 1.31-7.72, P ¼ 0.0106, n ¼ 291). In addition, direct targeting of the KRAS variant led to a significant reduction in EOC cell growth and survival in vitro. These findings confirm the importance of the KRAS variant in EOC, and indicate that the KRAS variant is a biomarker of poor outcome in EOC likely due to platinum resistance. In addition, this study supports the hypothesis that these tumors have continued dependence on such 3 0 UTR lesions, and that direct targeting may be a viable future treatment approach.
Studies suggest that patients carrying a BRCA variant of uncertain significance (VUS) may have li... more Studies suggest that patients carrying a BRCA variant of uncertain significance (VUS) may have lingering confusion concerning results interpretation. Counseling for uninformative BRCAnegative (UN) results is thought to be more straightforward, despite the fact that both results lead to similar methods of empiric cancer risk counseling. This study compared surgical choices and perceptions between 71 patients with VUS results and 714 patients with UN results. All patients underwent genetic counseling because of a personal or family history of breast or ovarian cancer between 1997 and 2010, and completed a two-year follow-up survey. Risk-reducing mastectomy rates in both groups were 7% (p=1.00) and risk-reducing oophorectomy rates were 5% and 3%, respectively (p=0.42). The VUS group reported less cancer distress reduction than the UN group (23.0% versus 35.8%, respectively, p=.043). Over 90% of both groups found the counseling process helpful. Overall, the study suggests that VUS results disclosed in genetic counseling did not cause excessive surgery or exaggerated cancer distress, though patients with a VUS found counseling somewhat less informative or reassuring. Future research on communication of VUS results, including pre-and post-test counseling, is essential for full realization of the potential for genomic medicine.
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Young women at high... more Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Young women at high risk of breast and/or ovarian cancer due to a BRCA mutation need risk-reducing options that preserve childbearing capacity. Purpose: Correlate changes in breast tissue determined by magnetic resonance imaging (MRI) & mammography with ovarian hormone levels following GnRHA treatment. Methods: In this prospective phase 2 biomarker chemoprevention trial, 10 premenopausal high-risk women, mean age 29.4 (21-43), were treated with intranasal GnRHA (deslorelin), low-dose add-back estradiol & testosterone once daily for 10 months. MPA was given for 10 days starting Day 140. Serum hormone levels were measured pre-administration of study drugs on Day 1, 29, 169 & 300. All participants underwent mammography, breast MRI & breast biopsy before & after 300 days of treatment. Mammographic density was measured & compared to volumetric breast density from MRI at both time points for all participants & fibroglandular tissue volume was also determined. Results: Significant decreases (p < .05) were shown in estradiol (-61%) and testosterone (-41%) over time. Nine out of 10 participants showed a mean reduction in MRI volumetric breast density of 17.3% (p=0.045), a mean reduction in MRI fibroglandular volume of 15.1% (p=0.041) and a mean reduction in mammographic density of 31.9% (p=0.0033). Conclusion: Changes in breast tissue composition were significant after 10 months of hormonal chemoprevention, validating the proof of principle that density as a risk biomarker can be manipulated in BRCA carriers. We documented reduction in breast density by both mammographic and MRI assessment. While greater quantitative change in density was detected by mammography, MRI yields additional qualitative structural observations. Our findings confirm that MRI can be used to measure hormonal chemoprevention effects in women at high-risk of breast cancer. ![Figure][1] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3557. doi:1538-7445.AM2012-3557 [1]: pending:yes
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 29, 2017
We aimed to establish the maximum tolerated dose (MTD) of the poly (ADP-ribose) (PAR) polymerase ... more We aimed to establish the maximum tolerated dose (MTD) of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2-(BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment post-progression, and to correlate PAR levels with clinical outcome. <br /><br />Experimental Design:Phase I patients received carboplatin (AUC of 5-6, every 21 days), with escalating doses of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID) and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome. <br /><br />Results:Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia (MTD: veliparib 150 mg po BID and carbopl...
Women with triple negative breast cancer (TNBC) have a high prevalence of BRCA1 mutations, and cu... more Women with triple negative breast cancer (TNBC) have a high prevalence of BRCA1 mutations, and current clinical guidelines recommend genetic testing for patients with TNBC aged ≤60 years. However, studies supporting this recommendation have included few older women with TNBC. METHODS Genetic testing results from women aged >60 years with TNBC enrolled in the Clinical Cancer Genomics Community Research Network (CCGCRN) registry were included in this analysis. Prevalence of breast cancer-associated pathogenic variants (PVs) was compared across age groups. RESULTS We identified 151 women with TNBC aged >60 years (median 65 years; SD 5.3). Of these, 130 (86%) underwent genetic testing, and a breast cancer-associated PV was identified in 16 (12.3%; 95% CI 7-19): BRCA1 (n = 6), BRCA2 (n = 5), PALB2 (n = 2), ATM (n = 1) and RAD51C (n = 2). We found no differences in the proportion of patients with close blood relatives with breast (≤50 years) or ovarian cancer (any age) between PV carriers (37.5%) and non-carriers (34.2%) (p = 0.79). Among PV's carriers, the proportion of older women with a BRCA1 PV was lower when compared to younger women (37.5% vs 77.2%; p < 0.01). CONCLUSION Breast cancer-associated PVs were found in an important proportion of women aged >60 years with TNBC undergoing genetic testing, including greater representation of BRCA2. These results suggest that older women with TNBC should be offered genetic testing, and that their exclusion based on chronologic age alone may not be appropriate.
Background:BRCA mutations are responsible for a significant proportion of hereditary breast and o... more Background:BRCA mutations are responsible for a significant proportion of hereditary breast and ovarian cancers. However, other cancer susceptibility genes are also associated with an increased risk of developing breast cancer (BC). In Mexico, approximately 15% of patients with BC have been identified with BRCA mutations. Despite our growing understanding of BRCA mutations, the contribution and characterization of non-BRCA mutations in Mexican patients with a BC diagnosis remains unknown. We aimed to investigate the spectrum of BC-associated mutations among Mexican patients with BC referred for genetic cancer risk assessment (GCRA) in the multinational Clinical Cancer Genomics Community Research Network (CCGCRN). Methods: Mexican patients with a primary BC who were enrolled in the IRB-approved CCGCRN registry protocol and underwent genetic counseling and multigene panel testing (MGPT) were included. Pathogenic and likely pathogenic variants (PV) in genes associated with increased BC...
1536 Background: Current standard-of-care practice for genetic cancer risk assessment (GCRA) focu... more 1536 Background: Current standard-of-care practice for genetic cancer risk assessment (GCRA) focuses on single-gene testing for specific hereditary cancer syndromes. Next-generation sequencing (NGS) technologies recently became available for clinical applications. This study explored the perspectives and experiences of community-based clinicians regarding NGS testing for personalized GCRA. Methods: A 27-item survey was developed and administered online to 325 members of an interdisciplinary nationwide clinical cancer genetics community of practice. Results: Of 94 (29%) respondents, 25 (27%) have ordered at least one multi-gene panel and only 2 (2.1%) have ordered a whole exome or genome test from a commercial vendor for GCRA. Concerns about clinical utility, the challenge of interpreting and communicating results, lack of knowledge about and potential costs were most often cited as reasons for not pursuing NGS testing. Respondents were significantly more confident about their abilit...
Women with BRCA1 or BRCA2 mutations have a high breast cancer (BC) risk. Breast density is an ind... more Women with BRCA1 or BRCA2 mutations have a high breast cancer (BC) risk. Breast density is an independent biomarker of BC risk. We demonstrated that deslorelin (D), a gonadotropin-releasing hormone agonist (GnRHA), reduced mammographic breast density among BRCA1 carriers (Weitzel, CCR 2007). We report here on correlative studies in a Phase II chemoprevention study of intranasal D plus low-dose add-back estradiol and testosterone for 10 months in 10 premenopausal high-risk women. Pre- and post-study measures included mammographic and MRI breast density; serum hormone levels; breast tissue gene expression by Affymetrix GeneChip Human Genome U133 Plus 2.0 Array; Q-PCR to validate the top genes; analysis of sera by 2D-PAGE and LC-MS/MS Mass Spectrometry, validated by a marker specific ELISA. Nine of 10 participants showed a mean reduction in MRI volumetric breast density of 17.3% (p=0.045), a mean reduction in MRI fibroglandular volume of 15.1% (p=0.041) and a mean reduction in mammogra...
BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To i... more BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854,
Background: Though germline TP53 pathogenic/likely pathogenic variants (PV) are associated with L... more Background: Though germline TP53 pathogenic/likely pathogenic variants (PV) are associated with Li–Fraumeni syndrome, many detected by multigene panels represent aberrant clonal expansion (ACE), most due to clonal hematopoiesis (CH). Discerning ACE/CH from germline variants and postzygotic mosaicism (PZM) is critically needed for risk assessment and management. Methods: Participants in the Li-Fraumeni & TP53 Understanding & Progress (LiFT UP) study with a TP53 PV were eligible. Demographics, personal/family cancer history, and clinical laboratory test reports were obtained. DNA from multiple tissues was analyzed using a custom QIAseq assay (ACE panel) that included TP53 and other CH-associated genes; the ACE panel and eyebrow follicles were assessed in a workflow to discern TP53 PV clinical categories. Results: Among 134 participants there was a significant difference for the age at diagnosis (P < 0.001), component cancers (P = 0.007), and clinical testing criteria (P < 0.001)...
Cancer Epidemiology, Biomarkers & Prevention, 2020
Background: The success of multisite collaborative research relies on effective data collection, ... more Background: The success of multisite collaborative research relies on effective data collection, harmonization, and aggregation strategies. Data Coordination Centers (DCC) serve to facilitate the implementation of these strategies. The utility of a DCC can be particularly relevant for research on rare diseases where collaboration from multiple sites to amass large aggregate datasets is essential. However, approaches to building a DCC have been scarcely documented. Methods: The Li-Fraumeni Exploration (LiFE) Consortium's DCC was created using multiple open source packages, including LAM/G Application (Linux, Apache, MySQL, Grails), Extraction-Transformation-Loading (ETL) Pentaho Data Integration Tool, and the Saiku-Mondrian client. This document serves as a resource for building a rare disease DCC for multi-institutional collaborative research. Results: The primary scientific and technological objective to create an online central repository into which data from all participating...
1514 Background: Germline TP53 mutations are associated with Li-Fraumeni syndrome (LFS). However,... more 1514 Background: Germline TP53 mutations are associated with Li-Fraumeni syndrome (LFS). However, approximately 20% of commercial laboratory multigene panel test (MGPT)-detected pathogenic TP53 variants represent aberrant clonal expansion (ACE), rather than a germline finding, and are often detected in individuals that lack classic features of LFS. Clonal hematopoiesis (CH) is a form of ACE, and in the absence of an abnormal hemogram is termed Clonal hematopoiesis of indeterminate potential (CHIP). CHIP is often associated with a pathogenic variant (PV) in hematopoietic pathway gene(s) at a variant allele frequency (VAF) less than expected for a heterozygous germline finding. The prevalence increases with age and exposure to chemotherapy. The presence of a skewed VAF is usually noted in a comment on a genetic test result, however, clinicians without genetic training often lack understanding of the comment and need strategies to discern the difference between germline findings, CHIP,...
e13030 Background: Older women with BC are less likely to undergo genetic cancer risk assessment ... more e13030 Background: Older women with BC are less likely to undergo genetic cancer risk assessment since a hallmark of hereditary BC is younger age at onset. Hence there are limited data regarding genetic risk assessment findings in older women with BC. We analyzed the clinical characteristics and germline variant profiles of women with history of BC referred for genetic counseling at age ≥ 65 years, enrolled in the Clinical Cancer Genomics Community Research Network registry. Methods: Women age ≥ 65 with a history of BC (invasive or ductal carcinoma in situ) who underwent genetic testing from 1997 to 2016 were included. The profile of those found to have BC-related pathogenic variants was analyzed. Demographic and clinical characteristics for those with and without germline variants were compared using Fisher’s test and x2statistics. Results: 1372 women age ≥ 65 with BC were identified. Genetic testing was performed in 75% (n = 1035), among whom 10.4% (n = 108) had a germline variant...
1518 Background: Eligibility for lung cancer screening is based largely on pack-years of smoking,... more 1518 Background: Eligibility for lung cancer screening is based largely on pack-years of smoking, missing many cases. To propose additional groups for screening, this observational study evaluated whether germline mutations associated with cancer risk accelerate onset of lung adenocarcinoma (LA) in ever- and never-smokers. Methods: Patients with LA and family history of cancer were recruited from our oncology clinic and the Clinical Cancer Genomics Community Research Network. With consent, blood samples were screened by large multi-gene panel for 4 categories of germline mutation [lung cancer-associated genes ( TP53, EGFR); BRCA2; other genes in Fanconi anemia (FA) pathway; other DNA repair genes]. Accelerated failure-time models of age at LA diagnosis, adjusted for sex, ethnicity, and packs per day, were constructed for never-smokers and ever-smokers. Statistical significance, at p<0.05 limited the False Discovery Rate to 5% across 8 hypotheses. Results: In never-smokers with LA...
Genetic Cancer Risk Assessment (GCRA) clinical referral and testing guidelines are limited for in... more Genetic Cancer Risk Assessment (GCRA) clinical referral and testing guidelines are limited for individuals and families with gastric cancer. In part, this is due to a lack of knowledge regarding hereditary gastric cancer susceptibility. The Clinical Cancer Genomics Community Research Network registry includes over 15,000 families seen for GCRA at City of Hope and 45 other collaborating sites. The purpose of this research was to identify variants conferring inherited gastric cancer susceptibility for individuals and families in our registry without previously known genetic predisposition. Adult research participants from our IRB-approved registry with a DNA sample and a personal history of gastric cancer were selected. Those with a previously identified genetic predisposition were excluded (n = 8). In families with more than one eligible individual, the individual with earliest onset of disease was selected. All histologies were included (i.e., intestinal and diffuse adenocarcinomas,...
Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2)... more Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. To identify mutation-specific cancer risks for carriers of BRCA1/2. Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. Mutations of BRCA1 or BRCA2. Breast and ovarian cancer risks. Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian c...
Journal of cancer education : the official journal of the American Association for Cancer Education, 2002
There is a gap in knowledge about hereditary cancer and genetic testing among primary care practi... more There is a gap in knowledge about hereditary cancer and genetic testing among primary care practitioners. Education is needed to enable identification and management of patients at high risk for cancer. A new cancer genetics curriculum was delivered through individual lectures and full-day conferences. Innovative marketing and conference organizational approaches were used to increase participation. The curriculum has been delivered to 7,400 health care professionals with diverse educational backgrounds. Conventional formats were successfully used to implement this new curriculum. CME evaluations indicated satisfaction with the programs and a clear need for and continued interest in cancer genetics applications.
Background-Prior studies have suggested that BRCA-related epithelial ovarian cancer (EOC) conveys... more Background-Prior studies have suggested that BRCA-related epithelial ovarian cancer (EOC) conveys improved survival compared to sporadic EOC, but few studies have studied differences between BRCA genotypes. We compared characteristics and outcome by genotype in BRCAassociated EOC. Methods-BRCA-associated EOC patients, between 01/30/1981 and 12/30/2008, were retrospectively identified through IRB-approved registry studies. Clinical characteristics, including event-free (EFS) and overall survival (OS), for BRCA1 vs. BRCA2 were examined. Results-197 cases were identified (148 BRCA1; 49 BRCA2); median follow-up was 63 months. BRCA2 patients were older (55.4 vs. 51.1 years; p<0.01) and had fewer poorlydifferentiated tumors (67% vs. 82%; p<0.05). No difference in EFS was observed. OS at 5-years was 75% in BRCA2 vs. 61% in BRCA1 patients; this was not statistically significant. A nonsignificant trend towards improved OS was observed in BRCA2 patients with advanced-stage disease (HR = 0.59, 95% CI 0.32-1.08).
Germline variants in the 3 0 untranslated region (3 0 UTR) of cancer genes disrupting microRNA (m... more Germline variants in the 3 0 untranslated region (3 0 UTR) of cancer genes disrupting microRNA (miRNA) regulation have recently been associated with cancer risk. A variant in the 3 0 UTR of the KRAS oncogene, referred to as the KRAS variant, is associated with both cancer risk and altered tumor biology. Here, we test the hypothesis that the KRAS variant can act as a biomarker of outcome in epithelial ovarian cancer (EOC), and investigate the cause of altered outcome in KRAS variant-positive EOC patients. As this variant seems to be associated with tumor biology, we additionally test the hypothesis that this variant can be directly targeted to impact cell survival. EOC patients with complete clinical data were genotyped for the KRAS variant and analyzed for outcome (n ¼ 536), response to neoadjuvant chemotherapy (n ¼ 125) and platinum resistance (n ¼ 306). Outcome was separately analyzed for women with known BRCA mutations (n ¼ 79). Gene expression was analyzed on a subset of tumors with available tissue. Cell lines were used to confirm altered sensitivity to chemotherapy associated with the KRAS variant. Finally, the KRAS variant was directly targeted through small-interfering RNA/miRNA oligonucleotides in cell lines and survival was measured. Postmenopausal EOC patients with the KRAS variant were significantly more likely to die of ovarian cancer by multivariate analysis (hazard ratio ¼ 1.67, 95% confidence interval: 1.09-2.57, P ¼ 0.019, n ¼ 279). Perhaps explaining this finding, EOC patients with the KRAS variant were significantly more likely to be platinum resistant (odds ratio ¼ 3.18, confidence interval: 1.31-7.72, P ¼ 0.0106, n ¼ 291). In addition, direct targeting of the KRAS variant led to a significant reduction in EOC cell growth and survival in vitro. These findings confirm the importance of the KRAS variant in EOC, and indicate that the KRAS variant is a biomarker of poor outcome in EOC likely due to platinum resistance. In addition, this study supports the hypothesis that these tumors have continued dependence on such 3 0 UTR lesions, and that direct targeting may be a viable future treatment approach.
Studies suggest that patients carrying a BRCA variant of uncertain significance (VUS) may have li... more Studies suggest that patients carrying a BRCA variant of uncertain significance (VUS) may have lingering confusion concerning results interpretation. Counseling for uninformative BRCAnegative (UN) results is thought to be more straightforward, despite the fact that both results lead to similar methods of empiric cancer risk counseling. This study compared surgical choices and perceptions between 71 patients with VUS results and 714 patients with UN results. All patients underwent genetic counseling because of a personal or family history of breast or ovarian cancer between 1997 and 2010, and completed a two-year follow-up survey. Risk-reducing mastectomy rates in both groups were 7% (p=1.00) and risk-reducing oophorectomy rates were 5% and 3%, respectively (p=0.42). The VUS group reported less cancer distress reduction than the UN group (23.0% versus 35.8%, respectively, p=.043). Over 90% of both groups found the counseling process helpful. Overall, the study suggests that VUS results disclosed in genetic counseling did not cause excessive surgery or exaggerated cancer distress, though patients with a VUS found counseling somewhat less informative or reassuring. Future research on communication of VUS results, including pre-and post-test counseling, is essential for full realization of the potential for genomic medicine.
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Young women at high... more Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Young women at high risk of breast and/or ovarian cancer due to a BRCA mutation need risk-reducing options that preserve childbearing capacity. Purpose: Correlate changes in breast tissue determined by magnetic resonance imaging (MRI) & mammography with ovarian hormone levels following GnRHA treatment. Methods: In this prospective phase 2 biomarker chemoprevention trial, 10 premenopausal high-risk women, mean age 29.4 (21-43), were treated with intranasal GnRHA (deslorelin), low-dose add-back estradiol & testosterone once daily for 10 months. MPA was given for 10 days starting Day 140. Serum hormone levels were measured pre-administration of study drugs on Day 1, 29, 169 & 300. All participants underwent mammography, breast MRI & breast biopsy before & after 300 days of treatment. Mammographic density was measured & compared to volumetric breast density from MRI at both time points for all participants & fibroglandular tissue volume was also determined. Results: Significant decreases (p < .05) were shown in estradiol (-61%) and testosterone (-41%) over time. Nine out of 10 participants showed a mean reduction in MRI volumetric breast density of 17.3% (p=0.045), a mean reduction in MRI fibroglandular volume of 15.1% (p=0.041) and a mean reduction in mammographic density of 31.9% (p=0.0033). Conclusion: Changes in breast tissue composition were significant after 10 months of hormonal chemoprevention, validating the proof of principle that density as a risk biomarker can be manipulated in BRCA carriers. We documented reduction in breast density by both mammographic and MRI assessment. While greater quantitative change in density was detected by mammography, MRI yields additional qualitative structural observations. Our findings confirm that MRI can be used to measure hormonal chemoprevention effects in women at high-risk of breast cancer. ![Figure][1] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3557. doi:1538-7445.AM2012-3557 [1]: pending:yes
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 29, 2017
We aimed to establish the maximum tolerated dose (MTD) of the poly (ADP-ribose) (PAR) polymerase ... more We aimed to establish the maximum tolerated dose (MTD) of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2-(BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment post-progression, and to correlate PAR levels with clinical outcome. <br /><br />Experimental Design:Phase I patients received carboplatin (AUC of 5-6, every 21 days), with escalating doses of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID) and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome. <br /><br />Results:Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia (MTD: veliparib 150 mg po BID and carbopl...
Women with triple negative breast cancer (TNBC) have a high prevalence of BRCA1 mutations, and cu... more Women with triple negative breast cancer (TNBC) have a high prevalence of BRCA1 mutations, and current clinical guidelines recommend genetic testing for patients with TNBC aged ≤60 years. However, studies supporting this recommendation have included few older women with TNBC. METHODS Genetic testing results from women aged >60 years with TNBC enrolled in the Clinical Cancer Genomics Community Research Network (CCGCRN) registry were included in this analysis. Prevalence of breast cancer-associated pathogenic variants (PVs) was compared across age groups. RESULTS We identified 151 women with TNBC aged >60 years (median 65 years; SD 5.3). Of these, 130 (86%) underwent genetic testing, and a breast cancer-associated PV was identified in 16 (12.3%; 95% CI 7-19): BRCA1 (n = 6), BRCA2 (n = 5), PALB2 (n = 2), ATM (n = 1) and RAD51C (n = 2). We found no differences in the proportion of patients with close blood relatives with breast (≤50 years) or ovarian cancer (any age) between PV carriers (37.5%) and non-carriers (34.2%) (p = 0.79). Among PV's carriers, the proportion of older women with a BRCA1 PV was lower when compared to younger women (37.5% vs 77.2%; p < 0.01). CONCLUSION Breast cancer-associated PVs were found in an important proportion of women aged >60 years with TNBC undergoing genetic testing, including greater representation of BRCA2. These results suggest that older women with TNBC should be offered genetic testing, and that their exclusion based on chronologic age alone may not be appropriate.
Background:BRCA mutations are responsible for a significant proportion of hereditary breast and o... more Background:BRCA mutations are responsible for a significant proportion of hereditary breast and ovarian cancers. However, other cancer susceptibility genes are also associated with an increased risk of developing breast cancer (BC). In Mexico, approximately 15% of patients with BC have been identified with BRCA mutations. Despite our growing understanding of BRCA mutations, the contribution and characterization of non-BRCA mutations in Mexican patients with a BC diagnosis remains unknown. We aimed to investigate the spectrum of BC-associated mutations among Mexican patients with BC referred for genetic cancer risk assessment (GCRA) in the multinational Clinical Cancer Genomics Community Research Network (CCGCRN). Methods: Mexican patients with a primary BC who were enrolled in the IRB-approved CCGCRN registry protocol and underwent genetic counseling and multigene panel testing (MGPT) were included. Pathogenic and likely pathogenic variants (PV) in genes associated with increased BC...
1536 Background: Current standard-of-care practice for genetic cancer risk assessment (GCRA) focu... more 1536 Background: Current standard-of-care practice for genetic cancer risk assessment (GCRA) focuses on single-gene testing for specific hereditary cancer syndromes. Next-generation sequencing (NGS) technologies recently became available for clinical applications. This study explored the perspectives and experiences of community-based clinicians regarding NGS testing for personalized GCRA. Methods: A 27-item survey was developed and administered online to 325 members of an interdisciplinary nationwide clinical cancer genetics community of practice. Results: Of 94 (29%) respondents, 25 (27%) have ordered at least one multi-gene panel and only 2 (2.1%) have ordered a whole exome or genome test from a commercial vendor for GCRA. Concerns about clinical utility, the challenge of interpreting and communicating results, lack of knowledge about and potential costs were most often cited as reasons for not pursuing NGS testing. Respondents were significantly more confident about their abilit...
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Papers by Sharon Sand