Sarah Asad | Ohio State University (original) (raw)

Papers by Sarah Asad

JCO Precision Oncology

PURPOSE To determine whether specific somatic copy-number alterations detectable in circulating t... more PURPOSE To determine whether specific somatic copy-number alterations detectable in circulating tumor DNA (ctDNA) from patients with metastatic triple-negative breast cancer (mTNBC) are associated with sensitivity to platinum chemotherapy. MATERIALS AND METHODS In this secondary analysis of a large cohort of patients with mTNBC whose ctDNA underwent ultralow-pass whole-genome sequencing, tumor fraction and somatic copy-number alterations were derived with the ichorCNA algorithm. Seventy-two patients were identified who had received a platinum-based chemotherapy regimen in the metastatic setting. Gene-level copy-number analyses were performed with GISTIC2.0. Cytobands were associated with progression-free survival (PFS) to platinum chemotherapy using Cox proportional hazards models. The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium data sets were interrogated for frequency of significant cytobands in primary triple-negative breast cancer (pTNBC)...

Journal of Clinical Oncology, 2021

1025 Background: Analysis of circulating tumor DNA (ctDNA) over time allows non-invasive evaluati... more 1025 Background: Analysis of circulating tumor DNA (ctDNA) over time allows non-invasive evaluation of tumor genomic evolution. We characterize changes in tumor fraction (TFx), somatic copy number alterations (SCNAs), and somatic mutations (muts) over time in patients (pts) with BRCA1/2 muts and metastatic breast cancer (mBC) who received a PARP inhibitor (PARPi) or platinum chemotherapy. Specifically, we seek to identify the frequency of BRCA1/2 reversion muts. Methods: Pts with mBC and germline or somatic BRCA1/2 muts were identified on a banking protocol of prospectively-collected serial samples of blood and plasma. Control pts without a BRCA1/2 mut were matched 2:1 by age and hormone receptor (HR) status. Ultra-low-pass whole genome sequencing (ULPWGS) with 0.1x depth was performed on all plasma samples (n = 103) and the ichorCNA algorithm was used to determine TFx and SCNAs. Targeted panel sequencing (TPS) of 402 cancer-related genes was performed at 10,000x depth on plasma sam...

Cancer Research, 2020

Background: Little is known regarding the effect of somatic tumor genomic testing on patient perc... more Background: Little is known regarding the effect of somatic tumor genomic testing on patient perceptions and psychological well-being. We previously demonstrated that patient perceptions of care can be negatively affected if their next cancer treatment is not supported by the genomic test. To further understand this, we investigated psychological effects of genomic testing, as well as sociodemographic and genomic comprehension factors that may attenuate these effects. Methods: In a prospective, single institution, single-arm trial, patients with metastatic breast cancer underwent next-generation sequencing (NGS) using Foundation Medicine at study entry, with sequencing results released to providers at time of next disease progression. We evaluated patient survey data before and after NGS, including questions about psychosocial characteristics, genetic comprehension, and perceived risks and expectations of the genomic testing. We evaluated psychosocial characteristics using 4 validat...

Cancer Research, 2020

Background: Triple-negative breast cancer (TNBC) accounts for a disproportionate amount of poor o... more Background: Triple-negative breast cancer (TNBC) accounts for a disproportionate amount of poor outcomes among breast cancers. A subset of TNBCs demonstrates an aggressive course with marked chemoresistance, rapid distant metastatic spread, and poor survival. The clinicopathologic and sociodemographic features associated with rapid relapse among TNBCs remain poorly understood. Primary Objective: To evaluate the relationship between clinicopathologic and sociodemographic features with rapid relapse in TNBC (rrTNBC). Methods: This large multi-institutional study analyzed a cohort of breast cancer patients diagnosed with TNBC who received treatment at one of ten academic centers that previously participated in a National Comprehensive Cancer Network (NCCN) outcomes database between 1998 and 2012. We defined rrTNBC as a distant metastatic recurrence event or death from any cause ≤24 months after diagnosis. We included patients with ≥2 years follow-up or had suffered a survival event wit...

Introduction: Cancer and its treatment has been shown to expose patients to higher cardiovascular... more Introduction: Cancer and its treatment has been shown to expose patients to higher cardiovascular risk compared to normal population. Hypothesis: To determine the trends of out of hospital cardiac ...

Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease and we have previousl... more Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease and we have previously shown that rapid relapse of TNBC is associated with distinct sociodemographic features. We hypothesized that rapid versus late relapse in TNBC is also defined by distinct clinical and genomic features of primary tumors. Methods: Using three publicly-available datasets, we identified 453 patients diagnosed with primary TNBC with adequate follow-up to be characterized as ‘rapid relapse’ (rrTNBC; distant relapse or death ≤2 years of diagnosis), ‘late relapse’ (lrTNBC; > 2 years) or ‘no relapse’ (nrTNBC: > 5 years no relapse/death). We explored basic clinical and primary tumor multi-omic data, including whole transcriptome (n = 453), and whole genome copy number and mutation data for 171 cancer-related genes (n = 317). Association of rapid relapse with clinical and genomic features were assessed using Pearson chi-squared tests, t-tests, ANOVA, and Fisher exact tests. We evaluated log...

Journal of the National Comprehensive Cancer Network

Background: Triple-negative breast cancer (TNBC) accounts for disproportionately poor outcomes in... more Background: Triple-negative breast cancer (TNBC) accounts for disproportionately poor outcomes in breast cancer, driven by a subset of rapid-relapse TNBC (rrTNBC) with marked chemoresistance, rapid metastatic spread, and poor survival. Our objective was to evaluate clinicopathologic and sociodemographic features associated with rrTNBC. Methods: We included patients diagnosed with stage I–III TNBC in 1996 through 2012 who received chemotherapy at 1 of 10 academic cancer centers. rrTNBC was defined as a distant metastatic recurrence event or death ≤24 months after diagnosis. Features associated with rrTNBC were included in a multivariable logistic model upon which backward elimination was performed with a P24 months), we found that insurance type and young age remained significant. Conclusions: Timing of relapse in TNBC is associated with stage of disease and distinct sociodemographic features, including insurance type, income, and age at diagnosis.

Genome Medicine

Background Circulating tumor DNA (ctDNA) offers minimally invasive means to repeatedly interrogat... more Background Circulating tumor DNA (ctDNA) offers minimally invasive means to repeatedly interrogate tumor genomes, providing opportunities to monitor clonal dynamics induced by metastasis and therapeutic selective pressures. In metastatic cancers, ctDNA profiling allows for simultaneous analysis of both local and distant sites of recurrence. Despite the promise of ctDNA sampling, its utility in real-time genetic monitoring remains largely unexplored. Methods In this exploratory analysis, we characterize high-frequency ctDNA sample series collected over narrow time frames from seven patients with metastatic triple-negative breast cancer, each undergoing treatment with Cabozantinib, a multi-tyrosine kinase inhibitor (NCT01738438, https://clinicaltrials.gov/ct2/show/NCT01738438). Applying orthogonal whole exome sequencing, ultra-low pass whole genome sequencing, and 396-gene targeted panel sequencing, we analyzed 42 plasma-derived ctDNA libraries, representing 4–8 samples per patient wi...

Journal of the American College of Surgeons

Annals of Surgical Oncology

A subset of triple-negative breast cancer (TNBC) is characterized by aggressive disease, rapid re... more A subset of triple-negative breast cancer (TNBC) is characterized by aggressive disease, rapid relapse, and mortality within 24 months of diagnosis, termed “rapid relapse” TNBC (rrTNBC). The objective of this study is to define the association between sociodemographic variables and surgical management among rrTNBC patients in the Surveillance, Epidemiology and End Results (SEER) Program. TNBC patients diagnosed from January 1, 2010 to December 31, 2014 with local or regional disease were identified in SEER. Patients were stratified as rrTNBC, defined as disease specific mortality ≤ 24 months after diagnosis, and non-rrTNBC. Chi-squared tests, t tests, and multivariable logistic regression were used to assess the association of rapid relapse with sociodemographic variables and surgical management. The cohort included 8% (1378/17,369) rrTNBCs. A higher proportion of rrTNBC patients had no surgery (11.7%) compared with non-rrTNBC (2.6%). Omission of axillary staging among patients who had surgery was 6.2% rrTNBC versus 4.5% non-rrTNBC. Black race (odds ratio [OR] 1.22, 95% confidence interval [CI] 1.05–1.43; p = 0.01; white ref), Medicaid or no insurance (Medicaid OR 1.53, 95% CI 1.31–1.79; p < 0.001; no insurance OR 1.74, 95% CI 1.31–2.32; p < 0.001; private ref), single status (OR 1.19, 95% CI 1.01–1.39; p = 0.03; married ref), no breast (OR 2.35, 95% CI 1.77–3.11; p < 0.001; mastectomy ref), and no axillary surgery (OR 1.44, 95% CI 1.13–1.83; p = 0.003 axillary surgery ref) were associated with rapid relapse. Medicaid or no insurance, single status, black race, and no surgery are associated with higher odds of rrTNBC in SEER. These results indicate an interplay between socioeconomic factors, clinical and genomic variables may be disproportionately contributing to worse outcomes among a subset of TNBC patients.

JAMA Oncology

Importance Adding carboplatin to standard neoadjuvant chemotherapy (NAC) in triple-negative breas... more Importance Adding carboplatin to standard neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) likely benefits a subset of patients; however, determinants of benefit are poorly understood. Objective To define the association of molecular subtype, tumor proliferation, and immunophenotype with benefit of carboplatin added to NAC for patients with stages II to III TNBC. Design, Setting, and Participants This was a prespecified secondary analysis of a phase 3, double-blind, randomized clinical trial (BrighTNess) that enrolled 634 women across 145 centers in 15 countries. Women with clinical stages II to III TNBC who had undergone pretreatment biopsy were eligible to participate. Whole transcriptome RNA sequencing was performed on the biopsy specimens. The prespecified end point was association of pathologic complete response (pCR) with gene expression-based molecular subtype, with secondary end points investigating established signatures (proliferation, immune) and exploratory analyses of immunophenotype. Data were collected from April 2014 to March 2016. The study analyses were performed from January 2018 to March 2019. Interventions Neoadjuvant chemotherapy with paclitaxel followed by doxorubicin and cyclophosphamide, or this same regimen with carboplatin or carboplatin plus veliparib. Main Outcomes and Measures Association of gene expression-based molecular subtype (PAM50 and TNBC subtypes) with pCR. Results Of the 634 women (median age, 51 [range, 22-78] years) enrolled in BrighTNess, 482 (76%) patients had evaluable RNA sequencing data, with similar baseline characteristics relative to the overall intention-to-treat population. Pathologic complete response was significantly more frequent in PAM50 basal-like vs nonbasal-like cancers overall (202 of 386 [52.3%] vs 34 of 96 [35.4%]; P = .003). Carboplatin benefit was not significantly different in basal-like vs nonbasal-like subgroups (P = .80 for interaction). In multivariable analysis, proliferation (hazard ratio, 0.36; 95% CI, 0.21-0.61; P < .001) and immune (hazard ratio, 0.62; 95% CI, 0.49-0.79; P < .001) signatures were independently associated with pCR. Tumors above the median for proliferation and immune signatures had the highest pCR rate (84 of 125; 67%), while those below the median for both signatures had the lowest pCR rate (42 of 125; 34%). Exploratory gene expression immune analyses suggested that tumors with higher inferred CD8+ T-cell infiltration may receive greater benefit with addition of carboplatin. Conclusions and Relevance In this secondary analysis of a randomized clinical trial, triple-negative breast cancer subtyping revealed high pCR rates in basal-like and immunomodulatory subsets. Analysis of biological processes related to basal-like and immunomodulatory phenotypes identified tumor cell proliferation and immune scores as independent factors associated with achieving pCR; the benefit of carboplatin on pCR was seen across all molecular subtypes. Further validation of immunophenotype with existing biomarkers may help to escalate or de-escalate therapy for patients with TNBC. Trial Registration ClinicalTrials.gov Identifier: NCT02032277.

Clinical Research (Excluding Clinical Trials)

Copy number aberrations (CNAs) are gains and losses of large genomic segments present across most... more Copy number aberrations (CNAs) are gains and losses of large genomic segments present across most cancer types and are a hallmark of cancer genomic alterations. However, the processes underlying CNAs and characteristic patterns of CNAs are poorly understood. Using single nucleotide variant (SNV) data, bioinformatic advances have identified underlying mutational signatures resulting from distinct mutational processes. Mutational signatures have led to a variety of discoveries, several of which are being investigated in clinical management of cancer. The development of algorithms able to uncover similar signatures for CNAs, rather than SNVs, is still in its infancy. Here we present an analysis package for the R programming language called CNSigs that allows for the robust and reproducible derivation of copy number signatures. Based on a list of extracted copy number features previously verified in ovarian cancer, we utilize mixed model approaches and non-negative matrix factorization to derive CNA signatures across cancer types. The development of a package to derive signatures from copy number data allows further investigation of underlying processes that may be responsible for these CNA fingerprints. To verify the reproducibility of the signatures, we derived signatures from two independent breast cancer datasets that use distinct copy number segmentation approaches. From these independent datasets we were able to recover the same signatures with high accuracy. We identified five signatures that are distinct from known breast cancer receptor-based or expression-based subtypes, yet reveal unique associations with underlying mutations, mutational processes, and transcriptional programs. To validate robustness, we applied the pipeline to 11 different cancer types from the TCGA dataset and showed that we were able to derive signatures from all of these cancer types of varying sample sizes. We identified certain signatures that cut across tumor types, while others are distinct to individual cancers. This work lays the groundwork for further analysis into the underlying molecular processes leading to these copy number signatures seen across cancer types. The CNSigs package also allows researchers to easily analyze their own samples to look for signatures in their copy number profiles and to compare these to signatures previously derived for their cancer type. Citation Format: David Tallman, Sinclair Stockard, Zachary T. Weber, Sarah Asad, Katharine Collier, Elizabeth Adams, Jerome Bey, Daniel G. Stover. CNSigs: An R package for the identification of copy number signatures [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5471.

BMC Cancer

Background To assess metastatic breast cancer (MBC) patient psychological factors, perceptions, a... more Background To assess metastatic breast cancer (MBC) patient psychological factors, perceptions, and comprehension of tumor genomic testing. Methods In a prospective, single institution, single-arm trial, patients with MBC underwent next-generation sequencing at study entry with sequencing results released at progression. Patients who completed surveys before undergoing sequencing were included in the present secondary analysis (n = 58). We administered four validated psychosocial measures: Center for Epidemiologic Studies Depression Scale, Beck Anxiety Inventory, Trust in Physician Scale, and Communication and Attitudinal Self-Efficacy scale for Cancer. Genetic comprehension was assessed using 7-question objective and 6-question subjective measures. Longitudinal data were assessed (n = 40) using paired Wilcoxon signed rank and McNemar’s test of agreement. Results There were no significant differences between the beginning and end of study in depression, anxiety, physician trust, or ...

JCO Precision Oncology

PURPOSE To evaluate the impact of targeted DNA sequencing on selection of cancer therapy for pati... more PURPOSE To evaluate the impact of targeted DNA sequencing on selection of cancer therapy for patients with metastatic breast cancer (MBC). PATIENTS AND METHODS In this prospective, single-center, single-arm trial, patients with MBC were enrolled within 10 weeks of starting a new therapy. At enrollment, tumor samples underwent next-generation sequencing for any of 315 cancer-related genes to high depth (> 500×) using FoundationOne CDx. Sequencing results were released to providers at the time of disease progression, and physician treatment recommendations were assessed via questionnaire. We evaluated three prespecified questions to assess patients’ perceptions of genomic testing. RESULTS In all, 100 patients underwent genomic testing, with a median of five mutations (range, 0 to 13 mutations) detected per patient. Genomic testing revealed one or more potential therapies in 98% of patients (98 of 100), and 60% of patients (60 of 100) had one or more recommended treatments with leve...

ABSTRACTPurposeTo assess metastatic breast cancer (MBC) patient perceptions and comprehension of ... more ABSTRACTPurposeTo assess metastatic breast cancer (MBC) patient perceptions and comprehension of tumor genomic testing and to evaluate associations with psychological wellbeing.MethodsIn a prospective, single institution, single-arm trial, patients with MBC underwent next-generation sequencing at study entry, with sequencing results released at progression. Patients who completed surveys before undergoing sequencing were included in the study (n=58). We administered four validated psychosocial measures: Center for Epidemiologic Studies Depression Scale, Beck Anxiety Inventory, Trust in Physician Scale, and Communication and Attitudinal Self-Efficacy scale for Cancer. Genetic comprehension was assessed using 7-question objective and 6-question subjective measures. Longitudinal data were assessed using paired Wilcoxon signed rank and McNemar’s test of agreement.ResultsThere were no significant differences between the beginning and end of study in depression, anxiety, physician trust, ...

ABSTRACTPurposeMetastatic relapse of triple-negative breast cancer (TNBC) within 2 years of diagn... more ABSTRACTPurposeMetastatic relapse of triple-negative breast cancer (TNBC) within 2 years of diagnosis is associated with particularly aggressive disease and a distinct clinical course relative to TNBCs that relapse beyond 2 years. We hypothesized that rapid relapse TNBCs (rrTNBC; metastatic relapse or death <2 years) reflect unique genomic features relative to late relapse (lrTNBC; >2 years).Patients and MethodsWe identified 453 primary TNBCs from three publicly-available datasets and characterized each as rrTNBc, lrTNBC, or ‘no relapse’ (nrTNBC: no relapse/death with at least 5 years follow-up). We compiled primary tumor clinical and multi-omic data, including transcriptome (n=453), copy number alterations (CNAs; n=317), and mutations in 171 cancer-related genes (n=317), then calculated published gene expression and immune signatures.ResultsPatients with rrTNBC were higher stage at diagnosis (Chi-square p<0.0001) while lrTNBC were more likely to be non-basal PAM50 subtype ...

Journal of Clinical Oncology

510 Background: In TNBC, the interplay between immunophenotype, tumor proliferation (prolif) and ... more 510 Background: In TNBC, the interplay between immunophenotype, tumor proliferation (prolif) and achievement of pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) remains unknown. Methods: RNA seq was performed on pre-tx research biopsies of stage II/III TNBC enrolled in BrighTNess. NAC regimens included paclitaxel alone or with carboplatin (Cb) or Cb plus veliparib, followed by AC. Computational analysis included subtyping (i.e. PAM50, Pietenpol), prolif (PAM50) and GeparSixto immune signature (GSIS). Cb-containing arms were combined due to similar pCR. Results: High quality RNA seq data was obtained from 482 of 634 pts. PAM50 classified 80.1% of tumors as basal-like. TNBC subtypes were mostly BL1 or BL2 (23.3%), IM (22.4%) or M/MSL (31.7%); 6% were LAR. pCR was higher for basal vs non-basal tumors (52.3% vs 35.4%, p = 0.003). IM had the highest pCR rate (64.2%, 95% CI 59.9%,68.5%). Basal-like was not a significant predictor for Cb benefit (p-interaction = 0.8)....

Poster Session Abstracts

Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease. Clinically, we obser... more Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease. Clinically, we observe three distinct TNBC outcomes: 1) rapid relapse (rrTNBC) characterized by aggressive drug resistant disease; 2) late relapse (lrTNBC) characterized by indolent or treatment responsive disease; and 3) no relapse (NoRTNBC). We hypothesized that distinct clinical and genomic features of primary tumors define rapid versus late relapse in TNBC. Approach: Using three publicly-available datasets (METABRIC, TCGA, and a prior gene expression meta-analysis), we identified 455 patients diagnosed with primary TNBC with adequate follow-up to be characterized as rrTNBC (relapse or death within 2 years of diagnosis), lrTNBC (relapse or death more than 2 years after diagnosis), or NoRTNBC (no relapse/death with at least 5 years follow-up). We compiled basic clinical (n=455 patients) and primary tumor multi-omic data, including whole transcriptome (n=455), whole genome copy number (n=317), and mutation data for 171 cancer-related genes (n=317). We evaluated intrinsic subtypes (PAM50, TNBCtype), 125 gene expression signatures, CIBERSORT immune subsets, copy number, and mutation frequency. Results: We first evaluated patients with relapse (rrTNBC+lrTNBC) vs. NoRTNBC. There was no significant difference in age, grade, stage at diagnosis, or PAM50 or TNBC subtype proportion between relapse and NoRTNBC. Among 125 expression signatures, five immune signatures were significantly higher in NoRTNBCs (FDR p = 0.3, all p Conclusions: Primary TNBC tumors destined for rapid, late, or no relapse reflect distinct genomic features. Anti-tumor immune signatures and subsets are enriched in patients who do not relapse yet no difference in mutational or copy number burden. Relative to rapid relapse TNBCs, late relapse TNBCs are enriched for non-basal tumors, estrogen/luminal expression signatures, and mutations in DNAH11 and PIK3CA. Citation Format: Zhang Y, Nock W, Asad S, Adams E, Singh J, Damicis A, Lustberg MB, Noonan A, Reinbolt R, Sardesai S, VanDeusen J, Wesolowski R, Williams N, Ramaswamy B, Stover DG. Multi-omic predictor of rapid and late relapse in primary triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-07-08.

JCO Precision Oncology

PURPOSE To determine whether specific somatic copy-number alterations detectable in circulating t... more PURPOSE To determine whether specific somatic copy-number alterations detectable in circulating tumor DNA (ctDNA) from patients with metastatic triple-negative breast cancer (mTNBC) are associated with sensitivity to platinum chemotherapy. MATERIALS AND METHODS In this secondary analysis of a large cohort of patients with mTNBC whose ctDNA underwent ultralow-pass whole-genome sequencing, tumor fraction and somatic copy-number alterations were derived with the ichorCNA algorithm. Seventy-two patients were identified who had received a platinum-based chemotherapy regimen in the metastatic setting. Gene-level copy-number analyses were performed with GISTIC2.0. Cytobands were associated with progression-free survival (PFS) to platinum chemotherapy using Cox proportional hazards models. The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium data sets were interrogated for frequency of significant cytobands in primary triple-negative breast cancer (pTNBC)...

Journal of Clinical Oncology, 2021

1025 Background: Analysis of circulating tumor DNA (ctDNA) over time allows non-invasive evaluati... more 1025 Background: Analysis of circulating tumor DNA (ctDNA) over time allows non-invasive evaluation of tumor genomic evolution. We characterize changes in tumor fraction (TFx), somatic copy number alterations (SCNAs), and somatic mutations (muts) over time in patients (pts) with BRCA1/2 muts and metastatic breast cancer (mBC) who received a PARP inhibitor (PARPi) or platinum chemotherapy. Specifically, we seek to identify the frequency of BRCA1/2 reversion muts. Methods: Pts with mBC and germline or somatic BRCA1/2 muts were identified on a banking protocol of prospectively-collected serial samples of blood and plasma. Control pts without a BRCA1/2 mut were matched 2:1 by age and hormone receptor (HR) status. Ultra-low-pass whole genome sequencing (ULPWGS) with 0.1x depth was performed on all plasma samples (n = 103) and the ichorCNA algorithm was used to determine TFx and SCNAs. Targeted panel sequencing (TPS) of 402 cancer-related genes was performed at 10,000x depth on plasma sam...

Cancer Research, 2020

Background: Little is known regarding the effect of somatic tumor genomic testing on patient perc... more Background: Little is known regarding the effect of somatic tumor genomic testing on patient perceptions and psychological well-being. We previously demonstrated that patient perceptions of care can be negatively affected if their next cancer treatment is not supported by the genomic test. To further understand this, we investigated psychological effects of genomic testing, as well as sociodemographic and genomic comprehension factors that may attenuate these effects. Methods: In a prospective, single institution, single-arm trial, patients with metastatic breast cancer underwent next-generation sequencing (NGS) using Foundation Medicine at study entry, with sequencing results released to providers at time of next disease progression. We evaluated patient survey data before and after NGS, including questions about psychosocial characteristics, genetic comprehension, and perceived risks and expectations of the genomic testing. We evaluated psychosocial characteristics using 4 validat...

Cancer Research, 2020

Background: Triple-negative breast cancer (TNBC) accounts for a disproportionate amount of poor o... more Background: Triple-negative breast cancer (TNBC) accounts for a disproportionate amount of poor outcomes among breast cancers. A subset of TNBCs demonstrates an aggressive course with marked chemoresistance, rapid distant metastatic spread, and poor survival. The clinicopathologic and sociodemographic features associated with rapid relapse among TNBCs remain poorly understood. Primary Objective: To evaluate the relationship between clinicopathologic and sociodemographic features with rapid relapse in TNBC (rrTNBC). Methods: This large multi-institutional study analyzed a cohort of breast cancer patients diagnosed with TNBC who received treatment at one of ten academic centers that previously participated in a National Comprehensive Cancer Network (NCCN) outcomes database between 1998 and 2012. We defined rrTNBC as a distant metastatic recurrence event or death from any cause ≤24 months after diagnosis. We included patients with ≥2 years follow-up or had suffered a survival event wit...

Introduction: Cancer and its treatment has been shown to expose patients to higher cardiovascular... more Introduction: Cancer and its treatment has been shown to expose patients to higher cardiovascular risk compared to normal population. Hypothesis: To determine the trends of out of hospital cardiac ...

Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease and we have previousl... more Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease and we have previously shown that rapid relapse of TNBC is associated with distinct sociodemographic features. We hypothesized that rapid versus late relapse in TNBC is also defined by distinct clinical and genomic features of primary tumors. Methods: Using three publicly-available datasets, we identified 453 patients diagnosed with primary TNBC with adequate follow-up to be characterized as ‘rapid relapse’ (rrTNBC; distant relapse or death ≤2 years of diagnosis), ‘late relapse’ (lrTNBC; > 2 years) or ‘no relapse’ (nrTNBC: > 5 years no relapse/death). We explored basic clinical and primary tumor multi-omic data, including whole transcriptome (n = 453), and whole genome copy number and mutation data for 171 cancer-related genes (n = 317). Association of rapid relapse with clinical and genomic features were assessed using Pearson chi-squared tests, t-tests, ANOVA, and Fisher exact tests. We evaluated log...

Journal of the National Comprehensive Cancer Network

Background: Triple-negative breast cancer (TNBC) accounts for disproportionately poor outcomes in... more Background: Triple-negative breast cancer (TNBC) accounts for disproportionately poor outcomes in breast cancer, driven by a subset of rapid-relapse TNBC (rrTNBC) with marked chemoresistance, rapid metastatic spread, and poor survival. Our objective was to evaluate clinicopathologic and sociodemographic features associated with rrTNBC. Methods: We included patients diagnosed with stage I–III TNBC in 1996 through 2012 who received chemotherapy at 1 of 10 academic cancer centers. rrTNBC was defined as a distant metastatic recurrence event or death ≤24 months after diagnosis. Features associated with rrTNBC were included in a multivariable logistic model upon which backward elimination was performed with a P24 months), we found that insurance type and young age remained significant. Conclusions: Timing of relapse in TNBC is associated with stage of disease and distinct sociodemographic features, including insurance type, income, and age at diagnosis.

Genome Medicine

Background Circulating tumor DNA (ctDNA) offers minimally invasive means to repeatedly interrogat... more Background Circulating tumor DNA (ctDNA) offers minimally invasive means to repeatedly interrogate tumor genomes, providing opportunities to monitor clonal dynamics induced by metastasis and therapeutic selective pressures. In metastatic cancers, ctDNA profiling allows for simultaneous analysis of both local and distant sites of recurrence. Despite the promise of ctDNA sampling, its utility in real-time genetic monitoring remains largely unexplored. Methods In this exploratory analysis, we characterize high-frequency ctDNA sample series collected over narrow time frames from seven patients with metastatic triple-negative breast cancer, each undergoing treatment with Cabozantinib, a multi-tyrosine kinase inhibitor (NCT01738438, https://clinicaltrials.gov/ct2/show/NCT01738438). Applying orthogonal whole exome sequencing, ultra-low pass whole genome sequencing, and 396-gene targeted panel sequencing, we analyzed 42 plasma-derived ctDNA libraries, representing 4–8 samples per patient wi...

Journal of the American College of Surgeons

Annals of Surgical Oncology

A subset of triple-negative breast cancer (TNBC) is characterized by aggressive disease, rapid re... more A subset of triple-negative breast cancer (TNBC) is characterized by aggressive disease, rapid relapse, and mortality within 24 months of diagnosis, termed “rapid relapse” TNBC (rrTNBC). The objective of this study is to define the association between sociodemographic variables and surgical management among rrTNBC patients in the Surveillance, Epidemiology and End Results (SEER) Program. TNBC patients diagnosed from January 1, 2010 to December 31, 2014 with local or regional disease were identified in SEER. Patients were stratified as rrTNBC, defined as disease specific mortality ≤ 24 months after diagnosis, and non-rrTNBC. Chi-squared tests, t tests, and multivariable logistic regression were used to assess the association of rapid relapse with sociodemographic variables and surgical management. The cohort included 8% (1378/17,369) rrTNBCs. A higher proportion of rrTNBC patients had no surgery (11.7%) compared with non-rrTNBC (2.6%). Omission of axillary staging among patients who had surgery was 6.2% rrTNBC versus 4.5% non-rrTNBC. Black race (odds ratio [OR] 1.22, 95% confidence interval [CI] 1.05–1.43; p = 0.01; white ref), Medicaid or no insurance (Medicaid OR 1.53, 95% CI 1.31–1.79; p < 0.001; no insurance OR 1.74, 95% CI 1.31–2.32; p < 0.001; private ref), single status (OR 1.19, 95% CI 1.01–1.39; p = 0.03; married ref), no breast (OR 2.35, 95% CI 1.77–3.11; p < 0.001; mastectomy ref), and no axillary surgery (OR 1.44, 95% CI 1.13–1.83; p = 0.003 axillary surgery ref) were associated with rapid relapse. Medicaid or no insurance, single status, black race, and no surgery are associated with higher odds of rrTNBC in SEER. These results indicate an interplay between socioeconomic factors, clinical and genomic variables may be disproportionately contributing to worse outcomes among a subset of TNBC patients.

JAMA Oncology

Importance Adding carboplatin to standard neoadjuvant chemotherapy (NAC) in triple-negative breas... more Importance Adding carboplatin to standard neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) likely benefits a subset of patients; however, determinants of benefit are poorly understood. Objective To define the association of molecular subtype, tumor proliferation, and immunophenotype with benefit of carboplatin added to NAC for patients with stages II to III TNBC. Design, Setting, and Participants This was a prespecified secondary analysis of a phase 3, double-blind, randomized clinical trial (BrighTNess) that enrolled 634 women across 145 centers in 15 countries. Women with clinical stages II to III TNBC who had undergone pretreatment biopsy were eligible to participate. Whole transcriptome RNA sequencing was performed on the biopsy specimens. The prespecified end point was association of pathologic complete response (pCR) with gene expression-based molecular subtype, with secondary end points investigating established signatures (proliferation, immune) and exploratory analyses of immunophenotype. Data were collected from April 2014 to March 2016. The study analyses were performed from January 2018 to March 2019. Interventions Neoadjuvant chemotherapy with paclitaxel followed by doxorubicin and cyclophosphamide, or this same regimen with carboplatin or carboplatin plus veliparib. Main Outcomes and Measures Association of gene expression-based molecular subtype (PAM50 and TNBC subtypes) with pCR. Results Of the 634 women (median age, 51 [range, 22-78] years) enrolled in BrighTNess, 482 (76%) patients had evaluable RNA sequencing data, with similar baseline characteristics relative to the overall intention-to-treat population. Pathologic complete response was significantly more frequent in PAM50 basal-like vs nonbasal-like cancers overall (202 of 386 [52.3%] vs 34 of 96 [35.4%]; P = .003). Carboplatin benefit was not significantly different in basal-like vs nonbasal-like subgroups (P = .80 for interaction). In multivariable analysis, proliferation (hazard ratio, 0.36; 95% CI, 0.21-0.61; P < .001) and immune (hazard ratio, 0.62; 95% CI, 0.49-0.79; P < .001) signatures were independently associated with pCR. Tumors above the median for proliferation and immune signatures had the highest pCR rate (84 of 125; 67%), while those below the median for both signatures had the lowest pCR rate (42 of 125; 34%). Exploratory gene expression immune analyses suggested that tumors with higher inferred CD8+ T-cell infiltration may receive greater benefit with addition of carboplatin. Conclusions and Relevance In this secondary analysis of a randomized clinical trial, triple-negative breast cancer subtyping revealed high pCR rates in basal-like and immunomodulatory subsets. Analysis of biological processes related to basal-like and immunomodulatory phenotypes identified tumor cell proliferation and immune scores as independent factors associated with achieving pCR; the benefit of carboplatin on pCR was seen across all molecular subtypes. Further validation of immunophenotype with existing biomarkers may help to escalate or de-escalate therapy for patients with TNBC. Trial Registration ClinicalTrials.gov Identifier: NCT02032277.

Clinical Research (Excluding Clinical Trials)

Copy number aberrations (CNAs) are gains and losses of large genomic segments present across most... more Copy number aberrations (CNAs) are gains and losses of large genomic segments present across most cancer types and are a hallmark of cancer genomic alterations. However, the processes underlying CNAs and characteristic patterns of CNAs are poorly understood. Using single nucleotide variant (SNV) data, bioinformatic advances have identified underlying mutational signatures resulting from distinct mutational processes. Mutational signatures have led to a variety of discoveries, several of which are being investigated in clinical management of cancer. The development of algorithms able to uncover similar signatures for CNAs, rather than SNVs, is still in its infancy. Here we present an analysis package for the R programming language called CNSigs that allows for the robust and reproducible derivation of copy number signatures. Based on a list of extracted copy number features previously verified in ovarian cancer, we utilize mixed model approaches and non-negative matrix factorization to derive CNA signatures across cancer types. The development of a package to derive signatures from copy number data allows further investigation of underlying processes that may be responsible for these CNA fingerprints. To verify the reproducibility of the signatures, we derived signatures from two independent breast cancer datasets that use distinct copy number segmentation approaches. From these independent datasets we were able to recover the same signatures with high accuracy. We identified five signatures that are distinct from known breast cancer receptor-based or expression-based subtypes, yet reveal unique associations with underlying mutations, mutational processes, and transcriptional programs. To validate robustness, we applied the pipeline to 11 different cancer types from the TCGA dataset and showed that we were able to derive signatures from all of these cancer types of varying sample sizes. We identified certain signatures that cut across tumor types, while others are distinct to individual cancers. This work lays the groundwork for further analysis into the underlying molecular processes leading to these copy number signatures seen across cancer types. The CNSigs package also allows researchers to easily analyze their own samples to look for signatures in their copy number profiles and to compare these to signatures previously derived for their cancer type. Citation Format: David Tallman, Sinclair Stockard, Zachary T. Weber, Sarah Asad, Katharine Collier, Elizabeth Adams, Jerome Bey, Daniel G. Stover. CNSigs: An R package for the identification of copy number signatures [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5471.

BMC Cancer

Background To assess metastatic breast cancer (MBC) patient psychological factors, perceptions, a... more Background To assess metastatic breast cancer (MBC) patient psychological factors, perceptions, and comprehension of tumor genomic testing. Methods In a prospective, single institution, single-arm trial, patients with MBC underwent next-generation sequencing at study entry with sequencing results released at progression. Patients who completed surveys before undergoing sequencing were included in the present secondary analysis (n = 58). We administered four validated psychosocial measures: Center for Epidemiologic Studies Depression Scale, Beck Anxiety Inventory, Trust in Physician Scale, and Communication and Attitudinal Self-Efficacy scale for Cancer. Genetic comprehension was assessed using 7-question objective and 6-question subjective measures. Longitudinal data were assessed (n = 40) using paired Wilcoxon signed rank and McNemar’s test of agreement. Results There were no significant differences between the beginning and end of study in depression, anxiety, physician trust, or ...

JCO Precision Oncology

PURPOSE To evaluate the impact of targeted DNA sequencing on selection of cancer therapy for pati... more PURPOSE To evaluate the impact of targeted DNA sequencing on selection of cancer therapy for patients with metastatic breast cancer (MBC). PATIENTS AND METHODS In this prospective, single-center, single-arm trial, patients with MBC were enrolled within 10 weeks of starting a new therapy. At enrollment, tumor samples underwent next-generation sequencing for any of 315 cancer-related genes to high depth (> 500×) using FoundationOne CDx. Sequencing results were released to providers at the time of disease progression, and physician treatment recommendations were assessed via questionnaire. We evaluated three prespecified questions to assess patients’ perceptions of genomic testing. RESULTS In all, 100 patients underwent genomic testing, with a median of five mutations (range, 0 to 13 mutations) detected per patient. Genomic testing revealed one or more potential therapies in 98% of patients (98 of 100), and 60% of patients (60 of 100) had one or more recommended treatments with leve...

ABSTRACTPurposeTo assess metastatic breast cancer (MBC) patient perceptions and comprehension of ... more ABSTRACTPurposeTo assess metastatic breast cancer (MBC) patient perceptions and comprehension of tumor genomic testing and to evaluate associations with psychological wellbeing.MethodsIn a prospective, single institution, single-arm trial, patients with MBC underwent next-generation sequencing at study entry, with sequencing results released at progression. Patients who completed surveys before undergoing sequencing were included in the study (n=58). We administered four validated psychosocial measures: Center for Epidemiologic Studies Depression Scale, Beck Anxiety Inventory, Trust in Physician Scale, and Communication and Attitudinal Self-Efficacy scale for Cancer. Genetic comprehension was assessed using 7-question objective and 6-question subjective measures. Longitudinal data were assessed using paired Wilcoxon signed rank and McNemar’s test of agreement.ResultsThere were no significant differences between the beginning and end of study in depression, anxiety, physician trust, ...

ABSTRACTPurposeMetastatic relapse of triple-negative breast cancer (TNBC) within 2 years of diagn... more ABSTRACTPurposeMetastatic relapse of triple-negative breast cancer (TNBC) within 2 years of diagnosis is associated with particularly aggressive disease and a distinct clinical course relative to TNBCs that relapse beyond 2 years. We hypothesized that rapid relapse TNBCs (rrTNBC; metastatic relapse or death <2 years) reflect unique genomic features relative to late relapse (lrTNBC; >2 years).Patients and MethodsWe identified 453 primary TNBCs from three publicly-available datasets and characterized each as rrTNBc, lrTNBC, or ‘no relapse’ (nrTNBC: no relapse/death with at least 5 years follow-up). We compiled primary tumor clinical and multi-omic data, including transcriptome (n=453), copy number alterations (CNAs; n=317), and mutations in 171 cancer-related genes (n=317), then calculated published gene expression and immune signatures.ResultsPatients with rrTNBC were higher stage at diagnosis (Chi-square p<0.0001) while lrTNBC were more likely to be non-basal PAM50 subtype ...

Journal of Clinical Oncology

510 Background: In TNBC, the interplay between immunophenotype, tumor proliferation (prolif) and ... more 510 Background: In TNBC, the interplay between immunophenotype, tumor proliferation (prolif) and achievement of pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) remains unknown. Methods: RNA seq was performed on pre-tx research biopsies of stage II/III TNBC enrolled in BrighTNess. NAC regimens included paclitaxel alone or with carboplatin (Cb) or Cb plus veliparib, followed by AC. Computational analysis included subtyping (i.e. PAM50, Pietenpol), prolif (PAM50) and GeparSixto immune signature (GSIS). Cb-containing arms were combined due to similar pCR. Results: High quality RNA seq data was obtained from 482 of 634 pts. PAM50 classified 80.1% of tumors as basal-like. TNBC subtypes were mostly BL1 or BL2 (23.3%), IM (22.4%) or M/MSL (31.7%); 6% were LAR. pCR was higher for basal vs non-basal tumors (52.3% vs 35.4%, p = 0.003). IM had the highest pCR rate (64.2%, 95% CI 59.9%,68.5%). Basal-like was not a significant predictor for Cb benefit (p-interaction = 0.8)....

Poster Session Abstracts

Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease. Clinically, we obser... more Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease. Clinically, we observe three distinct TNBC outcomes: 1) rapid relapse (rrTNBC) characterized by aggressive drug resistant disease; 2) late relapse (lrTNBC) characterized by indolent or treatment responsive disease; and 3) no relapse (NoRTNBC). We hypothesized that distinct clinical and genomic features of primary tumors define rapid versus late relapse in TNBC. Approach: Using three publicly-available datasets (METABRIC, TCGA, and a prior gene expression meta-analysis), we identified 455 patients diagnosed with primary TNBC with adequate follow-up to be characterized as rrTNBC (relapse or death within 2 years of diagnosis), lrTNBC (relapse or death more than 2 years after diagnosis), or NoRTNBC (no relapse/death with at least 5 years follow-up). We compiled basic clinical (n=455 patients) and primary tumor multi-omic data, including whole transcriptome (n=455), whole genome copy number (n=317), and mutation data for 171 cancer-related genes (n=317). We evaluated intrinsic subtypes (PAM50, TNBCtype), 125 gene expression signatures, CIBERSORT immune subsets, copy number, and mutation frequency. Results: We first evaluated patients with relapse (rrTNBC+lrTNBC) vs. NoRTNBC. There was no significant difference in age, grade, stage at diagnosis, or PAM50 or TNBC subtype proportion between relapse and NoRTNBC. Among 125 expression signatures, five immune signatures were significantly higher in NoRTNBCs (FDR p = 0.3, all p Conclusions: Primary TNBC tumors destined for rapid, late, or no relapse reflect distinct genomic features. Anti-tumor immune signatures and subsets are enriched in patients who do not relapse yet no difference in mutational or copy number burden. Relative to rapid relapse TNBCs, late relapse TNBCs are enriched for non-basal tumors, estrogen/luminal expression signatures, and mutations in DNAH11 and PIK3CA. Citation Format: Zhang Y, Nock W, Asad S, Adams E, Singh J, Damicis A, Lustberg MB, Noonan A, Reinbolt R, Sardesai S, VanDeusen J, Wesolowski R, Williams N, Ramaswamy B, Stover DG. Multi-omic predictor of rapid and late relapse in primary triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-07-08.