Jennifer Caswell-Jin, MD is an Assistant Professor of Medicine (Oncology) specializing in breast cancer care and research. She received her medical degree from Harvard Medical School in 2010, completed her internal medicine residency at the University of California, San Francisco in 2013, and completed her clinical fellowship in medical oncology at Stanford Hospital & Clinics in 2017. Her clinical translational research program is aimed at developing personalized approaches to care that improve the outcomes of people with breast cancer.
- Medical Oncology
Honors & Awards
AACR Associate Member Award, San Antonio Breast Cancer Symposium (2018)
Physician Scientist Training Award, Damon Runyon Cancer Research Foundation (2017)
Postdoctoral Fellowship Award, Susan G. Komen (2017)
ASCO Young Investigator Award, Conquer Cancer Foundation (2017)
SCI Fellowship Award, Stanford Cancer Institute (2017)
Board Certification: American Board of Internal Medicine, Medical Oncology (2018)
Fellowship: Stanford University Hematology and Oncology Fellowship (2017) CA
Board Certification: American Board of Internal Medicine, Internal Medicine (2013)
Residency: UCSF Internal Medicine Residency (2013) CA
Medical Education: Harvard Medical School (2010) MA
A.B., Harvard College, Biological Anthropology (2006)
Current Research and Scholarly Interests
My research is on the translational application of next-generation sequencing technologies to breast cancer care: (1) the value of hereditary cancer genetic panel testing in clinical practice, (2) the mechanisms by which inherited genetic variants lead to breast cancer development, and (3) the analysis of somatic tumor sequencing data to inform understanding of breast tumorigenesis, metastasis, and development of resistance in response to therapeutics.
Study of eFT226 in Subjects With Selected Advanced Solid Tumor Malignancies
This clinical trial is a Phase 1-2, open-label, sequential-group, dose-escalation and cohort-expansion study evaluating the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of Zotatifin (eFT226) in subjects with selected advanced solid tumor malignancies.
Study of Infigratinib in Combination With Tamoxifen in Hormone Receptor Positive, HER2 Negative, FGFR Altered Advanced Breast Cancer
The purpose of the study is identify the dose(s) of infigratinib to use in combination with tamoxifen to treat patients with a particular type of advanced breast cancer (hormone receptor-positive, HER2-negative, FGFR-altered breast cancer)
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Kody, 650-498-8583.
Graduate and Fellowship Programs
Oncology (Fellowship Program)
Chemotherapy Regimens Received by Women with BRCA1/2 Pathogenic Variants for Early-Stage Breast Cancer Treatment.
JNCI cancer spectrum
Genetic testing is widespread among breast cancer patients; however, no guideline recommends using germline genetic testing results to select a chemotherapy regimen. It is unknown whether breast cancer patients who carry pathogenic variants (PVs) in BRCA1/2 or other cancer-associated genes receive different chemotherapy regimens than non-carriers.We linked Surveillance, Epidemiology and End Results (SEER) registry records from Georgia and California to germline genetic testing results from four clinical laboratories. Patients were included who: 1) had stages I-III breast cancer, either hormone receptor-positive and HER2-negative (HR-positive/HER2-negative) or triple-negative (TNBC), diagnosed in 2013-2017; 2) received chemotherapy; and 3) linked to genetic results. Chemotherapy details were extracted from SEER text fields completed by registrars. We examined whether PV carriers received more intensive regimens (HR-positive, HER2-negative: ≥3 drugs including an anthracycline; TNBC: ≥4 drugs including an anthracycline and platinum) and/or less standard breast cancer agents (a platinum). All statistical tests were 2-sided.Among 2,293 patients, 1,451 had HR-positive/HER2-negative disease and 842 had TNBC. On multivariable analysis of women with HR-positive/HER2-negative disease, receipt of a more intensive chemotherapy regimen varied significantly by genetic results (p=.02), with platinum receipt more common among BRCA1/2 PV carriers (odds ratio 2.44, 95% confidence interval 1.36-4.38, p<.001). Among women with TNBC, chemotherapy agents did not vary significantly by genetic results.BRCA1/2 PV carriers with HR-positive/HER2-negative breast cancer had two-fold higher odds than non-carriers of receiving a platinum, as part of a more intensive chemotherapy regimen. This likely represents over-treatment and emphasizes the need to monitor how genetic testing results are managed in oncology practice.
View details for DOI 10.1093/jncics/pkac045
View details for PubMedID 35723570
Association of germline genetic testing results with chemotherapy regimens received by women with early-stage breast cancer.
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680300131
Contributions of screening, early-stage treatment, and metastatic treatment to breast cancer mortality reduction by molecular subtype in US women, 2000-2017.
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680300063
First-in-human phase 1/2 dose escalation and expansion study evaluating first-in-class eIF4A inhibitor zotatifin in patients with solid tumors.
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680300974
Breast cancer diagnosis and treatment during the COVID-19 pandemic in a nationwide, insured population.
Breast cancer research and treatment
The early months of the COVID-19 pandemic led to reduced cancer screenings and delayed cancer surgeries. We used insurance claims data to understand how breast cancer incidence and treatment after diagnosis changed nationwide over the course of the pandemic.Using the Optum Research Database from January 2017 to March 2021, including approximately 19 million US adults with commercial health insurance, we identified new breast cancer diagnoses and first treatment after diagnosis. We compared breast cancer incidence and proportion of newly diagnosed patients receiving pre-operative systemic therapy pre-COVID, in the first 2 months of the COVID pandemic and in the later part of the COVID pandemic.Average monthly breast cancer incidence was 19.3 (95% CI 19.1-19.5) cases per 100,000 women and men pre-COVID, 11.6 (95% CI 10.8-12.4) per 100,000 in April-May 2020, and 19.7 (95% CI 19.3-20.1) per 100,000 in June 2020-February 2021. Use of pre-operative systemic therapy was 12.0% (11.7-12.4) pre-COVID, 37.7% (34.9-40.7) for patients diagnosed March-April 2020, and 14.8% (14.0-15.7) for patients diagnosed May 2020-January 2021. The changes in breast cancer incidence across the pandemic did not vary by demographic factors. Use of pre-operative systemic therapy across the pandemic varied by geographic region, but not by area socioeconomic deprivation or race/ethnicity.In this US-insured population, the dramatic changes in breast cancer incidence and the use of pre-operative systemic therapy experienced in the first 2 months of the pandemic did not persist, although a modest change in the initial management of breast cancer continued.
View details for DOI 10.1007/s10549-022-06634-z
View details for PubMedID 35624175
Genetic and immunohistochemical profiling of small cell and large cell neuroendocrine carcinomas of the breast.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
Neuroendocrine carcinomas (NEC) of the breast are exceedingly rare tumors, which are classified in the WHO system as small cell (SCNEC) and large cell (LCNEC) carcinoma based on indistinguishable features from their lung counterparts. In contrast to lung and enteropancreatic NEC, the genomics of breast NEC have not been well-characterized. In this study, we examined the clinicopathologic, immunohistochemical, and genetic features of 13 breast NEC (7 SCNEC, 4 LCNEC, 2 NEC with ambiguous small versus large cell morphology [ANEC]). Co-alterations of TP53 and RB1 were identified in 86% (6/7) SCNEC, 100% (2/2) ANEC, and 50% (2/4) LCNEC. The one SCNEC without TP53/RB1 alteration had other p53 pathway aberrations (MDM2 and MDM4 amplification) and was immunohistochemically RB negative. PIK3CA/PTEN pathway alterations and ZNF703 amplifications were each identified in 46% (6/13) NEC. Two tumors (1 SCNEC, 1 LCNEC) were CDH1 mutated. By immunohistochemistry, 100% SCNEC (6/6) and ANEC (2/2) and 50% (2/4) LCNEC (83% NEC) showed RB loss, compared to 0% (0/8) grade 3 neuroendocrine tumors (NET) (p<0.001) and 38% (36/95) grade 3 invasive ductal carcinomas of no special type (IDC-NST) (p=0.004). NEC were also more often p53 aberrant (60% vs 0%, p=0.013), ER negative (69% vs 0%, p=0.005), and GATA3 negative (67% vs 0%, p=0.013) than grade 3 NET. Two mixed NEC had IDC-NST components, and 69% (9/13) of tumors were associated with carcinoma in situ (6neuroendocrine DCIS,2non-neuroendocrine DCIS, 1 non-neuroendocrine LCIS). NEC and IDC-NST components of mixed tumors were clonally related and immunophenotypically distinct, lacking ER and GATA3 expression in NEC relative to IDC-NST, with RB loss only in NEC of one ANEC. The findings provide insight into the pathogenesis of breast NEC, underscore their classification as a distinct tumor type, and highlight genetic similarities to extramammary NEC, including highly prevalent p53/RB pathway aberrations in SCNEC.
View details for DOI 10.1038/s41379-022-01090-y
View details for PubMedID 35590107
Patient perspectives on window of opportunity clinical trials in early-stage breast cancer.
Breast cancer research and treatment
Window of opportunity trials (WOT) are increasingly common in oncology research. In WOT participants receive a drug between diagnosis and anti-cancer treatment, usually for the purpose of investigating that drugs effect on cancer biology. This qualitative study aimed to understand patient perspectives on WOT.We recruited adults diagnosed with early-stage breast cancer awaiting definitive therapy at a single-academic medical center to participate in semi-structured interviews. Thematic and content analyses were performed to identify attitudes and factors that would influence decisions about WOT participation.We interviewed 25 women diagnosed with early-stage breast cancer. The most common positive attitudes toward trial participation were a desire to contribute to research and a hope for personal benefit, while the most common concerns were the potential for side effects and how they might impact fitness for planned treatment. Participants indicated family would be an important normative factor in decision-making and, during the COVID-19 pandemic, deemed the absence of family members during clinic visits a barrier to enrollment. Factors that could hinder participation included delay in standard treatment and the requirement for additional visits or procedures. Ultimately, most interviewees stated they would participate in a WOT if offered (N = 17/25).In this qualitative study, interviewees weighed altruism and hypothetical personal benefit against the possibility of side effect from a WOT. In-person family presence during trial discussion, challenging during COVID-19, was important for many. Our results may inform trial design and communication approaches in future window of opportunity efforts.
View details for DOI 10.1007/s10549-022-06611-6
View details for PubMedID 35538268
Twenty-one-gene recurrence score (RS) in germline (g)CHEK2 mutation-associated versus sporadic breast cancers (BC): A multi-site case-control study.
LIPPINCOTT WILLIAMS & WILKINS. 2021
View details for Web of Science ID 000708120605272
- Spatial proteomic characterization of HER2-positive breast tumors through neoadjuvant therapy predicts response NATURE CANCER 2021; 2 (4): 400-+
Spatial proteomic characterization of HER2-positive breast tumors through neoadjuvant therapy predicts response.
2021; 2 (4): 400-413
The addition of HER2-targeted agents to neoadjuvant chemotherapy has dramatically improved pathological complete response (pCR) rates in early-stage, HER2-positive breast cancer. Nonetheless, up to 50% of patients have residual disease after treatment, while others are likely overtreated. Here, we performed multiplex spatial proteomic characterization of 122 samples from 57 HER2-positive breast tumors from the neoadjuvant TRIO-US B07 clinical trial sampled pre-treatment, after 14-21 d of HER2-targeted therapy and at surgery. We demonstrated that proteomic changes after a single cycle of HER2-targeted therapy aids the identification of tumors that ultimately undergo pCR, outperforming pre-treatment measures or transcriptomic changes. We further developed and validated a classifier that robustly predicted pCR using a single marker, CD45, measured on treatment, and showed that CD45-positive cell counts measured via conventional immunohistochemistry perform comparably. These results demonstrate robust biomarkers that can be used to enable the stratification of sensitive tumors early during neoadjuvant HER2-targeted therapy, with implications for tailoring subsequent therapy.
View details for DOI 10.1038/s43018-021-00190-z
View details for PubMedID 34966897
View details for PubMedCentralID PMC8713949
- Androgen receptor agonists as breast cancer therapeutics. Nature medicine 2021
Performance of the IBIS/Tyrer-Cuzick model of breast cancer risk by race and ethnicity in the Women's Health Initiative.
The IBIS/Tyrer-Cuzick model is used clinically to guide breast cancer screening and prevention, but was developed primarily in non-Hispanic White women. Little is known about its long-term performance in a racially/ethnically diverse population.The Women's Health Initiative study enrolled postmenopausal women from 1993-1998. Women were included who were aged <80 years at enrollment with no prior breast cancer or mastectomy and with data required for IBIS/Tyrer-Cuzick calculation (weight; height; ages at menarche, first birth, and menopause; menopausal hormone therapy use; and family history of breast or ovarian cancer). Calibration was assessed by the ratio of observed breast cancer cases to the number expected by the IBIS/Tyrer-Cuzick model (O/E; calculated as the sum of cumulative hazards). Differential discrimination was tested for by self-reported race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, Asian or Pacific Islander, and American Indian or Alaskan Native) using Cox regression. Exploratory analyses, including simulation of a protective single-nucleotide polymorphism (SNP), rs140068132 at 6q25, were performed.During follow-up (median 18.9 years, maximum 23.4 years), 6783 breast cancer cases occurred among 90,967 women. IBIS/Tyrer-Cuzick was well calibrated overall (O/E ratio = 0.95; 95% CI, 0.93-0.97) and in most racial/ethnic groups, but overestimated risk for Hispanic women (O/E ratio = 0.75; 95% CI, 0.62-0.90). Discrimination did not differ by race/ethnicity. Exploratory simulation of the protective SNP suggested improved IBIS/Tyrer-Cuzick calibration for Hispanic women (O/E ratio = 0.80; 95% CI, 0.66-0.96).The IBIS/Tyrer-Cuzick model is well calibrated for several racial/ethnic groups over 2 decades of follow-up. Studies that incorporate genetic and other risk factors, particularly among Hispanic women, are essential to improve breast cancer-risk prediction.
View details for DOI 10.1002/cncr.33767
View details for PubMedID 34228814
Molecular Heterogeneity and Evolution in Breast Cancer
Annual review of cancer biology
2021; 5: 79-94
View details for DOI 10.1146/annurev-cancerbio-060220-014137
Treatment and Monitoring Variability in US Metastatic Breast Cancer Care.
JCO clinical cancer informatics
2021; 5: 600-614
Treatment and monitoring options for patients with metastatic breast cancer (MBC) are increasing, but little is known about variability in care. We sought to improve understanding of MBC care and its correlates by analyzing real-world claims data using a search engine with a novel query language to enable temporal electronic phenotyping.Using the Advanced Cohort Engine, we identified 6,180 women who met criteria for having estrogen receptor-positive, human epidermal growth factor receptor 2-negative MBC from IBM MarketScan US insurance claims (2007-2014). We characterized treatment, monitoring, and hospice usage, along with clinical and nonclinical factors affecting care.We observed wide variability in treatment modality and monitoring across patients and geography. Most women received first-recorded therapy with endocrine (67%) versus chemotherapy, underwent more computed tomography (CT) (76%) than positron emission tomography-CT, and were monitored using tumor markers (58%). Nearly half (46%) met criteria for aggressive disease, which were associated with receiving chemotherapy first, monitoring primarily with CT, and more frequent imaging. Older age was associated with endocrine therapy first, less frequent imaging, and less use of tumor markers. After controlling for clinical factors, care strategies varied significantly by nonclinical factors (median regional income with first-recorded therapy and imaging type, geographic region with these and with imaging frequency and use of tumor markers; P < .0001).Variability in US MBC care is explained by patient and disease factors and by nonclinical factors such as geographic region, suggesting that treatment decisions are influenced by local practice patterns and/or resources. A search engine designed to express complex electronic phenotypes from longitudinal patient records enables the identification of variability in patient care, helping to define disparities and areas for improvement.
View details for DOI 10.1200/CCI.21.00031
View details for PubMedID 34043432
Understanding patient perspectives on window of opportunity clinical trials.
AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000607202800180
Performance of the IBIS/Tyrer-Cuzick (TC) Model by race/ethnicity in the Women's Health Initiative.
AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000560368301027
Linking insurance claims across time to characterize treatment, monitoring, and end-of-life care in metastatic breast cancer.
AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000560368303141
- Characterizing the tumor and immune microenvironment through treatment to predict response to neoadjuvant HER2-targeted therapy using the Digital Spatial Profiler AMER ASSOC CANCER RESEARCH. 2020
- Tumor expression and microenvironment in HER2-positive breast cancer before and on HER2-targeted therapy: Analysis of microarray expression data from the TRIO-US B07 trial AMER ASSOC CANCER RESEARCH. 2020
Pathologic and molecular responses to neoadjuvant trastuzumab and/or lapatinib from a phase II randomized trial in HER2-positive breast cancer (TRIO-US B07).
2020; 11 (1): 5824
In this multicenter, open-label, randomized phase II investigator-sponsored neoadjuvant trial with funding provided by Sanofi and GlaxoSmithKline (TRIO-US B07, Clinical Trials NCT00769470), participants with early-stage HER2-positive breast cancer (N=128) were recruited from 13 United States oncology centers throughout the Translational Research in Oncology network. Participants were randomized to receive trastuzumab (T; N=34), lapatinib (L; N=36), or both (TL; N=58) as HER2-targeted therapy, with each participant given one cycle of this designated anti-HER2 therapy alone followed by six cycles of standard combination chemotherapy with the same anti-HER2 therapy. The primary objective was to estimate the rate of pathologic complete response (pCR) at the time of surgery in each of the three arms. In the intent-to-treat population, we observed similar pCR rates between T (47%, 95% confidence interval [CI] 30-65%) and TL (52%, 95% CI 38-65%), and a lower pCR rate with L (25%, 95% CI 13-43%). In the T arm, 100% of participants completed all protocol-specified treatment prior to surgery, as compared to 69% in the L arm and 74% in the TL arm. Tumor or tumor bed tissue was collected whenever possible pre-treatment (N=110), after one cycle of HER2-targeted therapy alone (N=89), and at time of surgery (N=59). Higher-level amplification of HER2 and hormone receptor (HR)-negative status were associated with a higher pCR rate. Large shifts in the tumor, immune, and stromal gene expression occurred after one cycle of HER2-targeted therapy. In contrast to pCR rates, the L-containing arms exhibited greater proliferation reduction than T at this timepoint. Immune expression signatures increased in all arms after one cycle of HER2-targeted therapy, decreasing again by the time of surgery. Our results inform approaches to early assessment of sensitivity to anti-HER2 therapy and shed light on the role of the immune microenvironment in response to HER2-targeted agents.
View details for DOI 10.1038/s41467-020-19494-2
View details for PubMedID 33203854
- Prevalence of Pathogenic Variants in Cancer Susceptibility Genes Among Women With Postmenopausal Breast Cancer. JAMA 2020; 323 (10): 995–97
- Re: Cascade Genetic Testing of Relatives for Hereditary Cancer Risk: Results of an Online Initiative Response JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE 2019; 111 (8): 874
Dynamics of breast-cancer relapse reveal late-recurring ER-positive genomic subgroups.
The rates and routes of lethal systemic spread in breast cancer are poorly understood owing to a lack of molecularly characterized patient cohorts with long-term, detailed follow-up data. Long-term follow-up is especially important for those with oestrogen-receptor (ER)-positive breast cancers, which can recur up to two decades after initial diagnosis1-6. It is therefore essential to identify patients who have a high risk of late relapse7-9. Here we present a statistical framework that models distinct disease stages (locoregional recurrence, distant recurrence, breast-cancer-related deathand death from other causes) and competing risks of mortality from breast cancer, while yielding individual risk-of-recurrence predictions. We apply this model to 3,240 patients with breast cancer, including 1,980 for whom molecular data are available, and delineate spatiotemporal patterns of relapse across different categories of molecular information (namely immunohistochemical subtypes; PAM50 subtypes, which are based on gene-expression patterns10,11; and integrative or IntClust subtypes, which are based on patterns of genomic copy-number alterations and gene expression12,13). We identify four late-recurring integrative subtypes, comprisingabout one quarter (26%) of tumours that are both positive for ER and negative for human epidermal growth factor receptor 2, each with characteristic tumour-driving alterations in genomic copy number and a high risk of recurrence (mean 47-62%) up to 20 years after diagnosis. We also define a subgroup of triple-negative breast cancers in which cancer rarely recurs after five years, and a separate subgroup in which patients remain at risk. Use of the integrative subtypes improves the prediction of late, distant relapse beyond what is possible with clinical covariates (nodal status, tumour size, tumour grade and immunohistochemical subtype). These findings highlight opportunities for improved patient stratification and biomarker-driven clinical trials.
View details for PubMedID 30867590
Using natural language processing to construct a metastatic breast cancer cohort from linked cancer registry and electronic medical records data.
2019; 2 (4): 528–37
Most population-based cancer databases lack information on metastatic recurrence. Electronic medical records (EMR) and cancer registries contain complementary information on cancer diagnosis, treatment and outcome, yet are rarely used synergistically. To construct a cohort of metastatic breast cancer (MBC) patients, we applied natural language processing techniques within a semisupervised machine learning framework to linked EMR-California Cancer Registry (CCR) data.We studied all female patients treated at Stanford Health Care with an incident breast cancer diagnosis from 2000 to 2014. Our database consisted of structured fields and unstructured free-text clinical notes from EMR, linked to CCR, a component of the Surveillance, Epidemiology and End Results Program (SEER). We identified de novo MBC patients from CCR and extracted information on distant recurrences from patient notes in EMR. Furthermore, we trained a regularized logistic regression model for recurrent MBC classification and evaluated its performance on a gold standard set of 146 patients.There were 11 459 breast cancer patients in total and the median follow-up time was 96.3 months. We identified 1886 MBC patients, 512 (27.1%) of whom were de novo MBC patients and 1374 (72.9%) were recurrent MBC patients. Our final MBC classifier achieved an area under the receiver operating characteristic curve (AUC) of 0.917, with sensitivity 0.861, specificity 0.878, and accuracy 0.870.To enable population-based research on MBC, we developed a framework for retrospective case detection combining EMR and CCR data. Our classifier achieved good AUC, sensitivity, and specificity without expert-labeled examples.
View details for DOI 10.1093/jamiaopen/ooz040
View details for PubMedID 32025650
View details for PubMedCentralID PMC6994019
- Cascade Genetic Testing of Relatives for Hereditary Cancer Risk: Results of an Online Initiative JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE 2019; 111 (1): 95–98
Chromatin regulators mediate anthracycline sensitivity in breast cancer.
Anthracyclines are a highly effective component of curative breast cancer chemotherapy but are associated with substantial morbidity1,2. Because anthracyclines work in part by inhibiting topoisomerase-II (TOP2) on accessible DNA3,4, we hypothesized that chromatin regulatory genes (CRGs) that mediate DNA accessibility might predict anthracycline response. We studied the role of CRGs in anthracycline sensitivity in breast cancer through integrative analysis of patient and cell line data. We identified a consensus set of 38 CRGs associated with anthracycline response across ten cell line datasets. By evaluating the interaction between expression and treatment in predicting survival in a metacohort of 1006 patients with early-stage breast cancer, we identified 54 CRGs whose expression levels dictate anthracycline benefit across the clinical subgroups; of these CRGs, 12 overlapped with those identified in vitro. CRGs that promote DNA accessibility, including Trithorax complex members, were associated with anthracycline sensitivity when highly expressed, whereas CRGs that reduce accessibility, such as Polycomb complex proteins, were associated with decreased anthracycline sensitivity. We show that KDM4B modulates TOP2 accessibility to chromatin, elucidating a mechanism of TOP2 inhibitor sensitivity. These findings indicate that CRGs mediate anthracycline benefit by altering DNA accessibility, with implications for the stratification of patients with breast cancer and treatment decision making.
View details for DOI 10.1038/s41591-019-0638-5
View details for PubMedID 31700186
Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy.
2019; 10 (1): 657
Genomic changes observed across treatment may result from either clonal evolution or geographically disparate sampling of heterogeneous tumors. Here we use computational modeling based on analysis of fifteen primary breast tumors and find that apparent clonal change between two tumor samples can frequently be explained by pre-treatment heterogeneity, such that at least two regions are necessary to detect treatment-induced clonal shifts. To assess for clonal replacement, we devise a summary statistic based on whole-exome sequencing of a pre-treatment biopsy and multi-region sampling of the post-treatment surgical specimen and apply this measure to five breast tumors treated with neoadjuvant HER2-targeted therapy. Two tumors underwent clonal replacement with treatment, and mathematical modeling indicates these two tumors had resistant subclones prior to treatment and rates of resistance-related genomic changes that were substantially larger than previous estimates. Our results provide a needed framework to incorporate primary tumor heterogeneity in investigating the evolution of resistance.
View details for PubMedID 30737380
Natural Language Processing Approaches to Detect the Timeline of Metastatic Recurrence of Breast Cancer.
JCO clinical cancer informatics
2019; 3: 1–12
Electronic medical records (EMRs) and population-based cancer registries contain information on cancer outcomes and treatment, yet rarely capture information on the timing of metastatic cancer recurrence, which is essential to understand cancer survival outcomes. We developed a natural language processing (NLP) system to identify patient-specific timelines of metastatic breast cancer recurrence.We used the OncoSHARE database, which includes merged data from the California Cancer Registry and EMRs of 8,956 women diagnosed with breast cancer in 2000 to 2018. We curated a comprehensive vocabulary by interviewing expert clinicians and processing radiology and pathology reports and progress notes. We developed and evaluated the following two distinct NLP approaches to analyze free-text notes: a traditional rule-based model, using rules for metastatic detection from the literature and curated by domain experts; and a contemporary neural network model. For each 3-month period (quarter) from 2000 to 2018, we applied both models to infer recurrence status for that quarter. We trained the NLP models using 894 randomly selected patient records that were manually reviewed by clinical experts and evaluated model performance using 179 hold-out patients (20%) as a test set.The median follow-up time was 19 quarters (5 years) for the training set and 15 quarters (4 years) for the test set. The neural network model predicted the timing of distant metastatic recurrence with a sensitivity of 0.83 and specificity of 0.73, outperforming the rule-based model, which had a specificity of 0.35 and sensitivity of 0.88 (P < .001).We developed an NLP method that enables identification of the occurrence and timing of metastatic breast cancer recurrence from EMRs. This approach may be adaptable to other cancer sites and could help to unlock the potential of EMRs for research on real-world cancer outcomes.
View details for DOI 10.1200/CCI.19.00034
View details for PubMedID 31584836
Response to Peshkin, Isaacs, and Schwartz.
Journal of the National Cancer Institute
View details for PubMedID 30838406
Using natural language processing to construct a metastatic breast cancer cohort from linked cancer registry and electronic medical records data.
View details for DOI 10.1093/jamiaopen/ooz040
Change in Survival in Metastatic Breast Cancer with Treatment Advances: Meta-Analysis and Systematic Review.
JNCI cancer spectrum
2018; 2 (4): pky062
Metastatic breast cancer (MBC) treatment has changed substantially over time, but we do not know whether survival post-metastasis has improved at the population level.We searched for studies of MBC patients that reported survival after metastasis in at least two time periods between 1970 and the present. We used meta-regression models to test for survival improvement over time in four disease groups: recurrent, recurrent estrogen (ER)-positive, recurrent ER-negative, and de novo stage IV. We performed sensitivity analyses based on bias in some studies that could lead earlier cohorts to include more aggressive cancers.There were 15 studies of recurrent MBC (N = 18 678 patients; 3073 ER-positive and 1239 ER-negative); meta-regression showed no survival improvement among patients recurring between 1980 and 1990, but median survival increased from 21 (95% confidence interval [CI] = 18 to 25) months to 38 (95% CI = 31 to 47) months from 1990 to 2010. For ER-positive MBC patients, median survival increased during 1990-2010 from 32 (95% CI = 23 to 43) to 57 (95% CI = 37 to 87) months, and for ER-negative MBC patients from 14 (95% CI = 11 to 19) to 33 (95% CI = 21 to 51) months. Among eight studies (N = 35 831) of de novo stage IV MBC, median survival increased during 1990-2010 from 20 (95% CI = 16 to 24) to 31 (95% CI = 24 to 39) months. Results did not change in sensitivity analyses.By bridging studies over time, we demonstrated improvements in survival for recurrent and de novo stage IV MBC overall and across ER-defined subtypes since 1990. These results can inform patient-doctor discussions about MBC prognosis and therapy.
View details for DOI 10.1093/jncics/pky062
View details for PubMedID 30627694
View details for PubMedCentralID PMC6305243
Pathogenic Variants in Less Familiar Cancer Susceptibility Genes: What Happens After Genetic Testing?
JCO precision oncology
2018; 2: 1-10
As genetic testing expands, patients are increasingly found to carry pathogenic variants in cancer susceptibility genes that are less familiar to most clinicians, specifically genes other than those causing hereditary breast ovarian cancer syndrome (BRCA1 and BRCA2) and Lynch syndrome. Little is known about the subsequent behaviors of such patients in terms of managing cancer risks and informing relatives.All adult patients who were counseled and tested at the Stanford Cancer Genetics Clinic from January 2013 to July 2015 and had a pathogenic variant in a non-BRCA1/2, non-Lynch syndrome gene were invited to participate in a telephone interview about adherence to risk-reducing recommendations, genetic testing by relatives, and new cancer incidence.Fifty-seven (40%) of 142 eligible patients were successfully contacted, and all 57 patients participated; median follow-up was 677 days (range, 247 to 1,401 days). Most patients (82%; 95% CI, 70% to 90%) recalled that a risk-reducing intervention (screening, medication, or surgery) was recommended, and most patients (85%; 95% CI, 72% to 93%) adhered to the recommendation. Nearly all patients (91%; 95% CI, 81% to 97%) shared results with relatives, and most patients (78%; 95% CI, 64% to 88%) reported that a relative was subsequently tested. During the follow-up period, 9% of patients (95% CI, 3% to 19%) developed second cancers, and in 14% of patients (95% CI, 7% to 26%), a first-degree relative developed cancer, some of which were detected by recommended screening.Patients with a pathogenic variant in a less familiar cancer susceptibility gene report high adherence to risk-reducing interventions. Furthermore, in the 57 carriers and subsequently tested relatives with two years of follow-up, a total of three cancers (one in a proband and two in relatives) were detected through interventions recommended on the basis of the pathogenic variant. These results suggest a potential benefit of genetic counseling and testing for pathogenic variants in less familiar genes.
View details for DOI 10.1200/PO.18.00167
View details for PubMedID 35135157
Pathogenic variants in less familiar cancer susceptibility genes: what happens after genetic testing?
JCO Precision Oncology
View details for DOI 10.1200/PO.18.00167
Racial/ethnic differences in multiple-gene sequencing results for hereditary cancer risk.
Genetics in medicine : official journal of the American College of Medical Genetics
PurposeWe examined racial/ethnic differences in the usage and results of germ-line multiple-gene sequencing (MGS) panels to evaluate hereditary cancer risk.MethodsWe collected genetic testing results and clinical information from 1,483 patients who underwent MGS at Stanford University between 1 January 2013 and 31 December 2015.ResultsAsians and Hispanics presented for MGS at younger ages than whites (48 and 47 vs. 55; P = 5E-16 and 5E-14). Across all panels, the rate of pathogenic variants (15%) did not differ significantly between racial groups. Rates by gene did differ: in particular, a higher percentage of whites than nonwhites carried pathogenic CHEK2 variants (3.8% vs. 1.0%; P = 0.002). The rate of a variant of uncertain significance (VUS) result was higher in nonwhites than whites (36% vs. 27%; P = 2E-4). The probability of a VUS increased with increasing number of genes tested; this effect was more pronounced for nonwhites than for whites (1.1% absolute difference in VUS rates testing BRCA1/2 vs. 8% testing 13 genes vs. 14% testing 28 genes), worsening the disparity.ConclusionIn this diverse cohort undergoing MGS testing, pathogenic variant rates were similar between racial/ethnic groups. By contrast, VUS results were more frequent among nonwhites, with potential significance for the impact of MGS testing by race/ethnicity.GENETICS in MEDICINE advance online publication, 27 July 2017; doi:10.1038/gim.2017.96.
View details for PubMedID 28749474
- Acute, Unilateral Breast Toxicity From Gemcitabine in the Setting of Thoracic Inlet Obstruction. Journal of oncology practice / American Society of Clinical Oncology 2016; 12 (8): 763-764
Multiple breast cancer risk variants are associated with differential transcript isoform expression in tumors
HUMAN MOLECULAR GENETICS
2015; 24 (25): 7421-7431
Genome-wide association studies have identified over 70 single-nucleotide polymorphisms (SNPs) associated with breast cancer. A subset of these SNPs are associated with quantitative expression of nearby genes, but the functional effects of the majority remain unknown. We hypothesized that some risk SNPs may regulate alternative splicing. Using RNA-sequencing data from breast tumors and germline genotypes from The Cancer Genome Atlas, we tested the association between each risk SNP genotype and exon-, exon-exon junction- or transcript-specific expression of nearby genes. Six SNPs were associated with differential transcript expression of seven nearby genes at FDR < 0.05 (BABAM1, DCLRE1B/PHTF1, PEX14, RAD51L1, SRGAP2D and STXBP4). We next developed a Bayesian approach to evaluate, for each SNP, the overlap between the signal of association with breast cancer and the signal of association with alternative splicing. At one locus (SRGAP2D), this method eliminated the possibility that the breast cancer risk and the alternate splicing event were due to the same causal SNP. Lastly, at two loci, we identified the likely causal SNP for the alternative splicing event, and at one, functionally validated the effect of that SNP on alternative splicing using a minigene reporter assay. Our results suggest that the regulation of differential transcript isoform expression is the functional mechanism of some breast cancer risk SNPs and that we can use these associations to identify causal SNPs, target genes and the specific transcripts that may mediate breast cancer risk.
View details for DOI 10.1093/hmg/ddv432
View details for Web of Science ID 000368373600021
View details for PubMedID 26472073
View details for PubMedCentralID PMC4664170
Genome-wide association study identifies variants at 16p13 associated with survival in multiple myeloma patients
Here we perform the first genome-wide association study (GWAS) of multiple myeloma (MM) survival. In a meta-analysis of 306 MM patients treated at UCSF and 239 patients treated at the Mayo clinic, we find a significant association between SNPs near the gene FOPNL on chromosome 16p13 and survival (rs72773978; P=6 × 10(-10)). Patients with the minor allele are at increased risk for mortality (HR: 2.65; 95% CI: 1.94-3.58) relative to patients homozygous for the major allele. We replicate the association in the IMMEnSE cohort including 772 patients, and a University of Utah cohort including 318 patients (rs72773978 P=0.044). Using publicly available data, we find that the minor allele was associated with increased expression of FOPNL and increased expression of FOPNL was associated with higher expression of centrosomal genes and with shorter survival. Polymorphisms at the FOPNL locus are associated with survival among MM patients.
View details for DOI 10.1038/ncomms8539
View details for Web of Science ID 000358852600004
View details for PubMedID 26198393
Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25
The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5' of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53-0.67, P=9 × 10(-18)), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21-0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49-0.80; P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations.
View details for DOI 10.1038/ncomms6260
View details for Web of Science ID 000343985400009
View details for PubMedCentralID PMC4204111
High mammographic density in women of Ashkenazi Jewish descent
BREAST CANCER RESEARCH
2013; 15 (3)
Percent mammographic density (PMD) adjusted for age and body mass index is one of the strongest risk factors for breast cancer and is known to be approximately 60% heritable. Here we report a finding of an association between genetic ancestry and adjusted PMD.We selected self-identified Caucasian women in the California Pacific Medical Center Research Institute Cohort whose screening mammograms placed them in the top or bottom quintiles of age-adjusted and body mass index-adjusted PMD. Our final dataset included 474 women with the highest adjusted PMD and 469 with the lowest genotyped on the Illumina 1 M platform. Principal component analysis (PCA) and identity-by-descent analyses allowed us to infer the women's genetic ancestry and correlate it with adjusted PMD.Women of Ashkenazi Jewish ancestry, as defined by the first principal component of PCA and identity-by-descent analyses, represented approximately 15% of the sample. Ashkenazi Jewish ancestry, defined by the first principal component of PCA, was associated with higher adjusted PMD (P = 0.004). Using multivariate regression to adjust for epidemiologic factors associated with PMD, including age at parity and use of postmenopausal hormone therapy, did not attenuate the association.Women of Ashkenazi Jewish ancestry, based on genetic analysis, are more likely to have high age-adjusted and body mass index-adjusted PMD. Ashkenazi Jews may have a unique set of genetic variants or environmental risk factors that increase mammographic density.
View details for DOI 10.1186/bcr3424
View details for Web of Science ID 000328937600004
View details for PubMedID 23668689
8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2010; 107 (21): 9742-9746
The 8q24 gene desert contains risk loci for multiple epithelial cancers, including colon, breast, and prostate. Recent evidence suggests these risk loci contain enhancers. In this study, data are presented showing that each risk locus bears epigenetic marks consistent with enhancer elements and forms a long-range chromatin loop with the MYC proto-oncogene located several hundred kilobases telomeric and that these interactions are tissue-specific. We therefore propose that the 8q24 risk loci operate through a common mechanism-as tissue-specific enhancers of MYC.
View details for DOI 10.1073/pnas.0910668107
View details for Web of Science ID 000278054700049
View details for PubMedID 20453196
Analysis of chimpanzee history based on genome sequence alignments
2008; 4 (4)
Population geneticists often study small numbers of carefully chosen loci, but it has become possible to obtain orders of magnitude for more data from overlaps of genome sequences. Here, we generate tens of millions of base pairs of multiple sequence alignments from combinations of three western chimpanzees, three central chimpanzees, an eastern chimpanzee, a bonobo, a human, an orangutan, and a macaque. Analysis provides a more precise understanding of demographic history than was previously available. We show that bonobos and common chimpanzees were separated approximately 1,290,000 years ago, western and other common chimpanzees approximately 510,000 years ago, and eastern and central chimpanzees at least 50,000 years ago. We infer that the central chimpanzee population size increased by at least a factor of 4 since its separation from western chimpanzees, while the western chimpanzee effective population size decreased. Surprisingly, in about one percent of the genome, the genetic relationships between humans, chimpanzees, and bonobos appear to be different from the species relationships. We used PCR-based resequencing to confirm 11 regions where chimpanzees and bonobos are not most closely related. Study of such loci should provide information about the period of time 5-7 million years ago when the ancestors of humans separated from those of the chimpanzees.
View details for DOI 10.1371/journal.pgen.1000057
View details for Web of Science ID 000255407400011
View details for PubMedID 18421364