Publications by authors named "Christina Yau"

82 Publications

Assessment of 25-Year Survival of Women With Estrogen Receptor-Positive/ERBB2-Negative Breast Cancer Treated With and Without Tamoxifen Therapy: A Secondary Analysis of Data From the Stockholm Tamoxifen Randomized Clinical Trial.

JAMA Netw Open 2021 Jun 1;4(6):e2114904. Epub 2021 Jun 1.

Department of Oncology and Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden.

Importance: Clinically used breast cancer markers, such as tumor size, tumor grade, progesterone receptor (PR) status, and Ki-67 status, are known to be associated with short-term survival, but the association of these markers with long-term (25-year) survival is unclear.

Objective: To assess the association of clinically used breast cancer markers with long-term survival and treatment benefit among postmenopausal women with lymph node-negative, estrogen receptor [ER]-positive and ERBB2-negative breast cancer who received tamoxifen therapy.

Design, Setting, And Participants: This study was a secondary analysis of data from a subset of 565 women with ER-positive/ERBB2-negative breast cancer who participated in the Stockholm tamoxifen (STO-3) randomized clinical trial. The STO-3 clinical trial was conducted from 1976 to 1990 and comprised 1780 postmenopausal women with lymph node-negative breast cancer who were randomized to receive adjuvant tamoxifen therapy or no endocrine therapy. Complete 25-year follow-up data through December 31, 2016, were obtained from Swedish national registers. Immunohistochemical markers were reannotated in 2014. Data were analyzed from April to December 2020.

Interventions: Patients in the original STO-3 clinical trial were randomized to receive 2 years of tamoxifen therapy vs no endocrine therapy. In 1983, patients who received tamoxifen therapy without cancer recurrence during the 2-year treatment and who consented to continued participation in the STO-3 study were further randomized to receive 3 additional years of tamoxifen therapy or no endocrine therapy.

Main Outcomes And Measures: Distant recurrence-free interval (DRFI) by clinically used breast cancer markers was assessed using Kaplan-Meier and multivariable Cox proportional hazards analyses adjusted for age, period of primary diagnosis, tumor size (T1a and T1b [T1a/b], T1c, and T2), tumor grade (1-3), PR status (positive vs negative), Ki-67 status (low vs medium to high), and STO-3 clinical trial arm (tamoxifen treatment vs no adjuvant treatment). A recursive partitioning analysis was performed to evaluate which markers were able to best estimate long-term DRFI.

Results: The study population comprised 565 postmenopausal women (mean [SD] age, 62.0 [5.3] years) with lymph node-negative, ER-positive/ERBB2-negative breast cancer. A statistically significant difference in long-term DRFI was observed by tumor size (88% for T1a/b vs 76% for T1c vs 63% for T2 tumors; log-rank P < .001) and tumor grade (81% for grade 1 vs 77% for grade 2 vs 65% for grade 3 tumors; log-rank P = .02) but not by PR status or Ki-67 status. Patients with smaller tumors (hazard ratio [HR], 0.31 [95% CI, 0.17-0.55] for T1a/b tumors and 0.58 [95% CI, 0.38-0.88] for T1c tumors) and grade 1 tumors (HR, 0.48; 95% CI, 0.24-0.95) experienced a significant reduction in the long-term risk of distant recurrence compared with patients with larger (T2) tumors and grade 3 tumors, respectively. A significant tamoxifen treatment benefit was observed among patients with larger tumors (HR, 0.53 [95% CI, 0.32-0.89] for T1c tumors and 0.34 [95% CI, 0.16-0.73] for T2 tumors), lower tumor grades (HR, 0.24 [95% CI, 0.07-0.82] for grade 1 tumors and 0.50 [95% CI, 0.31-0.80] for grade 2 tumors), and PR-positive status (HR, 0.38; 95% CI, 0.24-0.62). The recursive partitioning analysis revealed that tumor size was the most important characteristic associated with long-term survival, followed by clinical trial arm among patients with larger tumors.

Conclusions And Relevance: This secondary analysis of data from the STO-3 clinical trial indicated that, among the selected subgroup of patients, tumor size followed by tumor grade were the markers most significantly associated with long-term survival. Furthermore, a significant long-term tamoxifen treatment benefit was observed among patients with larger tumors, lower tumor grades, and PR-positive tumors.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.14904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246315PMC
June 2021

Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial.

Cancer Cell 2021 Jul 17;39(7):989-998.e5. Epub 2021 Jun 17.

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.

The combination of PD-L1 inhibitor durvalumab and PARP inhibitor olaparib added to standard paclitaxel neoadjuvant chemotherapy (durvalumab/olaparib/paclitaxel [DOP]) was investigated in the phase II I-SPY2 trial of stage II/III HER2-negative breast cancer. Seventy-three participants were randomized to DOP and 299 to standard of care (paclitaxel) control. DOP increased pathologic complete response (pCR) rates in all HER2-negative (20%-37%), hormone receptor (HR)-positive/HER2-negative (14%-28%), and triple-negative breast cancer (TNBC) (27%-47%). In HR-positive/HER2-negative cancers, MammaPrint ultra-high (MP2) cases benefited selectively from DOP (pCR 64% versus 22%), no benefit was seen in MP1 cancers (pCR 9% versus 10%). Overall, 12.3% of patients in the DOP arm experienced immune-related grade 3 adverse events versus 1.3% in control. Gene expression signatures associated with immune response were positively associated with pCR in both arms, while a mast cell signature was associated with non-pCR. DOP has superior efficacy over standard neoadjuvant chemotherapy in HER2-negative breast cancer, particularly in a highly sensitive subset of high-risk HR-positive/HER2-negative patients.
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http://dx.doi.org/10.1016/j.ccell.2021.05.009DOI Listing
July 2021

Event-Related Desynchronization During Mirror Visual Feedback: A Comparison of Older Adults and People After Stroke.

Front Hum Neurosci 2021 31;15:629592. Epub 2021 May 31.

Tung Wah Hospital, Hospital Authority, Hong Kong, Hong Kong.

Event-related desynchronization (ERD), as a proxy for mirror neuron activity, has been used as a neurophysiological marker for motor execution after mirror visual feedback (MVF). Using EEG, this study investigated ERD upon the immediate effects of single-session MVF in unimanual arm movements compared with the ERD effects occurring without a mirror, in two groups: stroke patients with left hemiplegia and their healthy counterparts. During EEG recordings, each group performed one session of mirror therapy training in three task conditions: with a mirror, with no mirror, and with a covered mirror. An asymmetry index was calculated from the subtraction of the event-related spectrum perturbations between the C3 and C4 electrodes located over the sensorimotor cortices contralateral and ipsilateral to the moved arm. Results of the effect of task versus group in contralateral and ipsilateral motor areas showed that there was a significant effect of task condition at the contralateral motor area in the high beta band (17-35 Hz) at C3. High beta ERD showed that the suppression was greater over the contralateral hemisphere than it was over the ipsilateral hemisphere in both study groups. The magnitude of low beta (12-16 Hz) ERD in patients with stroke was more suppressed in contralesional C3 under the no mirror compared to that of the covered mirror and similarly more suppressed in ipsilesional C4 ERD under the no mirror compared to that of the mirror condition. The correlation analysis revealed that the magnitude of ERSP power correlated significantly with arm severity in the low and high beta bands in patients with stroke, and a higher asymmetry index in the low beta band was associated with higher arm functioning under the no-mirror condition. There was a shift in sensorimotor ERD toward the contralateral hemisphere as induced by MVF accompanying unimanual movement in both stroke patients and healthy controls. The use of ERD in the low beta band as a neurophysiological marker to indicate the relationships between the amount of MVF-induced ERD attenuation and motor severity, and the outcome indicator for improving stroke patients' neuroplasticity in clinical trials using MVF are warranted to be explored in the future.
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http://dx.doi.org/10.3389/fnhum.2021.629592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200456PMC
May 2021

PRoBE the cloud toolkit: finding the best biomarkers of drug response within a breast cancer clinical trial.

JAMIA Open 2021 Apr 3;4(2):ooab038. Epub 2021 Jun 3.

Department of Surgery, University of California San Francisco, San Francisco, California, USA.

Objectives: In this paper, we discuss leveraging cloud-based platforms to collect, visualize, analyze, and share data in the context of a clinical trial. Our cloud-based infrastructure, Patient Repository of Biomolecular Entities (PRoBE), has given us the opportunity for uniform data structure, more efficient analysis of valuable data, and increased collaboration between researchers.

Materials And Methods: We utilize a multi-cloud platform to manage and analyze data generated from the clinical Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2 (I-SPY 2 TRIAL). A collaboration with the Institute for Systems Biology Cancer Gateway in the Cloud has additionally given us access to public genomic databases. Applications to I-SPY 2 data have been built using R Shiny, while leveraging Google's BigQuery tables and SQL commands for data mining.

Results: We highlight the implementation of PRoBE in several unique case studies including prediction of biomarkers associated with clinical response, access to the Pan-Cancer Atlas, and integrating pathology images within the cloud. Our data integration pipelines, documentation, and all codebase will be placed in a Github repository.

Discussion And Conclusion: We are hoping to develop risk stratification diagnostics by integrating additional molecular, magnetic resonance imaging, and pathology markers into PRoBE to better predict drug response. A robust cloud infrastructure and tool set can help integrate these large datasets to make valuable predictions of response to multiple agents. For that reason, we are continuously improving PRoBE to advance the way data is stored, accessed, and analyzed in the I-SPY 2 clinical trial.
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http://dx.doi.org/10.1093/jamiaopen/ooab038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172495PMC
April 2021

Integrative modeling identifies genetic ancestry-associated molecular correlates in human cancer.

STAR Protoc 2021 Jun 19;2(2):100483. Epub 2021 Apr 19.

Center for Computational and Genomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Cellular and molecular aberrations contribute to the disparity of human cancer incidence and etiology between ancestry groups. Multiomics profiling in The Cancer Genome Atlas (TCGA) allows for querying of the molecular underpinnings of ancestry-specific discrepancies in human cancer. Here, we provide a protocol for integrative associative analysis of ancestry with molecular correlates, including somatic mutations, DNA methylation, mRNA transcription, miRNA transcription, and pathway activity, using TCGA data. This protocol can be generalized to analyze other cancer cohorts and human diseases. For complete details on the use and execution of this protocol, please refer to Carrot-Zhang et al. (2020).
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http://dx.doi.org/10.1016/j.xpro.2021.100483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082263PMC
June 2021

Programmed cell death 1 (PD-1) receptor and programmed death ligand 1 (PD-L1) gene expression in primary breast cancer.

Breast Cancer Res Treat 2021 Jun 28;187(2):387-395. Epub 2021 Apr 28.

UCSF Helen Diller Family Comprehensive Cancer Center Precision Medicine Cancer Building, University of California San Francisco (UCSF), 1825, 4th Street, 3rd Floor, Box 1710, San Francisco, CA, 94158-1710, USA.

Purpose: The interaction of the programmed cell death 1 (PD-1) receptor on tumor-infiltrating lymphocytes with programmed death ligand 1 (PD-L1) on tumor cells downregulates anti-tumor immunity. This study evaluated associations between PD-1 and PD-L1 expression in primary breast cancer, clinical characteristics, and patient outcomes.

Methods: Microarray data from the Investigation of Serial Studies to predict your therapeutic response with imaging and molecular analysis (I-SPY 1) study (n = 149) was used to evaluate PD-1 and PD-L1 expression. Associations with clinical features and chemotherapy response were determined using Kruskal-Wallis and Wilcoxon rank sum tests, respectively. Recurrence-free survival (RFS) associations were determined with the Cox proportional hazard model. Associations of PD-1 and PD-L1 and selected genes associated with breast cancer, as well as a predictor of olaparib response (PARPi-7), were determined in I-SPY 1 and 2 other datasets: METABRIC (n = 1992) and TCGA (n = 817), using Pearson correlations.

Results: In I-SPY 1, PD-1 expression was higher in triple-negative breast cancer (TNBC) and HER2 + breast cancer (p = 0.003), and grade 2/3 tumors (p = 0.043), and was associated with pathologic complete response (p = 0.006). PD-L1 expression in the lowest quintile was associated with worse RFS, even after subtype adjustment (HR 2.33, p = 0.01). PD-1 and PD-L1 gene expression correlated with the expression of immune-related genes and PARPi-7.

Conclusions: PD-1 expression is higher in breast cancers with aggressive features such as TNBC. Low PD-L1 expression may be an adverse prognostic factor. PD-1 and PD-L1 gene expression correlates with the expression of immune-related and DNA damage repair genes.
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http://dx.doi.org/10.1007/s10549-021-06234-3DOI Listing
June 2021

Circulating tumor DNA and magnetic resonance imaging to predict neoadjuvant chemotherapy response and recurrence risk.

NPJ Breast Cancer 2021 Mar 25;7(1):32. Epub 2021 Mar 25.

Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.

We investigated whether serial measurements of circulating tumor DNA (ctDNA) and functional tumor volume (FTV) by magnetic resonance imaging (MRI) can be combined to improve prediction of pathologic complete response (pCR) and estimation of recurrence risk in early breast cancer patients treated with neoadjuvant chemotherapy (NAC). We examined correlations between ctDNA and FTV, evaluated the additive value of ctDNA to FTV-based predictors of pCR using area under the curve (AUC) analysis, and analyzed the impact of FTV and ctDNA on distant recurrence-free survival (DRFS) using Cox regressions. The levels of ctDNA (mean tumor molecules/mL plasma) were significantly correlated with FTV at all time points (p < 0.05). Median FTV in ctDNA-positive patients was significantly higher compared to those who were ctDNA-negative (p < 0.05). FTV and ctDNA trajectories in individual patients showed a general decrease during NAC. Exploratory analysis showed that adding ctDNA information early during treatment to FTV-based predictors resulted in numerical but not statistically significant improvements in performance for pCR prediction (e.g., AUC 0.59 vs. 0.69, p = 0.25). In contrast, ctDNA-positivity after NAC provided significant additive value to FTV in identifying patients with increased risk of metastatic recurrence and death (p = 0.004). In this pilot study, we demonstrate that ctDNA and FTV were correlated measures of tumor burden. Our preliminary findings based on a limited cohort suggest that ctDNA at surgery improves FTV as a predictor of metastatic recurrence and death. Validation in larger studies is warranted.
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http://dx.doi.org/10.1038/s41523-021-00239-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994408PMC
March 2021

Relation between rich-club organization versus brain functions and functional recovery after acute ischemic stroke.

Brain Res 2021 Jul 19;1763:147441. Epub 2021 Mar 19.

Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong Special Administrative Region. Electronic address:

Studies have shown the brain's rich-club organization may underpin brain function and be associated with various brain disorders. In this study, we aimed to investigate the relation between poststroke brain functions and functional recovery versus the rich-club organization of the structural brain network of patients after first-time acute ischemic stroke. A cohort of 16 acute ischemic stroke patients (11 males) was recruited. Structural brain networks were measured using diffusion tensor imaging within 1 week and at 1, 3 and 6 months after stroke. Motor impairment was assessed using the Upper-Extremity Fugl-Meyer motor scale and activities of daily living using the Barthel Index at the same time points as MRI. The rich-club regions that were stable over the course of stroke recovery included the bilateral dorsolateral superior frontal gyri, right supplementary motor area, and left median cingulate and paracingulate gyri. The network properties that correlated with poststroke brain functions were mainly the ratio between communication cost ratio and density ratio of rich-club, feeder and local connections. The recovery of both motor functions and activities of daily living were correlated with higher normalized rich club coefficients and a shorter length of local connections within a week after stroke. The communication cost ratio of feeder connections, the length of rich-club and local connections, and normalized rich club coefficients were found to be potential prognostic indicators of stroke recovery. Our results provide additional support to the notion that different types of network connections play different roles in brain functions as well as functional recovery.
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http://dx.doi.org/10.1016/j.brainres.2021.147441DOI Listing
July 2021

Whole-genome characterization of lung adenocarcinomas lacking the RTK/RAS/RAF pathway.

Cell Rep 2021 Feb;34(5):108707

Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(-) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observe focal deletions targeting the promoter or transcription start site of STK11 (n = 7) or KEAP1 (n = 3), and promoter mutations associated with the increased expression of ILF2 (n = 6). We also identify complex structural variations associated with high-level copy number amplifications. Moreover, an enrichment of focal deletions is found in TP53 mutant cases. Our results indicate that RPA(-) cases demonstrate tumor suppressor deletions and genome instability, but lack unique or recurrent genetic lesions compensating for the lack of RPAs. Larger WGS studies of RPA(-) cases are required to understand this important LUAD subset.
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http://dx.doi.org/10.1016/j.celrep.2021.108707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009291PMC
February 2021

Predicting breast cancer response to neoadjuvant treatment using multi-feature MRI: results from the I-SPY 2 TRIAL.

NPJ Breast Cancer 2020 Nov 27;6(1):63. Epub 2020 Nov 27.

University of Pennsylvania, Philadelphia, PA, USA.

Dynamic contrast-enhanced (DCE) MRI provides both morphological and functional information regarding breast tumor response to neoadjuvant chemotherapy (NAC). The purpose of this retrospective study is to test if prediction models combining multiple MRI features outperform models with single features. Four features were quantitatively calculated in each MRI exam: functional tumor volume, longest diameter, sphericity, and contralateral background parenchymal enhancement. Logistic regression analysis was used to study the relationship between MRI variables and pathologic complete response (pCR). Predictive performance was estimated using the area under the receiver operating characteristic curve (AUC). The full cohort was stratified by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status (positive or negative). A total of 384 patients (median age: 49 y/o) were included. Results showed analysis with combined features achieved higher AUCs than analysis with any feature alone. AUCs estimated for the combined versus highest AUCs among single features were 0.81 (95% confidence interval [CI]: 0.76, 0.86) versus 0.79 (95% CI: 0.73, 0.85) in the full cohort, 0.83 (95% CI: 0.77, 0.92) versus 0.73 (95% CI: 0.61, 0.84) in HR-positive/HER2-negative, 0.88 (95% CI: 0.79, 0.97) versus 0.78 (95% CI: 0.63, 0.89) in HR-positive/HER2-positive, 0.83 (95% CI not available) versus 0.75 (95% CI: 0.46, 0.81) in HR-negative/HER2-positive, and 0.82 (95% CI: 0.74, 0.91) versus 0.75 (95% CI: 0.64, 0.83) in triple negatives. Multi-feature MRI analysis improved pCR prediction over analysis of any individual feature that we examined. Additionally, the improvements in prediction were more notable when analysis was conducted according to cancer subtype.
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http://dx.doi.org/10.1038/s41523-020-00203-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695723PMC
November 2020

Use of 18F-FDG PET/CT as an Initial Staging Procedure for Stage II-III Breast Cancer: A Multicenter Value Analysis.

J Natl Compr Canc Netw 2020 11 2;18(11):1510-1517. Epub 2020 Nov 2.

1University of California, San Francisco, San Francisco, California.

Background: Metastatic staging imaging is not recommended for asymptomatic patients with stage I-II breast cancer. Greater distant metastatic disease risk may warrant baseline imaging in patients with stage II-III with high-risk biologic subtypes. NCCN Guidelines recommend considering CT of the chest, abdomen, and pelvis (CT CAP) and bone scan in appropriate patients. CT CAP and bone scan are considered standard of care (SoC), although PET/CT is a patient-centered alternative.

Methods: Data were available for 799 high-risk patients with clinical stage II-III disease who initiated screening for the I-SPY2 trial at 4 institutions. A total of 564 complete records were reviewed to compare PET/CT versus SoC. Costs were determined from the payer perspective using the national 2018 Medicare Physician Fee Schedule and representative reimbursements to the University of California, San Francisco (UCSF). Incremental cost-effectiveness ratio (ICER) measured cost of using PET/CT per percent of patients who avoided a false-positive (FP).

Results: The de novo metastatic disease rate was 4.6%. Imaging varied across the 4 institutions (P<.0001). The FP rate was higher using SoC versus PET/CT (22.1% vs 11.1%; P=.0009). Mean time between incidental finding on baseline imaging to FP determination was 10.8 days. Mean time from diagnosis to chemotherapy initiation was 44.3 days with SoC versus 37.5 days with PET/CT (P=.0001). Mean cost per patient was $1,132 (SoC) versus $1,477 (PET/CT) using the Medicare Physician Fee Schedule, with an ICER of $31. Using representative reimbursements to UCSF, mean cost per patient was $1,236 (SoC) versus $1,073 (PET/CT) for Medicare, and $3,083 (SoC) versus $1,656 (PET/CT) for a private payer, with ICERs of -$15 and -$130, respectively.

Conclusions: Considerable variation exists in metastatic staging practices. PET/CT reduced FP risk by half and decreased workup of incidental findings, allowing for earlier treatment start. PET/CT may be cost-effective, and at one institution was shown to be cost-saving. Better alignment is needed between hospital pricing strategies and payer coverage policies to deliver high-value care.
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http://dx.doi.org/10.6004/jnccn.2020.7598DOI Listing
November 2020

Mechanism of action biomarkers predicting response to AKT inhibition in the I-SPY 2 breast cancer trial.

NPJ Breast Cancer 2020 2;6:48. Epub 2020 Oct 2.

University of California, San Francisco, San Francisco, CA USA.

The AKT inhibitor MK2206 (M) was evaluated in I-SPY 2 and graduated in the HER2+, HR-, and HR- HER2+ signatures. We hypothesized that AKT signaling axis proteins/genes may specifically predict response to M and tested 26 phospho-proteins and 10 genes involved in AKT-mTOR-HER signaling; in addition, we tested 9 genes from a previous study in the metastatic setting. One hundred and fifty patients had gene expression data from pretreatment biopsies available for analysis (M: 94, control: 56) and 138 had protein data (M: 87, control: 51). Logistic modeling was used to assess biomarker performance in pre-specified analysis. In general, phospho-protein biomarkers of activity in the AKT-mTOR-HER pathway appeared more predictive of response to M than gene expression or total protein biomarkers in the same pathway; however, the nature of the predictive biomarkers differed in the HER2+ and TN groups. In the HER2+ subset, patients achieving a pCR in M had higher levels of multiple AKT kinase substrate phospho-proteins (e.g., pmTOR, pTSC2). In contrast, in the TN subset responding patients had lower levels of AKT pathway phospho-proteins, such as pAKT, pmTOR, and pTSC2. Pathway mutations did not appear to account for these associations. Additional exploratory whole-transcriptome analysis revealed immune signaling as strongly associated with response to M in the HER2+ subset. While our sample size is small, these results suggest that the measurement of particular AKT kinase substrate phospho-proteins could be predictive of MK2206 efficacy in both HER2+ and TN tumors and that immune signaling may play a role in response in HER2+ patients.
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http://dx.doi.org/10.1038/s41523-020-00189-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532145PMC
October 2020

A risk-associated Active transcriptome phenotype expressed by histologically normal human breast tissue and linked to a pro-tumorigenic adipocyte population.

Breast Cancer Res 2020 07 31;22(1):81. Epub 2020 Jul 31.

Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA.

Background: Previous studies have identified and validated a risk-associated Active transcriptome phenotype commonly expressed in the cancer-adjacent and histologically normal epithelium, stroma, and adipose containing peritumor microenvironment of clinically established invasive breast cancers, conferring a 2.5- to 3-fold later risk of dying from recurrent breast cancer. Expression of this Active transcriptome phenotype has not yet been evaluated in normal breast tissue samples unassociated with any benign or malignant lesions; however, it has been associated with increased peritumor adipocyte composition.

Methods: Detailed histologic and transcriptomic (RNAseq) analyses were performed on normal breast biopsy samples from 151 healthy, parous, non-obese (mean BMI = 29.60 ± 7.92) women, ages 27-66 who donated core breast biopsy samples to the Komen Tissue Bank, and whose average breast cancer risk estimate (Gail score) at the time of biopsy (1.27 ± 1.34) would not qualify them for endocrine prevention therapy.

Results: Full genome RNA sequencing (RNAseq) identified 52% (78/151) of these normal breast samples as expressing the Active breast phenotype. While Active signature genes were found to be most variably expressed in mammary adipocytes, donors with the Active phenotype had no difference in BMI but significantly higher Gail scores (1.46 vs. 1.18; p = 0.007). Active breast samples possessed 1.6-fold more (~ 80%) adipocyte nuclei, larger cross-sectional adipocyte areas (p < 0.01), and 0.5-fold fewer stromal and epithelial cell nuclei (p < 1e-6). Infrequent low-level expression of cancer gene hotspot mutations was detected but not enriched in the Active breast samples. Active samples were enriched in gene sets associated with adipogenesis and fat metabolism (FDR q ≤ 10%), higher signature scores for cAMP-dependent lipolysis known to drive breast cancer progression, white adipose tissue browning (Wilcoxon p < 0.01), and genes associated with adipocyte activation (leptin, adiponectin) and remodeling (CAV1, BNIP3), adipokine growth factors (IGF-1, FGF2), and pro-inflammatory fat signaling (IKBKG, CCL13).

Conclusions: The risk-associated Active transcriptome phenotype first identified in cancer-adjacent breast tissues also occurs commonly in healthy women without breast disease who do not qualify for breast cancer chemoprevention, and independently of breast expressed cancer-associated mutations. The risk-associated Active phenotype appears driven by a pro-tumorigenic adipocyte microenvironment that can predate breast cancer development.
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http://dx.doi.org/10.1186/s13058-020-01322-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395362PMC
July 2020

Association of Event-Free and Distant Recurrence-Free Survival With Individual-Level Pathologic Complete Response in Neoadjuvant Treatment of Stages 2 and 3 Breast Cancer: Three-Year Follow-up Analysis for the I-SPY2 Adaptively Randomized Clinical Trial.

JAMA Oncol 2020 09;6(9):1355-1362

Division of Hematology and Oncology, University of California, San Francisco.

Importance: Pathologic complete response (pCR) is a known prognostic biomarker for long-term outcomes. The I-SPY2 trial evaluated if the strength of this clinical association persists in the context of a phase 2 neoadjuvant platform trial.

Objective: To evaluate the association of pCR with event-free survival (EFS) and pCR with distant recurrence-free survival (DRFS) in subpopulations of women with high-risk operable breast cancer treated with standard therapy or one of several novel agents.

Design, Setting, And Participants: Multicenter platform trial of women with operable clinical stage 2 or 3 breast cancer with no prior surgery or systemic therapy for breast cancer; primary tumors were 2.5 cm or larger. Women with tumors that were ERBB2 negative/hormone receptor (HR) positive with low 70-gene assay score were excluded. Participants were adaptively randomized to one of several different investigational regimens or control therapy within molecular subtypes from March 2010 through 2016. The analysis included participants with follow-up data available as of February 26, 2019.

Interventions: Standard-of-care neoadjuvant therapy consisting of taxane treatment with or without (as control) one of several investigational agents or combinations followed by doxorubicin and cyclophosphamide.

Main Outcomes And Measures: Pathologic complete response and 3-year EFS and DRFS.

Results: Of the 950 participants (median [range] age, 49 [23-77] years), 330 (34.7%) achieved pCR. Three-year EFS and DRFS for patients who achieved pCR were both 95%. Hazard ratios for pCR vs non-pCR were 0.19 for EFS (95% CI, 0.12-0.31) and 0.21 for DRFS (95% CI, 0.13-0.34) and were similar across molecular subtypes, varying from 0.14 to 0.18 for EFS and 0.10 to 0.20 for DRFS.

Conclusions And Relevance: The 3-year outcomes from the I-SPY2 trial show that, regardless of subtype and/or treatment regimen, including 9 novel therapeutic combinations, achieving pCR after neoadjuvant therapy implies approximately an 80% reduction in recurrence rate. The goal of the I-SPY2 trial is to rapidly identify investigational therapies that may improve pCR when validated in a phase 3 confirmatory trial. Whether pCR is a validated surrogate in the sense that a therapy that improves pCR rate can be assumed to also improve long-term outcome requires further study.

Trial Registration: ClinicalTrials.gov Identifier: NCT01042379.
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http://dx.doi.org/10.1001/jamaoncol.2020.2535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378873PMC
September 2020

Comprehensive Analysis of Genetic Ancestry and Its Molecular Correlates in Cancer.

Cancer Cell 2020 05;37(5):639-654.e6

The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address:

We evaluated ancestry effects on mutation rates, DNA methylation, and mRNA and miRNA expression among 10,678 patients across 33 cancer types from The Cancer Genome Atlas. We demonstrated that cancer subtypes and ancestry-related technical artifacts are important confounders that have been insufficiently accounted for. Once accounted for, ancestry-associated differences spanned all molecular features and hundreds of genes. Biologically significant differences were usually tissue specific but not specific to cancer. However, admixture and pathway analyses suggested some of these differences are causally related to cancer. Specific findings included increased FBXW7 mutations in patients of African origin, decreased VHL and PBRM1 mutations in renal cancer patients of African origin, and decreased immune activity in bladder cancer patients of East Asian origin.
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http://dx.doi.org/10.1016/j.ccell.2020.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328015PMC
May 2020

Response to Carter et al.

JNCI Cancer Spectr 2020 Apr 5;4(2):pkaa016. Epub 2020 Mar 5.

Department of Surgery, University of California San Francisco, 1600 Divisadero St, San Francisco, CA 94115, USA.

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http://dx.doi.org/10.1093/jncics/pkaa016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192025PMC
April 2020

Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women With Early-Stage Breast Cancer: An Analysis of the Ongoing Phase 2 Adaptively Randomized I-SPY2 Trial.

JAMA Oncol 2020 05;6(5):676-684

Quantum Leap Healthcare Collaborative, San Francisco, California.

Importance: Approximately 25% of patients with early-stage breast cancer who receive (neo)adjuvant chemotherapy experience a recurrence within 5 years. Improvements in therapy are greatly needed.

Objective: To determine if pembrolizumab plus neoadjuvant chemotherapy (NACT) in early-stage breast cancer is likely to be successful in a 300-patient, confirmatory randomized phase 3 neoadjuvant clinical trial.

Design, Setting, And Participants: The I-SPY2 study is an ongoing open-label, multicenter, adaptively randomized phase 2 platform trial for high-risk, stage II/III breast cancer, evaluating multiple investigational arms in parallel. Standard NACT serves as the common control arm; investigational agent(s) are added to this backbone. Patients with ERBB2 (formerly HER2)-negative breast cancer were eligible for randomization to pembrolizumab between November 2015 and November 2016.

Interventions: Participants were randomized to receive taxane- and anthracycline-based NACT with or without pembrolizumab, followed by definitive surgery.

Main Outcomes And Measures: The primary end point was pathologic complete response (pCR). Secondary end points were residual cancer burden (RCB) and 3-year event-free and distant recurrence-free survival. Investigational arms graduated when demonstrating an 85% predictive probability of success in a hypothetical confirmatory phase 3 trial.

Results: Of the 250 women included in the final analysis, 181 were randomized to the standard NACT control group (median [range] age, 47 [24.77] years). Sixty-nine women (median [range] age, 50 [27-71] years) were randomized to 4 cycles of pembrolizumab in combination with weekly paclitaxel followed by AC; 40 hormone receptor (HR)-positive and 29 triple-negative. Pembrolizumab graduated in all 3 biomarker signatures studied. Final estimated pCR rates, evaluated in March 2017, were 44% vs 17%, 30% vs 13%, and 60% vs 22% for pembrolizumab vs control in the ERBB2-negative, HR-positive/ERBB2-negative, and triple-negative cohorts, respectively. Pembrolizumab shifted the RCB distribution to a lower disease burden for each cohort evaluated. Adverse events included immune-related endocrinopathies, notably thyroid abnormalities (13.0%) and adrenal insufficiency (8.7%). Achieving a pCR appeared predictive of long-term outcome, where patients with pCR following pembrolizumab plus chemotherapy had high event-free survival rates (93% at 3 years with 2.8 years' median follow-up).

Conclusions And Relevance: When added to standard neoadjuvant chemotherapy, pembrolizumab more than doubled the estimated pCR rates for both HR-positive/ERBB2-negative and triple-negative breast cancer, indicating that checkpoint blockade in women with early-stage, high-risk, ERBB2-negative breast cancer is highly likely to succeed in a phase 3 trial. Pembrolizumab was the first of 10 agents to graduate in the HR-positive/ERBB2-negative signature.

Trial Registration: ClinicalTrials.gov Identifier: NCT01042379.
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http://dx.doi.org/10.1001/jamaoncol.2019.6650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058271PMC
May 2020

MK-2206 and Standard Neoadjuvant Chemotherapy Improves Response in Patients With Human Epidermal Growth Factor Receptor 2-Positive and/or Hormone Receptor-Negative Breast Cancers in the I-SPY 2 Trial.

J Clin Oncol 2020 04 7;38(10):1059-1069. Epub 2019 Feb 7.

Masonic Cancer Center, University of Minnesota, Minneapolis, MN.

Purpose: The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer.

Patients And Methods: I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week.

Results: MK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform).

Conclusion: The Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.
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http://dx.doi.org/10.1200/JCO.19.01027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106976PMC
April 2020

Androgen receptor gene expression in primary breast cancer.

NPJ Breast Cancer 2019 10;5:47. Epub 2019 Dec 10.

3University of California San Francisco, 1600 Divisadero Street, San Francisco, CA 94115 USA.

We studied androgen receptor (AR) gene expression in primary breast cancer (BC) to determine associations with clinical characteristics and outcomes in the I-SPY 1 study. AR was evaluated in I-SPY 1 ( = 149) using expression microarrays. Associations of AR with clinical and tumor features were determined using the Wilcoxon rank sum test (two-level factors) or the Kruskal-Wallis test (multi-level factors). We identified an optimal AR cut-point to maximize recurrence-free survival (RFS) differences between AR biomarker stratified groups, and assessed the association between the AR stratified groups and RFS using the Cox proportional hazard model. Pearson correlations between AR and selected genes were determined in I-SPY 1, METABRIC ( = 1992), and TCGA ( = 817). AR was lower in triple negative BC vs. hormone receptor positive (HR+)/HER2- and HER2+ disease ( < 0.00001), and lower in basal-like BC ( < 0.00001). AR was higher in grade I/II vs. III tumors ( < 0.00001), in patients >age 50 ( = 0.05), and in node negative disease ( = 0.006). Higher AR was associated with better RFS ( = 0.0007), which remained significant after receptor subtype adjustment ( = 0.01). AR correlated with expression of luminal, HER2, and steroid hormone genes. AR expression was related to clinicopathologic features, intrinsic subtype, and correlated with improved outcome.
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http://dx.doi.org/10.1038/s41523-019-0142-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904475PMC
December 2019

Assessment of Long-term Distant Recurrence-Free Survival Associated With Tamoxifen Therapy in Postmenopausal Patients With Luminal A or Luminal B Breast Cancer.

JAMA Oncol 2019 Sep;5(9):1304-1309

Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.

Importance: Patients with estrogen receptor (ER)-positive breast cancer have a long-term risk for fatal disease. However, the tumor biological factors that influence the long-term risk and the benefit associated with endocrine therapy are not well understood.

Objective: To compare the long-term survival from tamoxifen therapy for patients with luminal A or luminal B tumor subtype.

Design, Setting, And Participants: Secondary analysis of patients from the Stockholm Tamoxifen (STO-3) trial conducted from 1976 to 1990, which randomized postmenopausal patients with lymph node-negative breast cancer to receive adjuvant tamoxifen or no endocrine therapy. Tumor tissue sections were assessed in 2014 using immunohistochemistry and Agilent microarrays. Only patients with luminal A or B subtype tumors were evaluated. Complete long-term follow-up data up to the end of the STO-3 trial on December 31, 2012, were obtained from the Swedish National registers. Data analysis for the secondary analysis was conducted in 2017 and 2018.

Interventions: Patients were randomized to receive at least 2 years of tamoxifen therapy or no endocrine therapy; patients without recurrence who reconsented were further randomized to 3 additional years of tamoxifen therapy or no endocrine therapy.

Main Outcomes And Measures: Distant recurrence-free interval (DRFI) by luminal A and luminal B subtype and trial arm was assessed by Kaplan-Meier analyses and time-dependent flexible parametric models to estimate time-varying hazard ratios (HRs) that were adjusted for patient and tumor characteristics.

Results: In the STO-3 treated trial arm, 183 patients had luminal A tumors and 64 patients had luminal B tumors. In the untreated arm, 153 patients had luminal A tumors and 62 had luminal B tumors. Age at diagnosis ranged from 45 to 73 years. A statistically significant difference in DRFI by trial arm was observed (log rank, P < .001 [luminal A subtype, n = 336], P = .04 [luminal B subtype, n = 126]): the 25-year DRFI for luminal A vs luminal B subtypes was 87% (95% CI, 82%-93%) vs 67% (95% CI, 56%-82%) for treated patients, and 70% (95% CI, 62%-79%) vs 54% (95% CI, 42%-70%) for untreated patients, respectively. Patients with luminal A tumors significantly benefited from tamoxifen therapy for 15 years after diagnosis (HR, 0.57; 95% CI, 0.35-0.94), and those with luminal B tumors benefited from tamoxifen therapy for 5 years (HR, 0.38; 95% CI, 0.24-0.59).

Conclusions And Relevance: Patients with luminal A subtype tumors had a long-term risk of distant metastatic disease, which was reduced by tamoxifen treatment, whereas patients with luminal B tumors had an early risk of distant metastatic disease, and tamoxifen benefit attenuated over time.
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http://dx.doi.org/10.1001/jamaoncol.2019.1856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692699PMC
September 2019

The WISDOM Personalized Breast Cancer Screening Trial: Simulation Study to Assess Potential Bias and Analytic Approaches.

JNCI Cancer Spectr 2018 Oct 8;2(4):pky067. Epub 2019 Jan 8.

Department of Surgery, University of California San Francisco, San Francisco, CA.

Background: WISDOM (Women Informed to Screen Depending on Measures of Risk) is a randomized trial to assess whether personalized breast cancer screening-where women are screened biannually, annually, biennially, or not at all depending on risk and age-can prevent as many advanced (stage IIB or higher) cancers as annual screening in women ages 40-74 years across 5 years of trial time. The short study time in combination with design choices of not requiring study entry and exit mammograms for all participants may introduce different sources of bias in favor of either the personalized or the annual arm.

Methods: We designed a simulation model and performed 5000 virtual WISDOM trials to assess potential biases. Each virtual trial simulated 65 000 randomly assigned participants who were each assigned a risk stratum and a time to stage of at least IIB cancer sampled from an exponential distribution with the hazard rate based on the risk stratum. Results from the virtual trials were used to evaluate two candidate analysis strategies with respect to susceptibility for introducing bias: 1) difference between arms in total number of events over total trial time, and 2) difference in number of events within complete screening cycles.

Results: Based on the simulations, about 86 stage IIB or higher cancers will be detected within the trial and the total exposure time will be about 74 000 years in each arm. Potential ascertainment bias is introduced at study entry and exit. Analysis strategy 1 works better for the nonscreened stratum, whereas method 2 is considerably more unbiased for the strata of women screened biennially or every 6 months.

Conclusion: Combining the two candidate analysis approaches gives a reasonably unbiased analysis based on the simulations and is the method we will use for the primary analysis in WISDOM. Publishing the WISDOM analysis approach provides transparency and can aid the design and analysis of other individualized screening trials.
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http://dx.doi.org/10.1093/jncics/pky067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649825PMC
October 2018

The WISDOM Personalized Breast Cancer Screening Trial: Simulation Study to Assess Potential Bias and Analytic Approaches.

JNCI Cancer Spectr 2018 Oct 8;2(4):pky067. Epub 2019 Jan 8.

Department of Surgery, University of California San Francisco, San Francisco, CA.

Background: WISDOM (Women Informed to Screen Depending on Measures of Risk) is a randomized trial to assess whether personalized breast cancer screening-where women are screened biannually, annually, biennially, or not at all depending on risk and age-can prevent as many advanced (stage IIB or higher) cancers as annual screening in women ages 40-74 years across 5 years of trial time. The short study time in combination with design choices of not requiring study entry and exit mammograms for all participants may introduce different sources of bias in favor of either the personalized or the annual arm.

Methods: We designed a simulation model and performed 5000 virtual WISDOM trials to assess potential biases. Each virtual trial simulated 65 000 randomly assigned participants who were each assigned a risk stratum and a time to stage of at least IIB cancer sampled from an exponential distribution with the hazard rate based on the risk stratum. Results from the virtual trials were used to evaluate two candidate analysis strategies with respect to susceptibility for introducing bias: 1) difference between arms in total number of events over total trial time, and 2) difference in number of events within complete screening cycles.

Results: Based on the simulations, about 86 stage IIB or higher cancers will be detected within the trial and the total exposure time will be about 74 000 years in each arm. Potential ascertainment bias is introduced at study entry and exit. Analysis strategy 1 works better for the nonscreened stratum, whereas method 2 is considerably more unbiased for the strata of women screened biennially or every 6 months.

Conclusion: Combining the two candidate analysis approaches gives a reasonably unbiased analysis based on the simulations and is the method we will use for the primary analysis in WISDOM. Publishing the WISDOM analysis approach provides transparency and can aid the design and analysis of other individualized screening trials.
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http://dx.doi.org/10.1093/jncics/pky067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649825PMC
October 2018

Mapping phospho-catalytic dependencies of therapy-resistant tumours reveals actionable vulnerabilities.

Nat Cell Biol 2019 06 3;21(6):778-790. Epub 2019 Jun 3.

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.

Phosphorylation networks intimately regulate mechanisms of response to therapies. Mapping the phospho-catalytic profile of kinases in cells or tissues remains a challenge. Here, we introduce a practical high-throughput system to measure the enzymatic activity of kinases using biological peptide targets as phospho-sensors to reveal kinase dependencies in tumour biopsies and cell lines. A 228-peptide screen was developed to detect the activity of >60 kinases, including ABLs, AKTs, CDKs and MAPKs. Focusing on BRAF tumours, we found mechanisms of intrinsic resistance to BRAF-targeted therapy in colorectal cancer, including targetable parallel activation of PDPK1 and PRKCA. Furthermore, mapping the phospho-catalytic signatures of melanoma specimens identifies RPS6KB1 and PIM1 as emerging druggable vulnerabilities predictive of poor outcome in BRAF patients. The results show that therapeutic resistance can be caused by the concerted upregulation of interdependent pathways. Our kinase activity-mapping system is a versatile strategy that innovates the exploration of actionable kinases for precision medicine.
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http://dx.doi.org/10.1038/s41556-019-0328-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170003PMC
June 2019

Synchronous Detection of Circulating Tumor Cells in Blood and Disseminated Tumor Cells in Bone Marrow Predicts Adverse Outcome in Early Breast Cancer.

Clin Cancer Res 2019 09 29;25(17):5388-5397. Epub 2019 May 29.

Division of Hematology/Oncology, University of California San Francisco, San Francisco, California.

Purpose: We examined the prognostic impact of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) detected at the time of surgery in 742 untreated patients with early breast cancer.

Experimental Design: DTCs in bone marrow were enumerated using the EPCAM-based immunomagnetic enrichment and flow cytometry (IE/FC) assay. CTCs in blood were enumerated either by IE/FC or CellSearch. Median follow-up was 7.1 years for distant recurrence-free survival (DRFS) and 9.1 years for breast cancer-specific survival (BCSS) and overall survival (OS). Cox regressions were used to estimate hazard ratios for DRFS, BCSS, and OS in all patients, as well as in hormone receptor-positive (HR-positive, 87%) and HR-negative (13%) subsets.

Results: In multivariate models, CTC positivity by IE/FC was significantly associated with reduced BCSS in both all ( = 288; = 0.0138) and HR-positive patients ( = 249; = 0.0454). CTC positivity by CellSearch was significantly associated with reduced DRFS in both all ( = 380; = 0.0067) and HR-positive patients ( = 328; = 0.0002). DTC status, by itself, was not prognostic; however, when combined with CTC status by IE/FC ( = 273), double positivity (CTC+/DTC+, 8%) was significantly associated with reduced DRFS ( = 0.0270), BCSS ( = 0.0205), and OS ( = 0.0168). In HR-positive patients, double positivity (9% of 235) was significantly associated with reduced DRFS ( = 0.0285), BCSS ( = 0.0357), and OS ( = 0.0092).

Conclusions: Detection of CTCs in patients with HR-positive early breast cancer was an independent prognostic factor for DRFS (using CellSearch) and BCSS (using IE/FC). Simultaneous detection of DTCs provided additional prognostic power for outcome, including OS.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726564PMC
September 2019

Evaluation of the HER/PI3K/AKT Family Signaling Network as a Predictive Biomarker of Pathologic Complete Response for Patients With Breast Cancer Treated With Neratinib in the I-SPY 2 TRIAL.

JCO Precis Oncol 2018 16;2. Epub 2018 Aug 16.

, , and , George Mason University, Manassas, VA; , , , , , , , and , University of California, San Francisco, San Francisco, CA; , , and , Netherlands Cancer Institute, Amsterdam, the Netherlands; , University of Pennsylvania, Philadelphia, PA; , University of Texas MD Anderson Cancer Center, Houston; , Berry Consultants, Austin, TX; , University of Minnesota, Minneapolis; and , Mayo Clinic, Rochester, MN.

Purpose: In the I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2), the pan-erythroblastic oncogene B inhibitor neratinib was available to all hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) subtypes and graduated in the HR-negative/HER2-positive signature. We hypothesized that neratinib response may be predicted by baseline HER2 epidermal growth factor receptor (EGFR) signaling activation/phosphorylation levels independent of total levels of HER2 or EGFR proteins.

Materials And Methods: Complete experimental and response data were available for between 130 and 193 patients. In qualifying analyses, which used logistic regression and treatment interaction analysis, 18 protein/phosphoprotein, 10 mRNA, and 12 DNA biomarkers that related to family signaling were evaluated. Exploratory analyses used Wilcoxon rank sum and tests without multiple comparison correction.

Results: pathway DNA biomarkers were either low prevalence or nonpredictive. In expression biomarker analysis, only one gene () was specifically associated with response to neratinib in the HER2-negative subset. In qualifying protein/phosphoprotein analyses that used reverse phase protein microarrays, six HER family markers were associated with neratinib response. After analysis was adjusted for HR/HER2 status, EGFR Y1173 (pEGFR) showed a significant biomarker-by-treatment interaction ( = .049). Exploratory analysis of HER family signaling in patients with triple-negative (TN) disease found that activation of EGFR Y1173 ( = .005) and HER2 Y1248 (pHER2) ( = .019) were positively associated with pathologic complete response. Exploratory analysis in this pEGFR/pHER2-activated TN subgroup identified elevated levels of estrogen receptor α ( < .006) in these patients.

Conclusion: Activation of HER family phosphoproteins associates with response to neratinib, but only EGFR Y1173 and appear to add value to the graduating signature. Activation of HER2 and EGFR in TN tumors may identify patients whose diseases respond to neratinib and implies that there is a subset of patients with TN disease who paradoxically exhibit HER family signaling activation and may achieve clinical benefit with neratinib; this concept must be validated in future studies.
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http://dx.doi.org/10.1200/PO.18.00024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446527PMC
August 2018

Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer.

Cell 2018 04;173(2):291-304.e6

Van Andel Research Institute, Grand Rapids, MI 49503, USA. Electronic address:

We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.
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http://dx.doi.org/10.1016/j.cell.2018.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957518PMC
April 2018

A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers.

Cancer Cell 2018 04 2;33(4):690-705.e9. Epub 2018 Apr 2.

Department of Epidemiology and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically significant subtypes, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs). Eleven SCNAs and 11 SMGs had not been identified in previous TCGA studies of the individual tumor types. We found functionally significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and gene/lncRNA interaction networks. Pathway analysis identified subtypes with high leukocyte infiltration, raising potential implications for immunotherapy. Using 16 key molecular features, we identified five prognostic subtypes and developed a decision tree that classified patients into the subtypes based on just six features that are assessable in clinical laboratories.
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http://dx.doi.org/10.1016/j.ccell.2018.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959730PMC
April 2018

Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas.

Cell Rep 2018 04;23(1):239-254.e6

Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer, Houston, TX 77030, USA.

DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.
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http://dx.doi.org/10.1016/j.celrep.2018.03.076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961503PMC
April 2018
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