Publications by authors named "Nancy E Davidson"

253 Publications

Ki67 Assessment in Breast Cancer: Are We There yet?

J Natl Cancer Inst 2020 Dec 28. Epub 2020 Dec 28.

Fred Hutchinson Cancer Research Center, University of Washington and Seattle Cancer Care Alliance, Seattle, WA.

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http://dx.doi.org/10.1093/jnci/djaa202DOI Listing
December 2020

Gender Differences in Faculty Rank and Subspecialty Choice among Academic Medical Oncologists.

Cancer Invest 2021 Jan 11;39(1):21-24. Epub 2020 Nov 11.

Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA, USA.

Gender parity within academic oncology is important. We hypothesized that gender differences exist in subspecialty choice and academic rank among medical oncologists. We performed a cross-sectional study of adult medical oncologists at the top 15 cancer centers. Gender, rank, subspecialty (breast, thoracic, gastrointestinal, and genitourinary) and board certification year were recorded. 570 medical oncologists were identified (60% men; 40% women). More women practice breast oncology (OR 3.1,  < 0.001), but less practice genitourinary oncology (OR 0.37,  < 0.001). 22% of women were full professors vs 34% of men (OR 0.55,  = 0.001). Gender differences persist in academic adult medical oncology.
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http://dx.doi.org/10.1080/07357907.2020.1846191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891896PMC
January 2021

Road Map to Safe and Well-Designed De-escalation Trials of Systemic Adjuvant Therapy for Solid Tumors.

J Clin Oncol 2020 12 14;38(34):4120-4129. Epub 2020 Oct 14.

Dana Farber Cancer Institute, Department of Medical Oncology, Boston, MA.

An important challenge in the field of cancer is finding the balance between delivering effective treatments and avoiding adverse effects and financial toxicity caused by innovative, yet expensive, drugs. To address this, several treatment de-escalation trials have been conducted, but only a few of these have provided clear answers. A few trials had poor accrual or had design flaws that led to conflicting results. Members of the Breast International Group (BIG) and North American Breast Cancer Group (NABCG) believe the way forward is to understand the lessons from these trials and listen more carefully to what truly matters to our patients. We reviewed several adjuvant trials of different cancer types and developed a road map for improving the design and implementation of future de-escalation trials. The road map incorporates patients' insights obtained through focused group discussions across the BIG-NABCG networks. Considerations for the development of de-escalation trials for systemic adjuvant treatment, including noninferiority trial design, choice of end points, and prioritization of a patient's perspectives, are presented in this consensus article.
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http://dx.doi.org/10.1200/JCO.20.01382DOI Listing
December 2020

Impact of adjuvant trastuzumab on locoregional failure rates in a randomized clinical trial: North Central Cancer Treatment Group N9831 (alliance) study.

Cancer 2020 12 15;126(24):5239-5246. Epub 2020 Sep 15.

Department of Hematology & Oncology, Mayo Clinic, Jacksonville, Florida.

Background: The goal of this study was to assess the impact of trastuzumab on locoregional failure.

Methods: The analysis included 2763 patients with HER2-positive (HER2+) breast cancer who were randomly assigned to adjuvant doxorubicin (A), cyclophosphamide (C), paclitaxel (T) and trastuzumab (H) (arm A, AC→T [n = 922]; arm B, AC→T→H [n = 988]; arm C, AC→T+H→H [n = 853]). Radiotherapy was given after AC→T concurrently with H. Radiotherapy was given after lumpectomy (L) or after mastectomy (M) with ≥4 positive lymph nodes but was optional for 1 to 3 positive lymph nodes. Locoregional failures at 10 years (LFR10) as first events were compared using competing risk analysis.

Results: The median follow-up was 13.0 years. The first site of failure was local-only in 96 cases, locoregional in 16 cases, regional in 32 cases, and not specified in 2 cases; LFR10 was 4.8% (95% CI 4.1%-5.7%). LFR10 was 5.5% (95% CI 4.3%-7.2%), 4.9% (95% CI 3.7%-6.4%), and 2.8% (95% CI 1.9%-4.1%) in arms A, B, and C (B vs A: hazard ratio [HR] 0.91, P = .62; C vs A: HR 0.72, P = .12). For estrogen receptor-positive patients, LFR10 was 3.7% (95% CI 2.8%-4.8%) and for estrogen receptor-negative patients, it was 6.1% (95% CI 5.0%-7.4%; HR 0.61, P = .004). Local treatment included L+RT (n = 1044 [38%]), M+RT (n = 1025 [37%]), and M (n = 694 [25%]). LFR10 was 6.% (95% CI 5.0%-7.8%), 3.0% (95% CI 2.1%-4.3%), and 5.5% (95% CI 4.0%-7.4%) for L+RT, M+RT, and M, respectively (M+RT vs L+RT: HR 0.43, P < .001; M vs L+RT: HR 0.88, P = .57). For 1 to 3 positive lymph nodes, LFR10 was 6.5% (95% CI 4.8%-8.9%), 4.1% (95% CI 2.4%-7.0%), and 4.3% (95% CI 2.9%-6.5%) in L+RT, M+RT, and M, respectively (M vs L+RT: HR 0.68, P = .14; M vs M+RT: HR 1.2, P = .6).

Conclusion: Low 10-year LFRs were seen regardless of trastuzumab use. Differences in local therapy in patients with 1 to 3 positive lymph nodes did not appear to improve local control. Local therapy studies for HER2+ and other tumor characteristics are important as the role of local therapies continues to evolve.
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http://dx.doi.org/10.1002/cncr.33154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686244PMC
December 2020

The Long and Winding Road for Breast Cancer Biomarkers to Reach Clinical Utility.

Clin Cancer Res 2020 Nov 28;26(21):5543-5545. Epub 2020 Aug 28.

Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington.

Tumor data from the ABCSG 5 trial of chemotherapy versus endocrine therapy for premenopausal ER breast cancer supports molecular subtyping by Ki-67 IHC as a prognostic marker. But while this tissue was handled uniformly, Ki-67 testing overall is unstandardized, complicating clinical utility. Increasing potential biomarkers herald more challenges in biomarker validation..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2451DOI Listing
November 2020

Proteomic and transcriptomic profiling identifies mediators of anchorage-independent growth and roles of inhibitor of differentiation proteins in invasive lobular carcinoma.

Sci Rep 2020 07 13;10(1):11487. Epub 2020 Jul 13.

Women's Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA.

Invasive lobular carcinoma (ILC) is a histological subtype of breast cancer with distinct molecular and clinical features from the more common subtype invasive ductal carcinoma (IDC). ILC cells exhibit anchorage-independent growth in ultra-low attachment (ULA) suspension cultures, which is largely attributed to the loss of E-cadherin. In addition to anoikis resistance, herein we show that human ILC cell lines exhibit enhanced cell proliferation in ULA cultures as compared to IDC cells. Proteomic comparison of ILC and IDC cell lines identified induction of PI3K/Akt and p90-RSK pathways specifically in ULA culture in ILC cells. Further transcriptional profiling uncovered unique upregulation of the inhibitors of differentiation family transcription factors ID1 and ID3 in ILC ULA culture, the knockdown of which diminished the anchorage-independent growth of ILC cell lines through cell cycle arrest. We find that ID1 and ID3 expression is higher in human ILC tumors as compared to IDC, correlated with worse prognosis uniquely in patients with ILC and associated with upregulation of angiogenesis and matrisome-related genes. Altogether, our comprehensive study of anchorage independence in human ILC cell lines provides mechanistic insights and clinical implications for metastatic dissemination of ILC and implicates ID1 and ID3 as novel drivers and therapeutic targets for lobular breast cancer.
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http://dx.doi.org/10.1038/s41598-020-68141-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359337PMC
July 2020

Managing Cancer Care During the COVID-19 Pandemic: Agility and Collaboration Toward a Common Goal.

J Natl Compr Canc Netw 2020 03 20:1-4. Epub 2020 Mar 20.

Seattle Cancer Care Alliance.

The first confirmed case of coronavirus disease 2019 (COVID-19) in the United States was reported on January 20, 2020, in Snohomish County, Washington. At the epicenter of COVID-19 in the United States, the Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, and University of Washington are at the forefront of delivering care to patients with cancer during this public health crisis. This Special Feature highlights the unique circumstances and challenges of cancer treatment amidst this global pandemic, and the importance of organizational structure, preparation, agility, and a shared vision for continuing to provide cancer treatment to patients in the face of uncertainty and rapid change.
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http://dx.doi.org/10.6004/jnccn.2020.7560DOI Listing
March 2020

Author Correction: CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer.

Nat Commun 2020 Jan 29;11(1):673. Epub 2020 Jan 29.

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-14429-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989459PMC
January 2020

Association Between 21-Gene Assay Recurrence Score and Locoregional Recurrence Rates in Patients With Node-Positive Breast Cancer.

JAMA Oncol 2020 04;6(4):505-511

Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois.

Importance: The 21-gene assay recurrence score is increasingly used to personalize treatment recommendations for systemic therapy in postmenopausal women with estrogen receptor (ER)- or progesterone receptor (PR)-positive, node-positive breast cancer; however, the relevance of the 21-gene assay to radiotherapy decisions remains uncertain.

Objective: To examine the association between recurrence score and locoregional recurrence (LRR) in a postmenopausal patient population treated with adjuvant chemotherapy followed by tamoxifen or tamoxifen alone.

Design, Setting, And Participants: This cohort study was a retrospective analysis of the Southwest Oncology Group S8814, a phase 3 randomized clinical trial of postmenopausal women with ER/PR-positive, node-positive breast cancer treated with tamoxifen alone, chemotherapy followed by tamoxifen, or concurrent tamoxifen and chemotherapy. Patients at North American clinical centers were enrolled from June 1989 to July 1995. Medical records from patients with recurrence score information were reviewed for LRR and radiotherapy use. Primary analysis included 316 patients and excluded 37 who received both mastectomy and radiotherapy, 9 who received breast-conserving surgery without documented radiotherapy, and 5 with unknown surgical type. All analyses were performed from January 22, 2016, to August 9, 2019.

Main Outcomes And Measures: The LRR was defined as a recurrence in the breast; chest wall; or axillary, infraclavicular, supraclavicular, or internal mammary lymph nodes. Time to LRR was tested with log-rank tests and Cox proportional hazards regression for multivariate models.

Results: The final cohort of this study comprised 316 women with a mean (range) age of 60.4 (44-81) years. Median (interquartile range) follow-up for those without LRR was 8.7 (7.0-10.2) years. Seven LRR events (5.8%) among 121 patients with low recurrence score and 27 LRR events (13.8%) among 195 patients with intermediate or high recurrence score occurred. The estimated 10-year cumulative incidence rates were 9.7% for those with a low recurrence score and 16.5% for the group with intermediate or high recurrence score (P = .02). Among patients who had a mastectomy without radiotherapy (n = 252), the differences in the 10-year actuarial LRR rates remained significant: 7.7 % for the low recurrence score group vs 16.8% for the intermediate or high recurrence score group (P = .03). A multivariable model controlling for randomized treatment, number of positive nodes, and surgical type showed that a higher recurrence score was prognostic for LRR (hazard ratio [HR], 2.36; 95% CI, 1.02-5.45; P = .04). In a subset analysis of patients with a mastectomy and 1 to 3 involved nodes who did not receive radiation therapy, the group with a low recurrence score had a 1.5% rate of LRR, whereas the group with an intermediate or high recurrence score had a 11.1% LRR (P = .051).

Conclusions And Relevance: This study found that higher recurrence scores were associated with increased LRR after adjustment for treatment, type of surgical procedure, and number of positive nodes. This finding suggests that the recurrence score may be used, along with accepted clinical variables, to assess the risk of LRR during radiotherapy decision-making.
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http://dx.doi.org/10.1001/jamaoncol.2019.5559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990911PMC
April 2020

CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer.

Nat Commun 2019 11 8;10(1):5114. Epub 2019 Nov 8.

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Triple-negative breast cancer (TNBC), which lacks estrogen receptor α (ERα), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression, is closely related to basal-like breast cancer. Previously, we and others report that cyclin E/cyclin-dependent kinase 2 (CDK2) phosphorylates enhancer of zeste homolog 2 (EZH2) at T416 (pT416-EZH2). Here, we show that transgenic expression of phospho-mimicking EZH2 mutant EZH2 in mammary glands leads to tumors with TNBC phenotype. Coexpression of EZH2 in mammary epithelia of HER2/Neu transgenic mice reprograms HER2-driven luminal tumors into basal-like tumors. Pharmacological inhibition of CDK2 or EZH2 allows re-expression of ERα and converts TNBC to luminal ERα-positive, rendering TNBC cells targetable by tamoxifen. Furthermore, the combination of either CDK2 or EZH2 inhibitor with tamoxifen effectively suppresses tumor growth and markedly improves the survival of the mice bearing TNBC tumors, suggesting that the mechanism-based combination therapy may be an alternative approach to treat TNBC.
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http://dx.doi.org/10.1038/s41467-019-13105-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841924PMC
November 2019

Use of Endocrine Therapy for Breast Cancer Risk Reduction: ASCO Clinical Practice Guideline Update.

J Clin Oncol 2019 11 3;37(33):3152-3165. Epub 2019 Sep 3.

American Society of Clinical Oncology, Alexandria, VA.

Purpose: To update the ASCO guideline on pharmacologic interventions for breast cancer risk reduction and provide guidance on clinical issues that arise when deciding to use endocrine therapy for breast cancer risk reduction.

Methods: An Expert Panel conducted targeted systematic literature reviews to identify new studies.

Results: A randomized clinical trial that evaluated the use of anastrozole for reduction of estrogen receptor-positive breast cancers in postmenopausal women at increased risk of developing breast cancer provided the predominant basis for the update.

Updated Recommendations: In postmenopausal women at increased risk, the choice of endocrine therapy now includes anastrozole (1 mg/day) in addition to exemestane (25 mg/day), raloxifene (60 mg/day), or tamoxifen (20 mg/day). The decision regarding choice of endocrine therapy should take into consideration age, baseline comorbidities, and adverse effect profiles. Clinicians should not prescribe anastrozole, exemestane, or raloxifene for breast cancer risk reduction to premenopausal women. Tamoxifen 20 mg/day for 5 years is still considered standard of care for risk reduction in premenopausal women who are at least 35 years old and have completed childbearing. Data on low-dose tamoxifen as an alternative to the standard dose for both pre- and postmenopausal women with intraepithelial neoplasia are discussed in the Clinical Considerations section of this article. Additional information is available at www.asco.org/breast-cancer-guidelines.
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http://dx.doi.org/10.1200/JCO.19.01472DOI Listing
November 2019

Extending Adjuvant Endocrine Therapy in Breast Cancer: Who, What, Why?

Oncology (Williston Park) 2019 06;33(6):243-6

Adjuvant endocrine therapy provides substantial benefit by reducing breast cancer recurrences and improving associated mortality in early-stage endocrine-responsive breast cancers (estrogen receptor- and/or progesterone receptor-positive). Residual risk of relapse, even after completion of 5 years of adjuvant endocrine therapy, has fueled development of extended therapy (beyond 5 years) trials. However, several questions remain when recommending extended adjuvant endocrine therapy, such as those concerning patient selection, agent of choice, use of biomarkers or clinical variables to assess residual risk of relapse, and duration of treatment. In this article, we will provide a case-based expert opinion on: 1) the duration of extended adjuvant endocrine therapy in both premenopausal and postmenopausal women; 2) use of biomarkers in guiding this decision; and 3) toxicities to be considered when recommending extended adjuvant endocrine therapy. We also provide key factors to consider, including patient preference, when guiding our patients in this important treatment decision.
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June 2019

Double Trouble: Contralateral Breast Cancer Risk Management in the Modern Era.

J Natl Cancer Inst 2019 07;111(7):641-643

Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle Cancer Care Alliance, Seattle, WA.

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http://dx.doi.org/10.1093/jnci/djy203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624165PMC
July 2019

AACR White Paper: Shaping the Future of Cancer Prevention - A Roadmap for Advancing Science and Public Health.

Cancer Prev Res (Phila) 2018 12;11(12):735-778

Division of Cancer Prevention & Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX.

The recent pace, extent, and impact of paradigm-changing cancer prevention science has been remarkable. The American Association for Cancer Research (AACR) convened a 3-day summit, aligned with five research priorities: (i) Precancer Atlas (PCA). (ii) Cancer interception. (iii) Obesity-cancer linkage, a global epidemic of chronic low-grade inflammation. (iv) Implementation science. (v) Cancer disparities. Aligned with these priorities, AACR co-led the Lancet Commission to formally endorse and accelerate the NCI Cancer Moonshot program, facilitating new global collaborative efforts in cancer control. The expanding scope of creative impact is perhaps most startling-from NCI-funded built environments to AACR Team Science Awarded studies of Asian cancer genomes informing global primary prevention policies; cell-free epigenetic marks identifying incipient neoplastic site; practice-changing genomic subclasses in myeloproliferative neoplasia (including germline variant tightly linked to JAK2 V617F haplotype); universal germline genetic testing for pancreatic cancer; and repurposing drugs targeting immune- and stem-cell signals (e.g., IL-1β, PD-1, RANK-L) to cancer interception. Microbiota-driven IL-17 can induce stemness and transformation in pancreatic precursors (identifying another repurposing opportunity). Notable progress also includes hosting an obesity special conference (connecting epidemiologic and molecular perspectives to inform cancer research and prevention strategies), co-leading concerted national implementation efforts in HPV vaccination, and charting the future elimination of cancer disparities by integrating new science tools, discoveries and perspectives into community-engaged research, including targeted counter attacks on e-cigarette ad exploitation of children, Hispanics and Blacks. Following this summit, two unprecedented funding initiatives were catalyzed to drive cancer prevention research: the NCI Cancer Moonshot (e.g., PCA and disparities); and the AACR-Stand Up To Cancer bold "Cancer Interception" initiative.
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http://dx.doi.org/10.1158/1940-6207.CAPR-18-0421DOI Listing
December 2018

Whole genome amplification of cell-free DNA enables detection of circulating tumor DNA mutations from fingerstick capillary blood.

Sci Rep 2018 11 23;8(1):17313. Epub 2018 Nov 23.

Women's Cancer Research Center, Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, Magee Womens Research Institute, Pittsburgh, PA, 15213, USA.

The ability to measure mutations in plasma cell-free DNA (cfDNA) has the potential to revolutionize cancer surveillance and treatment by enabling longitudinal monitoring not possible with solid tumor biopsies. However, obtaining sufficient quantities of cfDNA remains a challenge for assay development and clinical translation; consequently, large volumes of venous blood are typically required. Here, we test proof-of-concept for using smaller volumes via fingerstick collection. Matched venous and fingerstick blood were obtained from seven patients with metastatic breast cancer. Fingerstick blood was separated at point-of-care using a novel paper-based concept to isolate plasma centrifuge-free. Patient cfDNA was then analyzed with or without a new method for whole genome amplification via rolling-circle amplification (WG-RCA). We identified somatic mutations by targeted sequencing and compared the concordance of mutation detection from venous and amplified capillary samples by droplet-digital PCR. Patient mutations were detected with 100% concordance after WG-RCA, although in some samples, allele frequencies showed greater variation likely due to differential amplification or primer inaccessibility. These pilot findings provide physiological evidence that circulating tumor DNA is accessible by fingerstick and sustains presence/absence of mutation detection after whole-genome amplification. Further refinement may enable simpler and less-invasive methods for longitudinal or theranostic surveillance of metastatic cancer.
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http://dx.doi.org/10.1038/s41598-018-35470-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251935PMC
November 2018

Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update.

J Clin Oncol 2019 02 19;37(5):423-438. Epub 2018 Nov 19.

10 University of Michigan, Ann Arbor, MI.

Purpose: To update the ASCO clinical practice guideline on adjuvant endocrine therapy based on emerging data about the optimal duration of aromatase inhibitor (AI) treatment.

Methods: ASCO conducted a systematic review of randomized clinical trials from 2012 to 2018. Guideline recommendations were based on the Panel's review of the evidence from six trials.

Results: The six included studies of AI treatment beyond 5 years of therapy demonstrated that extension of AI treatment was not associated with an overall survival advantage but was significantly associated with lower risks of breast cancer recurrence and contralateral breast cancer compared with placebo. Bone-related toxic effects were more common with extended AI treatment.

Recommendations: The Panel recommends that women with node-positive breast cancer receive extended therapy, including an AI, for up to a total of 10 years of adjuvant endocrine treatment. Many women with node-negative breast cancer should consider extended therapy for up to a total of 10 years of adjuvant endocrine treatment based on considerations of recurrence risk using established prognostic factors. The Panel noted that the benefits in absolute risk of reduction were modest and that, for lower-risk node-negative or limited node-positive cancers, an individualized approach to treatment duration that is based on considerations of risk reduction and tolerability was appropriate. A substantial portion of the benefit for extended adjuvant AI therapy was derived from prevention of second breast cancers. Shared decision making between clinicians and patients is appropriate for decisions about extended adjuvant endocrine treatment, including discussions about the absolute benefits in the reduction of breast cancer recurrence, the prevention of second breast cancers, and the impact of adverse effects of treatment. Additional information can be found at www.asco.org/breast-cancer-guidelines .
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http://dx.doi.org/10.1200/JCO.18.01160DOI Listing
February 2019

Gonadotropin-Releasing Hormone (GnRH) Agonists for Fertility Preservation: Is POEMS the Final Verse?

J Natl Cancer Inst 2019 02;111(2):107-108

Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Department of Medicine, University of Washington, Seattle, WA.

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http://dx.doi.org/10.1093/jnci/djy188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376902PMC
February 2019

Comprehensive Phenotypic Characterization of Human Invasive Lobular Carcinoma Cell Lines in 2D and 3D Cultures.

Cancer Res 2018 11 18;78(21):6209-6222. Epub 2018 Sep 18.

Women's Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, Pittsburgh, Pennsylvania.

Invasive lobular carcinoma (ILC) is the second most common subtype of breast cancer following invasive ductal carcinoma (IDC) and characterized by the loss of E-cadherin-mediated adherens junctions. Despite displaying unique histologic and clinical features, ILC still remains a chronically understudied disease, with limited knowledge gleaned from available laboratory research models. Here we report a comprehensive 2D and 3D phenotypic characterization of four estrogen receptor-positive human ILC cell lines: MDA-MB-134, SUM44, MDA-MB-330, and BCK4. Compared with the IDC cell lines MCF7, T47D, and MDA-MB-231, ultra-low attachment culture conditions revealed remarkable anchorage independence unique to ILC cells, a feature not evident in soft-agar gels. Three-dimensional Collagen I and Matrigel culture indicated a generally loose morphology for ILC cell lines, which exhibited differing preferences for adhesion to extracellular matrix proteins in 2D. Furthermore, ILC cells were limited in their ability to migrate and invade in wound-scratch and transwell assays, with the exception of haptotaxis to Collagen I. Transcriptional comparison of these cell lines confirmed the decreased cell proliferation and E-cadherin-mediated intercellular junctions in ILC while uncovering the induction of novel pathways related to cyclic nucleotide phosphodiesterase activity, ion channels, drug metabolism, and alternative cell adhesion molecules such as N-cadherin, some of which were differentially regulated in ILC versus IDC tumors. Altogether, these studies provide an invaluable resource for the breast cancer research community and facilitate further functional discoveries toward understanding ILC, identifying novel drug targets, and ultimately improving the outcome of patients with ILC. These findings provide the breast cancer research community with a comprehensive assessment of human invasive lobular carcinoma (ILC) cell line signaling and behavior in various culture conditions, aiding future endeavors to develop therapies and to ultimately improve survival in patients with ILC. .
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507416PMC
November 2018

Inhibition of histone lysine-specific demethylase 1 elicits breast tumor immunity and enhances antitumor efficacy of immune checkpoint blockade.

Oncogene 2019 01 15;38(3):390-405. Epub 2018 Aug 15.

Women's Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.

Immunotherapy strategies have been emerging as powerful weapons against cancer. Early clinical trials reveal that overall response to immunotherapy is low in breast cancer patients, suggesting that effective strategies to overcome resistance to immunotherapy are urgently needed. In this study, we investigated whether epigenetic reprograming by modulating histone methylation could enhance effector T lymphocyte trafficking and improve therapeutic efficacy of immune checkpoint blockade in breast cancer with focus on triple-negative breast cancer (TNBC) subtype. In silico analysis of The Cancer Genome Atlas (TCGA) data shows that expression of histone lysine-specific demethylase 1 (LSD1) is inversely associated with the levels of cytotoxic T cell-attracting chemokines (C-C motif chemokine ligand 5 (CCL5), C-X-C motif chemokine ligand 9 and 10 (CXCL9, CXCL10)) and programmed death-ligand 1 (PD-L1) in clinical TNBC specimens. Tiling chromatin immunoprecipitation study showed that re-expression of chemokines by LSD1 inhibition is associated with increased H3K4me2 levels at proximal promoter regions. Rescue experiments using concurrent treatment with small interfering RNA or inhibitor of chemokine receptors blocked LSD1 inhibitor-enhanced CD8+ T cell migration, indicating a critical role of key T cell chemokines in LSD1-mediated CD8+ lymphocyte trafficking to the tumor microenvironment. In mice bearing TNBC xenograft tumors, anti-PD-1 antibody alone failed to elicit obvious therapeutic effect. However, combining LSD1 inhibitors with PD-1 antibody significantly suppressed tumor growth and pulmonary metastasis, which was associated with reduced Ki-67 level and augmented CD8+ T cell infiltration in xenograft tumors. Overall, these results suggest that LSD1 inhibition may be an effective adjuvant treatment with immunotherapy as a novel management strategy for poorly immunogenic breast tumors.
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http://dx.doi.org/10.1038/s41388-018-0451-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336685PMC
January 2019

Systemic Therapy for Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: ASCO Clinical Practice Guideline Update Summary.

J Oncol Pract 2018 08 10;14(8):501-504. Epub 2018 Jul 10.

The University of Texas MD Anderson Cancer Center, Houston, TX; American Society of Clinical Oncology, Alexandria, VA; Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA.

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http://dx.doi.org/10.1200/JOP.18.00290DOI Listing
August 2018

Recommendations on Disease Management for Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases: ASCO Clinical Practice Guideline Update.

J Clin Oncol 2018 09 25;36(27):2804-2807. Epub 2018 Jun 25.

Naren Ramakrishna, University of Florida Health Cancer Center at Orlando Health, Orlando; Jennifer Levinson, Ponte Vedra Beach, FL; Sarah Temin, American Society of Clinical Oncology, Alexandria, VA; Sarat Chandarlapaty and Shanu Modi, Memorial Sloan Kettering Cancer Center; Francisco J. Esteva, New York University Langone Medical Center, New York; Jeffrey J. Kirshner, Hematology/Oncology Associates of Central New York, East Syracuse, NY; Jennie R. Crews, Seattle Cancer Care Alliance, Seattle, WA; Nancy E. Davidson, Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA; Sharon H. Giordano, University of Texas MD Anderson Cancer Center, Houston; Debra A. Patt, Texas Oncology, Austin, TX; Ian E. Krop, Eric P. Winer, and Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; and Jane Perlmutter, Ann Arbor, MI.

Purpose To update the formal expert consensus-based guideline recommendations for practicing oncologists and others on the management of brain metastases for patients with human epidermal growth factor receptor 2-positive advanced breast cancer to 2018. Methods An Expert Panel conducted a targeted systematic literature review (for both systemic treatment and CNS metastases) and identified 622 articles. Outcomes of interest included overall survival, progression-free survival, and adverse events. In 2014, the American Society of Clinical Oncology (ASCO) convened a panel of medical oncology, radiation oncology, guideline implementation, and advocacy experts, and conducted a systematic review of the literature. When that failed to yield sufficiently strong quality evidence, the Expert Panel undertook a formal expert consensus-based process to produce these recommendations. ASCO used a modified Delphi process. The panel members drafted recommendations, and a group of other experts joined them for two rounds of formal ratings of the recommendations. Results Of the 622 publications identified and reviewed, no additional evidence was identified that would warrant a change to the 2014 recommendations. Recommendations Patients with brain metastases should receive appropriate local therapy and systemic therapy, if indicated. Local therapies include surgery, whole-brain radiotherapy, and stereotactic radiosurgery. Treatments depend on factors such as patient prognosis, presence of symptoms, resectability, number and size of metastases, prior therapy, and whether metastases are diffuse. Other options include systemic therapy, best supportive care, enrollment in a clinical trial, and/or palliative care. Clinicians should not perform routine magnetic resonance imaging to screen for brain metastases, but rather should have a low threshold for magnetic resonance imaging of the brain because of the high incidence of brain metastases among patients with HER2-positive advanced breast cancer. Additional information is available at www.asco.org/breast-cancer-guidelines .
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http://dx.doi.org/10.1200/JCO.2018.79.2713DOI Listing
September 2018

Systemic Therapy for Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: ASCO Clinical Practice Guideline Update.

J Clin Oncol 2018 09 25;36(26):2736-2740. Epub 2018 Jun 25.

Sharon H. Giordano, The University of Texas MD Anderson, Houston; Debra A. Patt, Texas Oncology, Austin, TX; Sarah Temin, American Society of Clinical Oncology, Alexandria, VA; Sarat Chandarlapaty and Shanu Modi, Memorial Sloan Kettering Cancer Center; Francisco J. Esteva, New York University Langone Medical Center, New York; Jeffrey J. Kirshner, Hematology/Oncology Associates of Central New York, East Syracuse, NY; Jennie R. Crews, Seattle Cancer Care Alliance; Nancy E. Davidson, Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA; Ian E. Krop, Nancy U. Lin, and Eric P. Winer, Dana-Farber Cancer Institute, Boston, MA; Jennifer Levinson, Ponte Vedra Beach; Naren Ramakrishna, Orlando Health University of Florida Health Cancer Center, Orlando, FL; and Jane Perlmutter, Ann Arbor, MI.

Purpose To update evidence-based guideline recommendations for practicing oncologists and others on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer to 2018. Methods An Expert Panel conducted a targeted systematic literature review (for both systemic treatment and CNS metastases) and identified 622 articles. Outcomes of interest included overall survival, progression-free survival, and adverse events. Results Of the 622 publications identified and reviewed, no additional evidence was identified that would warrant a change to the 2014 recommendations. Recommendations HER2-targeted therapy is recommended for patients with HER2-positive advanced breast cancer, except for those with clinical congestive heart failure or significantly compromised left ventricular ejection fraction, who should be evaluated on a case-by-case basis. Trastuzumab, pertuzumab, and taxane for first-line treatment and trastuzumab emtansine for second-line treatment are recommended. In the third-line setting, clinicians should offer other HER2-targeted therapy combinations or trastuzumab emtansine (if not previously administered) and may offer pertuzumab if the patient has not previously received it. Optimal duration of chemotherapy is at least 4 to 6 months or until maximum response, depending on toxicity and in the absence of progression. HER2-targeted therapy can continue until time of progression or unacceptable toxicities. For patients with HER2-positive and estrogen receptor-positive/progesterone receptor-positive breast cancer, clinicians may recommend either standard first-line therapy or, for selected patients, endocrine therapy plus HER2-targeted therapy or endocrine therapy alone. Additional information is available at www.asco.org/breast-cancer-guidelines .
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http://dx.doi.org/10.1200/JCO.2018.79.2697DOI Listing
September 2018

Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer.

N Engl J Med 2018 Jul 4;379(2):122-137. Epub 2018 Jun 4.

From the Peter MacCallum Cancer Centre, St. Vincent's Hospital, University of Melbourne, Melbourne, VIC, and Breast Cancer Trials Australia and New Zealand, University of Newcastle, Newcastle, NSW (P.A.F.), and the University of Sydney, Sydney (A.S.C.) - all in Australia; the Institute of Oncology of Southern Switzerland, Ospedale San Giovanni, Bellinzona (O.P.), Breast Cancer St. Gallen, St. Gallen (T.R.), and the International Breast Cancer Study Group Coordinating Center (R.M., M.R.-P., B.R., A.S.C.), University Hospital Inselspital (M.R.-P.), Bern - all in Switzerland; the University of Chicago Medical Center, Chicago (G.F.F.); the University of Calgary, Calgary, AB, Canada (B.A.W.); the Division of Medical Senology, European Institute of Oncology (M.C.), and the European Institute of Oncology and International Breast Cancer Study Group (A.G.), Milan, Ospedale Papa Giovanni XXIII, Bergamo (C.T.), Azienda Socio Sanitaria Territoriale Sette Laghi-Ospedale di Circolo and Fondazione Macchi, Varese (G.P.), Medical Oncology and Cancer Prevention, IRCCS, National Cancer Institute, Aviano (F.P., S.S.), the Department of Medicine, School of Medical Oncology, University of Udine, Udine (F.P.), Salvatore Maugeri Foundation, Pavia (L.P.), and the Hospital of Prato-Azienda Unità Sanitaria Locale Toscana Centro, Prato (A.D.L.) - all in Italy; the National Institute of Oncology, Budapest, Hungary (I.L.); Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru (H.L.G.); University Hospital 12 de Octubre, Madrid (E.C.), Vall d'Hebron Institute of Oncology and Vall d'Hebron University Hospital, Barcelona (M.B.), and Instituto Valenciano de Oncologia, Valencia (M.A.C.) - all in Spain; the Susan F. Smith Center for Women's Cancers (H.J.B., E.P.W.) and the International Breast Cancer Study Group Statistical Center, Department of Biostatistics and Computational Biology (R.D.G., M.M.R.), Dana-Farber Cancer Institute, Harvard Medical School, the Harvard T.H. Chan School of Public Health, and Frontier Science and Technology Research Foundation (R.D.G.) - all in Boston; Institut Bergonié Comprehensive Cancer Center, Université de Bordeaux, Bordeaux, France (H.R.B., M.D.); the Angeles Clinic and Research Institute, Santa Monica, CA (S.M.); Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond (C.E.G.); Mayo Clinic, Rochester, MN (M.P.G., J.N.I.); Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore (V.S.); Fred Hutchinson Cancer Research Center, University of Washington, Seattle (N.E.D.); Weston Park Hospital, Sheffield, United Kingdom (R.C.); and the Department of Obstetrics and Gynecology, University Medical Center, Regensburg, Germany (S.B.).

Background: In the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT), the 5-year rates of recurrence of breast cancer were significantly lower among premenopausal women who received the aromatase inhibitor exemestane plus ovarian suppression than among those who received tamoxifen plus ovarian suppression. The addition of ovarian suppression to tamoxifen did not result in significantly lower recurrence rates than those with tamoxifen alone. Here, we report the updated results from the two trials.

Methods: Premenopausal women were randomly assigned to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression in SOFT and to receive tamoxifen plus ovarian suppression or exemestane plus ovarian suppression in TEXT. Randomization was stratified according to the receipt of chemotherapy.

Results: In SOFT, the 8-year disease-free survival rate was 78.9% with tamoxifen alone, 83.2% with tamoxifen plus ovarian suppression, and 85.9% with exemestane plus ovarian suppression (P=0.009 for tamoxifen alone vs. tamoxifen plus ovarian suppression). The 8-year rate of overall survival was 91.5% with tamoxifen alone, 93.3% with tamoxifen plus ovarian suppression, and 92.1% with exemestane plus ovarian suppression (P=0.01 for tamoxifen alone vs. tamoxifen plus ovarian suppression); among the women who remained premenopausal after chemotherapy, the rates were 85.1%, 89.4%, and 87.2%, respectively. Among the women with cancers that were negative for HER2 who received chemotherapy, the 8-year rate of distant recurrence with exemestane plus ovarian suppression was lower than the rate with tamoxifen plus ovarian suppression (by 7.0 percentage points in SOFT and by 5.0 percentage points in TEXT). Grade 3 or higher adverse events were reported in 24.6% of the tamoxifen-alone group, 31.0% of the tamoxifen-ovarian suppression group, and 32.3% of the exemestane-ovarian suppression group.

Conclusions: Among premenopausal women with breast cancer, the addition of ovarian suppression to tamoxifen resulted in significantly higher 8-year rates of both disease-free and overall survival than tamoxifen alone. The use of exemestane plus ovarian suppression resulted in even higher rates of freedom from recurrence. The frequency of adverse events was higher in the two groups that received ovarian suppression than in the tamoxifen-alone group. (Funded by Pfizer and others; SOFT and TEXT ClinicalTrials.gov numbers, NCT00066690 and NCT00066703 , respectively.).
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http://dx.doi.org/10.1056/NEJMoa1803164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193457PMC
July 2018

HDAC5-LSD1 axis regulates antineoplastic effect of natural HDAC inhibitor sulforaphane in human breast cancer cells.

Int J Cancer 2018 09 20;143(6):1388-1401. Epub 2018 Apr 20.

Women's Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Our recent studies have shown that cross-talk between histone deacetylase 5 (HDAC5) and lysine-specific demethylase 1 (LSD1) facilitates breast cancer progression. In this work, we demonstrated that regulatory activity at -356 to -100 bp promoter element plays a critical role in governing HDAC5 transcription. By using DNA affinity precipitation and mass spectrometry, we identified a group of factors that bind to this element. Among these factors, Upstream Transcription Factor 1 (USF1) was shown to play a critical role in controlling HDAC5 transcription. Through screening a panel of epigenetic modifying drugs, we showed that a natural bioactive HDAC inhibitor, sulforaphane, downregulated HDAC5 transcription by blocking USF1 activity. Sulforaphane facilitated LSD1 ubiquitination and degradation in an HDAC5-dependent manner. A comparative microarray analysis demonstrated a genome wide cooperative effect of HDAC5 and LSD1 on cancer-related gene expression. shRNA knockdown and sulforaphane inhibition of HDAC5/LSD1 exhibited similar effects on expression of HDAC5/LSD1 target genes. We also showed that coordinated cross-talk of HDAC5 and LSD1 is essential for the antitumor efficacy of sulforaphane. Combination treatment with sulforaphane and a potent LSD1 inhibitor resulted in synergistic growth inhibition in breast cancer cells, but not in normal breast epithelial cells. Furthermore, combined therapy with sulforaphane and LSD1 inhibitor exhibited superior inhibitory effect on MDA-MB-231 xenograft tumor growth. Taken together, our work demonstrates that HDAC5-LSD1 axis is an effective drug target for breast cancer. Inhibition of HDAC5-LSD1 axis with sulforaphane blocks breast cancer growth and combined treatment with LSD1 inhibitor improves the therapeutic efficacy of sulforaphane.
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http://dx.doi.org/10.1002/ijc.31419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105499PMC
September 2018

Future cancer research priorities in the USA: a Lancet Oncology Commission.

Lancet Oncol 2017 11 31;18(11):e653-e706. Epub 2017 Oct 31.

Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.

We are in the midst of a technological revolution that is providing new insights into human biology and cancer. In this era of big data, we are amassing large amounts of information that is transforming how we approach cancer treatment and prevention. Enactment of the Cancer Moonshot within the 21st Century Cures Act in the USA arrived at a propitious moment in the advancement of knowledge, providing nearly US$2 billion of funding for cancer research and precision medicine. In 2016, the Blue Ribbon Panel (BRP) set out a roadmap of recommendations designed to exploit new advances in cancer diagnosis, prevention, and treatment. Those recommendations provided a high-level view of how to accelerate the conversion of new scientific discoveries into effective treatments and prevention for cancer. The US National Cancer Institute is already implementing some of those recommendations. As experts in the priority areas identified by the BRP, we bolster those recommendations to implement this important scientific roadmap. In this Commission, we examine the BRP recommendations in greater detail and expand the discussion to include additional priority areas, including surgical oncology, radiation oncology, imaging, health systems and health disparities, regulation and financing, population science, and oncopolicy. We prioritise areas of research in the USA that we believe would accelerate efforts to benefit patients with cancer. Finally, we hope the recommendations in this report will facilitate new international collaborations to further enhance global efforts in cancer control.
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http://dx.doi.org/10.1016/S1470-2045(17)30698-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178838PMC
November 2017

Incident Cancer in Cancer Survivors-When Cancer Lurks in the Background.

Authors:
Nancy E Davidson

JAMA Oncol 2018 06;4(6):836-837

Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, University of Washington School of Medicine, Seattle.

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http://dx.doi.org/10.1001/jamaoncol.2017.4167DOI Listing
June 2018

Nitro-fatty acid inhibition of triple-negative breast cancer cell viability, migration, invasion, and tumor growth.

J Biol Chem 2018 01 20;293(4):1120-1137. Epub 2017 Nov 20.

From the Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260,

Triple-negative breast cancer (TNBC) comprises ∼20% of all breast cancers and is the most aggressive mammary cancer subtype. Devoid of the estrogen and progesterone receptors, along with the receptor tyrosine kinase ERB2 (HER2), that define most mammary cancers, there are no targeted therapies for patients with TNBC. This, combined with a high metastatic rate and a lower 5-year survival rate than for other breast cancer phenotypes, means there is significant unmet need for new therapeutic strategies. Herein, the anti-neoplastic effects of the electrophilic fatty acid nitroalkene derivative, 10-nitro-octadec-9-enoic acid (nitro-oleic acid, NO-OA), were investigated in multiple preclinical models of TNBC. NO-OA reduced TNBC cell growth and viability , attenuated TNFα-induced TNBC cell migration and invasion, and inhibited the tumor growth of MDA-MB-231 TNBC cell xenografts in the mammary fat pads of female nude mice. The up-regulation of these aggressive tumor cell growth, migration, and invasion phenotypes is mediated in part by the constitutive activation of pro-inflammatory nuclear factor κB (NF-κB) signaling in TNBC. NO-OA inhibited TNFα-induced NF-κB transcriptional activity in human TNBC cells and suppressed downstream NF-κB target gene expression, including the metastasis-related proteins intercellular adhesion molecule-1 and urokinase-type plasminogen activator. The mechanisms accounting for NF-κB signaling inhibition by NO-OA in TNBC cells were multifaceted, as NO-OA () inhibited the inhibitor of NF-κB subunit kinase β phosphorylation and downstream inhibitor of NF-κB degradation, () alkylated the NF-κB RelA protein to prevent DNA binding, and () promoted RelA polyubiquitination and proteasomal degradation. Comparisons with non-tumorigenic human breast epithelial MCF-10A and MCF7 cells revealed that NO-OA more selectively inhibited TNBC function. This was attributed to more facile mechanisms for maintaining redox homeostasis in normal breast epithelium, including a more favorable thiol/disulfide balance, greater extents of multidrug resistance protein-1 (MRP1) expression, and greater MRP1-mediated efflux of NO-OA-glutathione conjugates. These observations reveal that electrophilic fatty acid nitroalkenes react with more alkylation-sensitive targets in TNBC cells to inhibit growth and viability.
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http://dx.doi.org/10.1074/jbc.M117.814368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787792PMC
January 2018

A metastasis biomarker (MetaSite ™ Score) is associated with distant recurrence in hormone receptor-positive, HER2-negative early-stage breast cancer.

NPJ Breast Cancer 2017 8;3:42. Epub 2017 Nov 8.

Albert Einstein College of Medicine, Bronx, NY USA.

Metastasis is the primary cause of death in early-stage breast cancer. We evaluated the association between a metastasis biomarker, which we call "Tumor Microenviroment of Metastasis" (TMEM), and risk of recurrence. TMEM are microanatomic structures where invasive tumor cells are in direct contact with endothelial cells and macrophages, and which serve as intravasation sites for tumor cells into the circulation. We evaluated primary tumors from 600 patients with Stage I-III breast cancer treated with adjuvant chemotherapy in trial E2197 (NCT00003519), plus endocrine therapy for hormone receptor (HR)+ disease. TMEM were identified and enumerated using an analytically validated, fully automated digital pathology/image analysis method (MetaSite ™), hereafter referred to as MetaSite Score (MS). The objectives were to determine the association between MS and distant relapse free interval (DRFI) and relapse free interval (RFI). MS was not associated with tumor size or nodal status, and correlated poorly with Oncotype DX Recurrence Score ( = 0.29) in 297 patients with HR+/HER2- disease. Proportional hazards models revealed a significant positive association between continuous MS and DRFI ( = 0.001) and RFI ( = 0.00006) in HR+/HER2- disease in years 0-5, and by MS tertiles for DRFI ( = 0.04) and RFI ( = 0.01), but not after year 5 or in triple negative or HER2+ disease. Multivariate models in HR+/HER- disease including continuous MS, clinical covariates, and categorical Recurrence Score (<18, 18-30, > 30) showed MS is an independent predictor for 5-year RFI ( = 0.05). MetaSite Score provides prognostic information for early recurrence complementary to clinicopathologic features and Recurrence Score.
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http://dx.doi.org/10.1038/s41523-017-0043-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678158PMC
November 2017

Functional characterization of lysine-specific demethylase 2 (LSD2/KDM1B) in breast cancer progression.

Oncotarget 2017 Oct 19;8(47):81737-81753. Epub 2017 Jul 19.

Women's Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Flavin-dependent histone demethylases govern histone H3K4 methylation and act as important chromatin modulators that are extensively involved in regulation of DNA replication, gene transcription, DNA repair, and heterochromatin gene silencing. While the activities of lysine-specific demethylase 1 (LSD1/KDM1A) in facilitating breast cancer progression have been well characterized, the roles of its homolog LSD2 (KDM1B) in breast oncogenesis are relatively less understood. In this study, we showed that LSD2 protein level was significantly elevated in malignant breast cell lines compared with normal breast epithelial cell line. TCGA- Oncomine database showed that LSD2 expression is significantly higher in basal-like breast tumors compared to other breast cancer subtypes or normal breast tissue. Overexpression of LSD2 in MDA-MB-231 cells significantly altered the expression of key important epigenetic modifiers such as LSD1, HDAC1/2, and DNMT3B; promoted cellular proliferation; and augmented colony formation in soft agar; while attenuating motility and invasion. Conversely, siRNA-mediated depletion of endogenous LSD2 hindered growth of multiple breast cancer cell lines while shRNA-mediated LSD2 depletion augmented motility and invasion. Moreover, LSD2 overexpression in MDA-MB-231 cells facilitated mammosphere formation, enriched the subpopulation of CD49f/EpCAM and ALDH, and induced the expression of pluripotent stem cell markers, NANOG and SOX2. In xenograft studies using immune-compromised mice, LSD2-overexpressing MDA-MB-231 cells displayed accelerated tumor growth but significantly fewer lung metastases than controls. Taken together, our findings provide novel insights into the critical and multifaceted roles of LSD2 in the regulation of breast cancer progression and cancer stem cell enrichment.
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http://dx.doi.org/10.18632/oncotarget.19387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669845PMC
October 2017

Searching for the IDEAL Duration of Adjuvant Endocrine Therapy.

J Natl Cancer Inst 2018 01;110(1)

Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle Cancer Care Alliance, Seattle, WA.

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http://dx.doi.org/10.1093/jnci/djx143DOI Listing
January 2018