Publications by authors named "Carey K Anders"

88 Publications

Effects of Breast Cancer Adjuvant Chemotherapy Regimens on Expression of the Aging Biomarker, .

JNCI Cancer Spectr 2020 Dec 18;4(6):pkaa082. Epub 2020 Dec 18.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Although chemotherapy saves lives, increasing evidence shows that chemotherapy accelerates aging. We previously demonstrated that mRNA expression of , a biomarker of senescence and molecular aging, increased early and dramatically after beginning adjuvant anthracycline-based regimens in early stage breast cancer patients. Here, we determined if changes in expression vary by chemotherapy regimen among early stage breast cancer patients.

Methods: We conducted a study of stage I-III breast cancer patients receiving adjuvant or neoadjuvant chemotherapy. expression was analyzed prechemotherapy and postchemotherapy (median 6.2 months after the last chemotherapy) in peripheral blood T lymphocytes. Chemotherapy-induced change in expression was compared among regimens. All statistical tests were 2-sided.

Results: In 146 women, chemotherapy was associated with a statistically significant increase in expression (accelerated aging of 17 years; < .001). Anthracycline-based regimens were associated with the largest increases (accelerated aging of 23 to 26 years; ≤ .008). Nonanthracycline-based regimens demonstrated a much smaller increase (accelerated aging of 9 to 11 years; ≤ .15). In addition to the type of chemotherapy regimen, baseline levels, but not chronologic age or race, were also associated with the magnitude of increases in . Patients with lower levels at baseline were more likely to experience larger increases.

Conclusions: Our findings suggest that the aging effects of chemotherapy may be influenced by both chemotherapy type and the patient's baseline level. Measurement of expression is not currently available in the clinic, but nonanthracycline regimens offering similar efficacy as anthracycline regimens might be favored.
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http://dx.doi.org/10.1093/jncics/pkaa082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771421PMC
December 2020

Salting the Soil: Targeting the Microenvironment of Brain Metastases.

Mol Cancer Ther 2021 Mar 5;20(3):455-466. Epub 2021 Jan 5.

Duke Brain and Spine Metastases Center, Duke University, Durham, North Carolina.

Paget's "seed and soil" hypothesis of metastatic spread has acted as a foundation of the field for over a century, with continued evolution as mechanisms of the process have been elucidated. The central nervous system (CNS) presents a unique soil through this lens, relatively isolated from peripheral circulation and immune surveillance with distinct cellular and structural composition. Research in primary and metastatic brain tumors has demonstrated that this tumor microenvironment (TME) plays an essential role in the growth of CNS tumors. In each case, the cancerous cells develop complex and bidirectional relationships that reorganize the local TME and reprogram the CNS cells, including endothelial cells, pericytes, astrocytes, microglia, infiltrating monocytes, and lymphocytes. These interactions create a structurally and immunologically permissive TME with malignant processes promoting positive feedback loops and systemic consequences. Strategies to interrupt interactions with the native CNS components, on "salting the soil," to create an inhospitable environment are promising in the preclinical setting. This review aims to examine the general and specific pathways thus far investigated in brain metastases and related work in glioma to identify targetable mechanisms that may have general application across the spectrum of intracranial tumors.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0579DOI Listing
March 2021

HER2-positive breast cancer brain metastasis: A new and exciting landscape.

Cancer Rep (Hoboken) 2020 Sep 3:e1274. Epub 2020 Sep 3.

Duke Center for Brain and Spine Metastasis, Duke Cancer Institute, Durham, North Carolina, USA.

Background: Brain metastases (BrM) incidence is 25% to 50% in women with advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Radiation and surgery are currently the main local treatment approaches for central nervous system (CNS) metastases. Systemic anti-HER2 therapy following a diagnosis of BrM improves outcomes. Previous preclinical data has helped elucidate HER2 brain trophism, the blood-brain/blood-tumor barrier(s), and the brain tumor microenvironment, all of which can lead to development of novel therapeutic options.

Recent Findings: Several anti-HER2 agents are currently available and reviewed here, some of which have recently shown promising effects in BrM patients, specifically. New strategies driven by and focusing on brain metastasis-specific genomics, immunotherapy, and preventive strategies have shown promising results and are under development.

Conclusions: The field of HER2+ breast cancer, particularly for BrM, continues to evolve as new therapeutic strategies show promising results in recent clinical trials. Increasing inclusion of patients with BrM in clinical studies, and a focus on assessing their outcomes both intracranially and extracranially, is changing the landscape for patients with HER2+ CNS metastases by demonstrating the ability of newer agents to improve outcomes.
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http://dx.doi.org/10.1002/cnr2.1274DOI Listing
September 2020

Clinicopathologic features of breast cancer reclassified as HER2-amplified by fluorescence in situ hybridization with alternative chromosome 17 probes.

Ann Diagn Pathol 2020 Oct 8;48:151576. Epub 2020 Aug 8.

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA. Electronic address:

Objective: Dual probe fluorescence in situ hybridization (FISH) assays for determination of human epidermal growth factor receptor 2 (HER2) gene amplification in breast cancer provide a ratio of HER2 to chromosome 17. The ratio may be skewed by copy number alterations (CNA) in the control locus for chromosome 17 (CEP17). We analyzed the impact of alternative chromosome 17 control probes on HER2 status in a series of breast cancers with an emphasis on patients reclassified as amplified.

Methods: Breast cancer patients with equivocal HER2 immunohistochemistry (2+) and equivocal FISH with CEP17 were included. Reclassification of HER2 status was assessed with alternative chromosome 17 control probes (LIS1 and RARA).

Results: A total of 40 unique patients with 46 specimens reflexed to alternative chromosome 17 probe testing were identified. The majority (>80%) of patients had pT1-2, hormone receptor-positive tumors with an intermediate or high combined histologic grade. There were 34/46 (73.9%) specimens reclassified as amplified with alternative probes, corresponding to 29/40 (72.5%) patients. Of the patients reclassified as amplified with alternative probes, 34.5% (10/29) received HER2-targeted therapy.

Conclusion: In this series, the majority of breast cancers tested with alternative chromosome 17 control probes under the 2013 ASCO/CAP Guidelines were converted to HER2-amplified. The treatment data and the clinicopathologic profile of the tumors suggest that most of these patients will neither receive nor benefit from HER2-targeted therapy. The findings support the recommendation in the 2018 ASCO/CAP HER2 Guidelines to discontinue the use of alternative chromosome 17 probes.
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http://dx.doi.org/10.1016/j.anndiagpath.2020.151576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907993PMC
October 2020

A Phase II Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone Receptor-Positive Breast Cancer.

Clin Cancer Res 2020 Oct 21;26(20):5310-5319. Epub 2020 Jul 21.

Division of Medical Oncology, Department of Internal Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina.

Purpose: The primary objective was to evaluate intracranial objective response rate (iORR) in patients receiving abemaciclib with brain or leptomeningeal metastases (LM) secondary to hormone receptor-positive (HR) metastatic breast cancer (MBC). Secondary objectives evaluated extracranial response, abemaciclib pharmacokinetics, brain metastases tissue exposure, and safety.

Patients And Methods: This nonrandomized, phase II study (NCT02308020) enrolled patients in tumor subtype-specific cohorts A-D: A (HR, HER2 MBC), B (HR, HER2 MBC), C (HR MBC LM), and D (brain metastases surgical resection). Abemaciclib 200 mg was administered twice daily as monotherapy or with endocrine therapy, or 150 mg twice daily with trastuzumab. Cohorts A and B used a Simon two-stage design.

Results: In cohort A ( = 58), 3 patients were confirmed responders resulting in an iORR of 5.2% [95% confidence interval (CI), 0.0-10.9], and the intracranial clinical benefit rate (iCBR) was 24% (95% CI, 13.1-35.2). Median overall survival (OS) was 12.5 months (95% CI, 9.3-16.4). A volumetric decrease in target intracranial lesions was experienced by 38% of patients. In cohort B ( = 27), there were no confirmed intracranial responses. An iCBR of 11% (95% CI, 0.0-23.0) was observed. Median OS was 10.1 months (95% CI, 4.2-14.3). A volumetric decrease in target intracranial lesions was experienced by 22% of patients. In cohort C ( = 10), one confirmed complete parenchymal response was observed. In cohort D ( = 9), unbound brain metastases concentrations of total active abemaciclib analytes were 96- [cyclin-dependent kinase 4 (CDK4)] and 19-fold (CDK6) above IC. Safety was consistent with prior studies.

Conclusions: This study did not meet its primary endpoint. Abemaciclib was associated with an iCBR of 24% in patients with heavily pretreated HR, HER2 MBC. Abemaciclib achieved therapeutic concentrations in brain metastases tissue, far exceeding those necessary for CDK4 and CDK6 inhibition. Further studies are warranted, including assessing novel abemaciclib-based combinations.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1764DOI Listing
October 2020

Efficacy and pharmacodynamics of niraparib in BRCA-mutant and wild-type intracranial triple-negative breast cancer murine models.

Neurooncol Adv 2019 May-Dec;1(1):vdz005. Epub 2019 Jun 4.

Duke Cancer Institute, Duke University Health System, Durham, North Carolina.

Background: Despite the poor prognosis of triple-negative breast cancer (TNBC) brain metastases, there are no approved systemic therapies. We explored the DNA-damaging poly(ADP-ribose) polymerase inhibitor (PARPi) niraparib in intracranial mouse models of breast cancer susceptibility protein (BRCA)mutant TNBC.

Methods: Mice bearing intracranial human-derived TNBC cell lines (SUM149, MDA-MB-231Br, or MDA-MB-436) were treated with niraparib and monitored for survival; intracranial tissues were analyzed for PAR levels and niraparib concentration by mass spectrometry. RNASeq data of primary breast cancers using The Cancer Genome Atlas were analyzed for DNA damage signatures. Combined RAD51 and PARP inhibition in TNBC cell lines was assessed in vitro by colony-forming assays.

Results: Daily niraparib increased median survival and decreased tumor burden in the mutant MDA-MB-436 model, but not in the mutant SUM149 or wild-type MDA-MB-231Br models despite high concentrations in intracranial tumors. RAD51 inhibitor B02 was shown to sensitize all cell lines to PARP inhibition (PARPi). In the analysis of mutant primary human TNBCs, gene expression predictors of PARPi sensitivity and DNA repair signatures demonstrate widespread heterogeneity, which may explain the differential response to PARPi. Interestingly, these signatures are significantly correlated to expression including PARPi sensitivity ( = 0.602, = 0.758).

Conclusions: Niraparib penetrates intracranial tumor tissues in mouse models of TNBC with impressive single-agent efficacy in -mutant MDA-MB-436. Clinical evaluation of niraparib to treat TNBC brain metastases, an unmet clinical need desperate for improved therapies, is warranted. Further compromising DNA repair through RAD51 inhibition may further augment TNBC's response to PARPi.
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http://dx.doi.org/10.1093/noajnl/vdz005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212882PMC
June 2019

Brain Metastasis Cell Lines Panel: A Public Resource of Organotropic Cell Lines.

Cancer Res 2020 10 8;80(20):4314-4323. Epub 2020 Jul 8.

Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, and Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Spread of cancer to the brain remains an unmet clinical need in spite of the increasing number of cases among patients with lung, breast cancer, and melanoma most notably. Although research on brain metastasis was considered a minor aspect in the past due to its untreatable nature and invariable lethality, nowadays, limited but encouraging examples have questioned this statement, making it more attractive for basic and clinical researchers. Evidences of its own biological identity (i.e., specific microenvironment) and particular therapeutic requirements (i.e., presence of blood-brain barrier, blood-tumor barrier, molecular differences with the primary tumor) are thought to be critical aspects that must be functionally exploited using preclinical models. We present the coordinated effort of 19 laboratories to compile comprehensive information related to brain metastasis experimental models. Each laboratory has provided details on the cancer cell lines they have generated or characterized as being capable of forming metastatic colonies in the brain, as well as principle methodologies of brain metastasis research. The Brain Metastasis Cell Lines Panel (BrMPanel) represents the first of its class and includes information about the cell line, how tropism to the brain was established, and the behavior of each model . These and other aspects described are intended to assist investigators in choosing the most suitable cell line for research on brain metastasis. The main goal of this effort is to facilitate research on this unmet clinical need, to improve models through a collaborative environment, and to promote the exchange of information on these valuable resources.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572582PMC
October 2020

Receptor discordance in breast cancer brain metastases: when knowledge is power.

Neuro Oncol 2020 08;22(8):1060-1061

Duke Cancer Institute, Division of Medical Oncology, Department of Medicine, Durham, North Carolina.

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http://dx.doi.org/10.1093/neuonc/noaa131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594573PMC
August 2020

What's the Price? Toxicities of Targeted Therapies in Breast Cancer Care.

Am Soc Clin Oncol Educ Book 2020 May;40:55-70

Division of Hematology and Oncology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC.

Agents with mechanisms novel to breast cancer care have been approved to treat breast cancer. These agents include drugs that target cyclin-dependent kinases, phosphoinositide 3-kinase gene mutations, PARP, checkpoint regulation, and novel antibody-drug conjugates. However, these novel approaches bring a risk of toxicities quite different from those of conventional cytotoxic chemotherapy. Here, we review these agents and discuss related adverse events, with particular attention to endocrine, pulmonary, and dermatologic toxicities. Endocrine toxicities associated with novel cancer therapies for breast cancer are distinct and often present with symptoms related to the specific hormonal deficiencies and rarely hormonal excess. Given the complex and sometimes irreversible nature of these toxicities, once recognized, transdisciplinary management with an endocrinologist experienced with managing drug-related toxicities is encouraged. Drug-related pneumonitis is a serious concern with new targeted therapies. Presentation may not be easily distinguished, and a multidisciplinary team approach can optimize patient care. Heightened awareness is crucial for early detection and treatment. Management should follow recommendations provided by the National Cancer Institute Common Terminology Criteria for Adverse Events and agent-specific guidelines. Cutaneous toxicities from anticancer therapies represent a common and often poorly characterized challenge for patients with breast cancer. Although our understanding of dermatologic effects from novel therapies continues to improve, the breadth of toxicities spans all dermatologic conditions. Targeted therapies offer effective and often novel therapeutic strategies for patients with breast cancer but also bring new adverse event profiles. In this era, it will be important both to closely follow monitoring recommendations and to remain vigilant for emerging toxicities.
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http://dx.doi.org/10.1200/EDBK_279465DOI Listing
May 2020

Current multidisciplinary management of brain metastases.

Cancer 2020 04 23;126(7):1390-1406. Epub 2020 Jan 23.

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.

Brain metastasis (BM), the most common adult brain tumor, develops in 20% to 40% of patients with late-stage cancer and traditionally are associated with a poor prognosis. The management of patients with BM has become increasingly complex because of new and emerging systemic therapies and advancements in radiation oncology and neurosurgery. Current therapies include stereotactic radiosurgery, whole-brain radiation therapy, surgical resection, laser-interstitial thermal therapy, systemic cytotoxic chemotherapy, targeted agents, and immune-checkpoint inhibitors. Determining the optimal treatment for a specific patient has become increasingly individualized, emphasizing the need for multidisciplinary discussions of patients with BM. Recognizing and addressing the sequelae of BMs and their treatment while maintaining quality of life and neurocognition is especially important because survival for patients with BMs has improved. The authors present current and emerging treatment options for patients with BM and suggest approaches for managing sequelae and disease recurrence.
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http://dx.doi.org/10.1002/cncr.32714DOI Listing
April 2020

Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors.

J Immunother Cancer 2019 10 18;7(1):265. Epub 2019 Oct 18.

Womens Cancer Research Center, UPMC Hillman Cancer Center, Magee Womens Research Institute, Pittsburgh, USA.

The interplay between the immune system and tumor progression is well recognized. However, current human breast cancer immunophenotyping studies are mostly focused on primary tumors with metastatic breast cancer lesions remaining largely understudied. To address this gap, we examined exome-capture RNA sequencing data from 50 primary breast tumors (PBTs) and their patient-matched metastatic tumors (METs) in brain, ovary, bone and gastrointestinal tract. We used gene expression signatures as surrogates for tumor infiltrating lymphocytes (TILs) and compared TIL patterns in PBTs and METs. Enrichment analysis and deconvolution methods both revealed that METs had a significantly lower abundance of total immune cells, including CD8+ T cells, regulatory T cells and dendritic cells. An exception was M2-like macrophages, which were significantly higher in METs across the organ sites examined. Multiplex immunohistochemistry results were consistent with data from the in-silico analysis and showed increased macrophages in METs. We confirmed the finding of a significant reduction in immune cells in brain METs (BRMs) by pathologic assessment of TILs in a set of 49 patient-matched pairs of PBT/BRMs. These findings indicate that METs have an overall lower infiltration of immune cells relative to their matched PBTs, possibly due to immune escape. RNAseq analysis suggests that the relative levels of M2-like macrophages are increased in METs, and their potential role in promoting breast cancer metastasis warrants further study.
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http://dx.doi.org/10.1186/s40425-019-0755-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798422PMC
October 2019

Pre- and Postoperative Neratinib for HER2-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium 022.

Clin Breast Cancer 2020 04 22;20(2):145-151.e2. Epub 2019 Aug 22.

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

Purpose: This pilot study was performed to test our ability to administer neratinib monotherapy before clinically recommended craniotomy in patients with HER2-positive metastatic breast cancer to the central nervous system, to examine neratinib's central nervous system penetration at craniotomy, and to examine postoperative neratinib maintenance.

Patients And Methods: Patients with HER2-positive brain metastases undergoing clinically indicated cranial resection of a parenchymal tumor received neratinib 240 mg orally once a day for 7 to 21 days preoperatively, and resumed therapy postoperatively in 28-day cycles. Exploratory evaluations of time to disease progression, survival, and correlative tissue, cerebrospinal fluid (CSF), and blood-based analyses examining neratinib concentrations were planned. The study was registered at ClinicalTrials.gov under number NCT01494662.

Results: We enrolled 5 patients between May 22, 2013, and October 18, 2016. As of March 1, 2019, patients had remained on the study protocol for 1 to 75+ postoperative cycles pf therapy. Two patients had grade 3 diarrhea. Evaluation of the CSF showed low concentrations of neratinib; nonetheless, 2 patients continued to receive therapy without disease progression for at least 13 cycles, with one on-study treatment lasting for nearly 6 years. Neratinib distribution in surgical tissue was variable for 1 patient, while specimens from 2 others did not produce conclusive results as a result of limited available samples.

Conclusion: Neratinib resulted in expected rates of diarrhea in this small cohort, with 2 of 5 patients receiving the study treatment for durable periods. Although logistically challenging, we were able to test a limited number of CSF- and parenchymal-based neratinib concentrations. Our findings from resected tumor tissue in one patient revealed heterogeneity in drug distribution and tumor histopathology.
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http://dx.doi.org/10.1016/j.clbc.2019.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035200PMC
April 2020

Erratum: Multidisciplinary Management of Breast Cancer During Pregnancy.

Oncologist 2018 Jun 18;23(6):746. Epub 2018 Jun 18.

[This corrects the article DOI: 10.1634/theoncologist.2016-0208.].
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http://dx.doi.org/10.1634/theoncologist.2016-0208erratumDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067951PMC
June 2018

The Evolving Modern Management of Brain Metastasis.

Clin Cancer Res 2019 11 18;25(22):6570-6580. Epub 2019 Jun 18.

Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.

The incidence of brain metastases is increasing as cancer therapies improve and patients live longer, providing new challenges to the multidisciplinary teams that care for these patients. Brain metastatic cancer cells possess unique characteristics that allow them to penetrate the blood-brain barrier, colonize the brain parenchyma, and persist in the intracranial environment. In addition, brain metastases subvert the innate and adaptive immune system, permitting evasion of the antitumor immune response. Better understanding of the above mechanisms will allow for development and delivery of more effective therapies for brain metastases. In this review, we outline the molecular mechanisms underlying development, survival, and immunosuppression of brain metastases. We also discuss current and emerging treatment strategies, including surgery, radiation, disease-specific and mutation-targeted systemic therapy, and immunotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1624DOI Listing
November 2019

Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision Making for Early-Stage, Operable Breast Cancer: Update of the ASCO Endorsement of the Cancer Care Ontario Guideline.

J Clin Oncol 2019 08 17;37(22):1965-1977. Epub 2019 Jun 17.

11Kimmel Cancer Center at Johns Hopkins, Baltimore, MD.

Purpose: To update the American Society of Clinical Oncology endorsement of the Cancer Care Ontario recommendations on the Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision Making for Early-Stage, Operable Breast Cancer.

Methods: Two phase III trials-the Trial Assigning Individualized Options for Treatment (TAILORx) in women with hormone receptor-positive, node-negative tumors and the Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy (MINDACT) trial-provided the evidence for this update.

Updated Recommendations: Shared decision making between clinicians and patients is appropriate for adjuvant systemic therapy for breast cancer. For patients older than age 50 years and whose tumors have Onco DX recurrence scores less than 26, and for patients age 50 years or younger whose tumors have Onco DX recurrence scores less than 16, there is little to no benefit from chemotherapy. Clinicians may offer endocrine therapy alone for these patients. For patients age 50 years or younger with recurrence scores of 16 to 25, clinicians may offer chemoendocrine therapy. Patients with recurrence scores greater than 30 should be considered candidates for chemoendocrine therapy. Based on informal consensus, the Panel recommends that oncologists may offer chemoendocrine therapy to patients with Onco DX scores of 26 to 30.The MammaPrint assay could be used to guide decisions on withholding adjuvant systemic chemotherapy in patients with hormone receptor-positive lymph node-negative breast cancer and in select patients with lymph node-positive cancers. In both patients with node-positive and node-negative disease, evidence of clinical utility of the MammaPrint assay was only apparent in those determined to be at high clinical risk; the Panel thus did not recommend use of MammaPrint assay in patients determined to be at low clinical risk. Remaining recommendations from the 2016 ASCO guideline endorsement are unchanged.Additional information is available at www.asco.org/breast-cancer-guidelines.
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http://dx.doi.org/10.1200/JCO.19.00948DOI Listing
August 2019

Patient-reported and clinician-reported chemotherapy-induced peripheral neuropathy in patients with early breast cancer: Current clinical practice.

Cancer 2019 09 15;125(17):2945-2954. Epub 2019 May 15.

Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina.

Background: In the current study, the authors investigated the incidence of moderate to severe chemotherapy-induced peripheral neuropathy (CIPN) for chemotherapy regimens commonly used in current clinical practice for the treatment of patients with early breast cancer. Patient-reported and clinician-assessed CIPN severity scores were compared, and risk factors for CIPN severity were identified.

Methods: Patients completed a Patient-Reported Symptom Monitoring form and oncologists completed a Common Terminology Criteria for Adverse Events form. CIPN reports were collected prospectively during regularly scheduled infusion visits throughout the duration of chemotherapy.

Results: The sample included 184 women with a mean age of 55 years; approximately 73% were white. The 4 chemotherapy regimens used were doxorubicin and cyclophosphamide plus paclitaxel (60 patients); docetaxel and cyclophosphamide (50 patients); docetaxel, carboplatin, and anti-human epidermal growth factor receptor 2 (HER2) (24 patients); and doxorubicin and cyclophosphamide plus paclitaxel and carboplatin (18 patients). All patients treated with doxorubicin and cyclophosphamide plus paclitaxel and doxorubicin and cyclophosphamide plus paclitaxel and carboplatin received paclitaxel; all patients treated with docetaxel and cyclophosphamide and docetaxel, carboplatin, and anti-HER2 received docetaxel. The chemotherapy dose was reduced in 52 patients (28%); in 15 patients (29%), this reduction was due to CIPN. Chemotherapy was discontinued in 26 patients (14%), 8 because of CIPN. Agreement between patient-reported and clinician-assessed CIPN severity scores was minimal (weighted Cohen kappa, P = .34). Patient-reported moderate to severe CIPN was higher for paclitaxel (50%) compared with docetaxel (17.7%) (P < .001). Pretreatment arthritis and/or rheumatism (relative risk [RR], 1.58; 95% CI, 1.06-2.35 [P = .023]) and regimens containing paclitaxel (RR, 2.88; 95% CI, 1.72-4.83 [P < .0001]) were associated with higher CIPN severity. Being married (RR, 0.57; 95% CI, 0.37-0.887 [P = .01]) was found to be associated with lower CIPN severity.

Conclusions: The discrepancy between patient-reported and clinician-assessed CIPN underscores the need for both patient and clinician perspectives regarding this common, dose-limiting, and potentially disabling side effect of chemotherapy.
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http://dx.doi.org/10.1002/cncr.32175DOI Listing
September 2019

ATTAIN: Phase III study of etirinotecan pegol versus treatment of physician's choice in patients with metastatic breast cancer and brain metastases.

Future Oncol 2019 Jul 10;15(19):2211-2225. Epub 2019 May 10.

IOB Institute of Oncology, Quironsalud Group, 28034 Madrid & 08023 Barcelona, Spain.

The increasing incidence of breast cancer brain metastases is a major clinical problem with its associated poor prognosis and limited treatment options. The long-acting topoisomerase-1 inhibitor, etirinotecan pegol, was designed to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels. Motivated by improved survival findings from subgroup analyses from the Phase III BEACON trial, this ongoing randomized, Phase III trial compares etirinotecan pegol to drugs commonly used for advanced breast cancer in patients with stable, treated breast cancer brain metastases who have been previously treated with an anthracycline, taxane and capecitabine. The primary end point is overall survival. Secondary end points include objective response rate, progression-free survival and time to CNS disease progression or recurrence in patients with/without CNS lesions present at study entry. Trial registration number: NCT02915744.
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http://dx.doi.org/10.2217/fon-2019-0180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466911PMC
July 2019

TBCRC 022: A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases.

J Clin Oncol 2019 05 12;37(13):1081-1089. Epub 2019 Mar 12.

1 Dana-Farber Cancer Institute, Boston, MA.

Purpose: Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer to the CNS are limited. We previously reported modest activity of neratinib monotherapy for HER2-positive breast cancer brain metastases. Here we report the results from additional study cohorts.

Patients And Methods: Patients with measurable, progressive, HER2-positive brain metastases (92% after receiving CNS surgery and/or radiotherapy) received neratinib 240 mg orally once per day plus capecitabine 750 mg/m twice per day for 14 days, then 7 days off. Lapatinib-naïve (cohort 3A) and lapatinib-treated (cohort 3B) patients were enrolled. If nine or more of 35 (cohort 3A) or three or more of 25 (cohort 3B) had CNS objective response rates (ORR), the drug combination would be deemed promising. The primary end point was composite CNS ORR in each cohort separately, requiring a reduction of 50% or more in the sum of target CNS lesion volumes without progression of nontarget lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression.

Results: Forty-nine patients enrolled in cohorts 3A (n = 37) and 3B (n = 12; cohort closed for slow accrual). In cohort 3A, the composite CNS ORR = 49% (95% CI, 32% to 66%), and the CNS ORR in cohort 3B = 33% (95% CI, 10% to 65%). Median progression-free survival was 5.5 and 3.1 months in cohorts 3A and 3B, respectively; median survival was 13.3 and 15.1 months. Diarrhea was the most common grade 3 toxicity (29% in cohorts 3A and 3B).

Neratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted.
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http://dx.doi.org/10.1200/JCO.18.01511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494354PMC
May 2019

Patient-Reported Toxicities During Chemotherapy Regimens in Current Clinical Practice for Early Breast Cancer.

Oncologist 2019 06 14;24(6):762-771. Epub 2018 Dec 14.

School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Background: This study explores the incidence of patient-reported major toxicity-symptoms rated "moderate," "severe," or "very severe"-for chemotherapy regimens commonly used in early breast cancer.

Patients And Methods: Female patients aged 21 years or older completed a validated Patient-Reported Symptom Monitoring instrument and rated 17 symptoms throughout adjuvant or neoadjuvant chemotherapy. Fisher's exact tests compared differences in percentages in symptom ratings, and general linear regression was used to model the incidence of patient-reported major toxicity.

Results: In 152 patients, the mean age was 54 years (range, 24-77), and 112 (74%) were white; 51% received an anthracycline-based regimen. The proportion of patients rating fatigue, constipation, myalgia, diarrhea, nausea, peripheral neuropathy, and swelling of arms or legs as a major toxicity at any time during chemotherapy varied significantly among four chemotherapy regimens ( < .05). The mean (SD) number of symptoms rated major toxicities was 6.3 (3.6) for anthracycline-based and 4.4 (3.5) for non-anthracycline-based regimens ( = .001; possible range, 0-17 symptoms). Baseline higher body mass index ( = .03), patient-reported Karnofsky performance status ≤80 ( = .0003), and anthracycline-based regimens ( = .0003) were associated with greater total number of symptoms rated major toxicities (alternative model: chemotherapy duration, < .0001). Twenty-six percent of dose reductions (26 of 40), 75% of hospitalizations (15 of 20), and 94% of treatment discontinuations (15 of 16) were in anthracycline-based regimens.

Conclusion: Capturing multiple toxicity outcomes throughout chemotherapy enables oncologists and patients to understand the range of side effects as they discuss treatment efficacies. Continuous symptom monitoring may aid in the timely development of interventions that minimize toxicity and improve outcomes IMPLICATIONS FOR PRACTICE: This study investigated patient-reported toxicities for 17 symptoms recorded prospectively during adjuvant and neoadjuvant chemotherapy regimens for early breast cancer. An analysis of four commonly used chemotherapy regimens identified significant differences among regimens in both individual symptoms and total number of symptoms rated moderate, severe, or very severe. Longer chemotherapy regimens, such as anthracycline-based regimens followed by paclitaxel, had higher proportions of symptoms rated major toxicities. The inclusion of patient perspectives on multiple toxicity outcomes at the same time at multiple time points during chemotherapy has the potential for improving patient-provider communication regarding symptom management, patient satisfaction, and long-term clinical outcomes.
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http://dx.doi.org/10.1634/theoncologist.2018-0590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656489PMC
June 2019

Tracking plasma DNA mutation dynamics in estrogen receptor positive metastatic breast cancer with dPCR-SEQ.

NPJ Breast Cancer 2018 5;4:39. Epub 2018 Dec 5.

1Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC USA.

Serial monitoring of plasma DNA mutations in estrogen receptor positive metastatic breast cancer (ER + MBC) holds promise as an early predictor of therapeutic response. Here, we developed dPCR-SEQ, a customized assay that utilizes digital PCR-based target enrichment followed by next-generation sequencing to analyze plasma DNA mutations in , , and . We validated dPCR-SEQ in a prospective cohort of 58 patients with ER + MBC and demonstrate excellent concordance with hotspot mutation abundance measured by conventional digital PCR. The dPCR-SEQ assay revealed , , and plasma ctDNA mutations in 55%, 32%, and 32% of the study patients, respectively. We also observed dynamic changes in , , and ctDNA mutant allele fraction (MAF) that were frequently discordant between the different genes. Thus, monitoring plasma DNA mutation dynamics using a dPCR-SEQ assay is feasible, accurate, and may be investigated as a biomarker of therapeutic response in ER + MBC.
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http://dx.doi.org/10.1038/s41523-018-0093-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281679PMC
December 2018

Dual HER2-Targeting in the Adjuvant Setting: Where We Have Been and Where We Are Going.

Oncology (Williston Park) 2018 Oct;32(10):483-7

Adjuvant human epidermal growth factor receptor 2 (HER2)-directed treatment has changed dramatically over the past decade. Historically, the addition of 1 year of trastuzumab to adjuvant chemotherapy has significantly improved both disease-free survival and overall survival across several studies. More recently, and in the metastatic setting, dual HER2-targeted therapy-beyond that of trastuzumab alone, and in combination with monoclonal antibodies such as pertuzumab and tyrosine kinase inhibitors such as lapatinib-has shown a survival benefit. As is common in drug development, promising agents in the metastatic setting are then examined in the curative setting. This article will provide an overview of the efficacy of dual HER2-targeted therapy in the adjuvant setting as reported in the APHINITY, ExteNET, and ALTTO trials. Potential toxicities with dual HER2-targeted therapy and the financial consequences of adding additional HER2-targeted therapy, beyond trastuzumab, in the adjuvant setting will also be discussed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791354PMC
October 2018

Breast cancer in adolescents and young adults.

Pediatr Blood Cancer 2018 12 28;65(12):e27397. Epub 2018 Aug 28.

Oregon Health and Science University, Portland, Oregon.

Breast cancer is the most common cancer of adolescents and young adult (AYA) women aged 15 to 39 years, accounting for 5.6% of all invasive breast cancer in women. In comparison with older women, AYAs are more likely to have familial cancer predisposition genes, larger breast tumors, unfavorable biological characteristics, distant metastatic disease at diagnosis, and adverse outcome. Endocrine therapy and some chemotherapy recommendations differ between young and older women. AYAs require coordinated multidisciplinary care, treatment regimens that minimize late effects such as premature menopause and osteoporosis, and proactive management of psychological and sexual health during and after cancer treatment.
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http://dx.doi.org/10.1002/pbc.27397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192832PMC
December 2018

LCCC 1025: a phase II study of everolimus, trastuzumab, and vinorelbine to treat progressive HER2-positive breast cancer brain metastases.

Breast Cancer Res Treat 2018 Oct 25;171(3):637-648. Epub 2018 Jun 25.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 170 Manning Drive, CB #7305, Chapel Hill, NC, 27599-7305, USA.

Purpose: HER2 + breast cancer (BC) is an aggressive subtype with high rates of brain metastases (BCBM). Two-thirds of HER2 + BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy. This phase II study evaluated everolimus (E), a brain-permeable mTOR inhibitor, trastuzumab (T), and vinorelbine (V) in patients with HER2 + BCBM.

Patients And Methods: Eligible patients had progressive HER2 + BCBM. The primary endpoint was intracranial response rate (RR); secondary objectives were CNS clinical benefit rate (CBR), extracranial RR, time to progression (TTP), overall survival (OS), and targeted sequencing of tumors from enrolled patients. A two-stage design distinguished intracranial RR of 5% versus 20%.

Results: 32 patients were evaluable for toxicity, 26 for efficacy. Intracranial RR was 4% (1 PR). CNS CBR at 6 mos was 27%; at 3 mos 65%. Median intracranial TTP was 3.9 mos (95% CI 2.2-5). OS was 12.2 mos (95% CI 0.6-20.2). Grade 3-4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). Mutations in TP53 and PIK3CA were common in BCBM. Mutations in the PI3K/mTOR pathway were not associated with response. ERBB2 amplification was higher in BCBM compared to primary BC; ERBB2 amplification in the primary BC trended toward worse OS.

Conclusion: While intracranial RR to ETV was low in HER2 + BCBM patients, one-third achieved CNS CBR; TTP/OS was similar to historical control. No new toxicity signals were observed. Further analysis of the genomic underpinnings of BCBM to identify tractable prognostic and/or predictive biomarkers is warranted.

Clinical Trial: (NCT01305941).
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http://dx.doi.org/10.1007/s10549-018-4852-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779035PMC
October 2018

Understanding patterns of brain metastasis in breast cancer and designing rational therapeutic strategies.

Ann Transl Med 2018 May;6(9):163

Division of Hematology/Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.

One of the most feared sequelae after a diagnosis of advanced breast cancer is development of metastases to the brain as this diagnosis can affect physical function, independence, relationships, quality of life, personality, and ultimately one's sense of self. The propensity to develop breast cancer brain metastases (BCBMs) varies by subtype, occurring in up to one half of those with triple negative breast cancer (TNBC), approximately a third of HER+ breast cancers and 14% in hormone positive disease. Median survival after BCBM diagnosis can be as short as 5 months in TNBC and 10-18 months in the other subtypes. Here, we review the biology of BCBMs and how it informs the rational design of new therapeutic approaches and agents. We discuss application of novel targeted and immunotherapies by breast cancer subtype. It is noteworthy that there are no U.S. Food and Drug Administration (FDA)-approved treatments specifically for BCBMs currently. Nevertheless, there are legitimate grounds for hope as patients with BCBMs are now being included in clinical trials of systemic therapies and a better understanding of the biology and genetic underpinning of BCBMs is driving an increased range of options for patients.
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http://dx.doi.org/10.21037/atm.2018.04.35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985267PMC
May 2018

Integrated RNA and DNA sequencing reveals early drivers of metastatic breast cancer.

J Clin Invest 2018 04 26;128(4):1371-1383. Epub 2018 Feb 26.

Department of Genetics.

Breast cancer metastasis remains a clinical challenge, even within a single patient across multiple sites of the disease. Genome-wide comparisons of both the DNA and gene expression of primary tumors and metastases in multiple patients could help elucidate the underlying mechanisms that cause breast cancer metastasis. To address this issue, we performed DNA exome and RNA sequencing of matched primary tumors and multiple metastases from 16 patients, totaling 83 distinct specimens. We identified tumor-specific drivers by integrating known protein-protein network information with RNA expression and somatic DNA alterations and found that genetic drivers were predominantly established in the primary tumor and maintained through metastatic spreading. In addition, our analyses revealed that most genetic drivers were DNA copy number changes, the TP53 mutation was a recurrent founding mutation regardless of subtype, and that multiclonal seeding of metastases was frequent and occurred in multiple subtypes. Genetic drivers unique to metastasis were identified as somatic mutations in the estrogen and androgen receptor genes. These results highlight the complexity of metastatic spreading, be it monoclonal or multiclonal, and suggest that most metastatic drivers are established in the primary tumor, despite the substantial heterogeneity seen in the metastases.
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http://dx.doi.org/10.1172/JCI96153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873890PMC
April 2018

Live birth outcomes after adolescent and young adult breast cancer.

Int J Cancer 2018 05 4;142(10):1994-2002. Epub 2018 Jan 4.

Department of Epidemiology, University of North Carolina, Chapel Hill, NC.

Reproductive outcomes are an important survivorship concern for women diagnosed with cancer as adolescents and young adults (AYAs). We examined the incidence of live birth and the prevalence of adverse birth outcomes according to tumor and treatment characteristics among AYAs with breast cancer. Women diagnosed with breast cancer at ages 15-39 during 2000-2013 were identified using the North Carolina Central Cancer Registry (n = 4,978). Cancer registry records were linked to state birth certificate files from 2000 to 2014 to identify births to women with and without a breast cancer history. The breast cancer cohort was followed until live birth, death, age 46, or December 31, 2014, whichever occurred first. For each birth to breast cancer survivors (n = 338), we sampled 20 births to women without a recorded cancer diagnosis, with frequency matching on maternal age and year of delivery. The cumulative incidence of live births after breast cancer was 8% at 10 years. Births were less common among women treated with chemotherapy. Overall, the prevalence of preterm birth, low birth weight, small-for-gestational age (SGA) and Cesarean delivery did not differ substantially between births to women with and without breast cancer. However, births to women with ER-negative disease were more likely to be preterm (PR = 1.84; 95% CI: 1.11-3.06). In this population-based study, <10% of AYA breast cancer survivors had a live birth within 10 years of their diagnosis. The increase in risk of preterm delivery among ER-negative survivors in our cohort warrants further investigation in larger studies.
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http://dx.doi.org/10.1002/ijc.31227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867233PMC
May 2018

The incidence and predictive factors for leptomeningeal spread after stereotactic radiation for breast cancer brain metastases.

Breast J 2018 05 18;24(3):424-425. Epub 2017 Dec 18.

Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC, USA.

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http://dx.doi.org/10.1111/tbj.12919DOI Listing
May 2018

A Phase I Trial of the PI3K Inhibitor Buparlisib Combined With Capecitabine in Patients With Metastatic Breast Cancer.

Clin Breast Cancer 2018 08 28;18(4):289-297. Epub 2017 Oct 28.

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC.

Background: Buparlisib is an oral pan-class I phosphotidyinositol-3-kinase (PI3K) inhibitor. The present phase I study evaluated the safety, pharmacokinetics, and efficacy of buparlisib with capecitabine in patients with metastatic breast cancer.

Patients And Methods: Patients received buparlisib once daily (range, 50 to 100 mg) for 3 weeks with capecitabine twice daily (range, 1000 to 1250 mg/m) for 2 weeks with a 1-week break. Dose escalation used a traditional "3 + 3" design with standard definitions of dose-limiting toxicity (DLT) and maximum tolerated dose.

Results: Of the 25 patients enrolled, 23 were evaluable for DLT and 17 were evaluable for response. The maximum tolerated dose of the combination was buparlisib 100 mg daily and capecitabine 1000 mg/m twice daily. DLTs included grade 3 hyperglycemia and grade 3 confusion. The most common grade 3 toxicities were diarrhea and elevation of aspartate aminotransferase and alanine transaminase. One patient exhibited a complete response to treatment and four had a confirmed partial response. In cohorts 3 and 4, in which the buparlisib dose remained constant but the capecitabine dose was increased, significant increases in the buparlisib plasma concentration were noted.

Conclusion: The combination of buparlisib with capecitabine in patients with metastatic breast cancer was generally well-tolerated, with several patients demonstrating prolonged responses. Unexpectedly low rates of PIK3CA mutations (3 of 17) were seen, and only 2 of 7 tumors with subtyping were luminal, making exploration of these putative predictive markers impossible. Further study of the combination is not unreasonable, with expanded pharmacokinetics and sequencing analysis to better elucidate potential drug-drug interactions and more accurate predictive biomarkers of response.
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http://dx.doi.org/10.1016/j.clbc.2017.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924643PMC
August 2018

Biology and Etiology of Young-Onset Breast Cancers among Premenopausal African American Women: Results from the AMBER Consortium.

Cancer Epidemiol Biomarkers Prev 2017 12 13;26(12):1722-1729. Epub 2017 Sep 13.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

African American (AA) women have higher incidence of aggressive, young-onset (<40 years) breast cancers. Young- and older-onset disease may have distinct tumor biologies and etiologies; however, studies investigating age differences among AA women have been rare and generally underpowered. We examined tumor characteristics and breast cancer risk factors associated with premenopausal young (<40) vs. older (≥40) AA women's breast cancer in the African American Breast Cancer Epidemiology and Risk Consortium (2,008 cases and 5,144 controls). Unconditional logistic regression models assessed heterogeneity of tumor biology and risk factor associations by age, overall, and by estrogen receptor status. Premenopausal AA women <40 years had higher frequency of poorer-prognosis tumor characteristics compared with older women, including negative estrogen and progesterone receptor status, triple-negative subtype, higher grade, higher stage, and larger tumors. Adiposity (i.e., waist-to-hip ratio) and family history of breast cancer were more strongly associated with young-onset disease [case-control OR = 1.46, 95% confidence interval (CI) = 1.04-2.05; OR = 3.10, 95% CI = 2.08-4.63, respectively] compared with older-onset disease (OR = 1.11, 95% CI = 0.91-1.35; OR = 1.57, 95% CI = 1.26-1.94). Breastfeeding showed a slight inverse risk association among young women (OR = 0.70, 95% CI = 0.43-1.16). Oral contraceptive use was associated with increased risk regardless of age. Considering various cutoff points for young age (<40, <45, <50), age-related heterogeneity was greatest when <40 was used. Among premenopausal AA women, diagnosis before age 40 is associated with more aggressive breast tumor biology and some etiologic differences. Modifiable risk factors including breastfeeding, adiposity, and oral contraceptive use may be important targets for mitigating harms of young-onset breast cancer. .
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http://dx.doi.org/10.1158/1055-9965.EPI-17-0450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903207PMC
December 2017