Publications by authors named "George W Sledge"

256 Publications

The optimal duration of endocrine therapy in hormone receptor-positive breast cancer.

Authors:
George W Sledge

Clin Adv Hematol Oncol 2021 Jun;19(6):383-404

Stanford University Medical Center, Palo Alto, California.

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June 2021

Treatment and Monitoring Variability in US Metastatic Breast Cancer Care.

JCO Clin Cancer Inform 2021 May;5:600-614

Department of Medicine, Stanford University School of Medicine, Stanford, CA.

Purpose: Treatment and monitoring options for patients with metastatic breast cancer (MBC) are increasing, but little is known about variability in care. We sought to improve understanding of MBC care and its correlates by analyzing real-world claims data using a search engine with a novel query language to enable temporal electronic phenotyping.

Methods: Using the Advanced Cohort Engine, we identified 6,180 women who met criteria for having estrogen receptor-positive, human epidermal growth factor receptor 2-negative MBC from IBM MarketScan US insurance claims (2007-2014). We characterized treatment, monitoring, and hospice usage, along with clinical and nonclinical factors affecting care.

Results: We observed wide variability in treatment modality and monitoring across patients and geography. Most women received first-recorded therapy with endocrine (67%) versus chemotherapy, underwent more computed tomography (CT) (76%) than positron emission tomography-CT, and were monitored using tumor markers (58%). Nearly half (46%) met criteria for aggressive disease, which were associated with receiving chemotherapy first, monitoring primarily with CT, and more frequent imaging. Older age was associated with endocrine therapy first, less frequent imaging, and less use of tumor markers. After controlling for clinical factors, care strategies varied significantly by nonclinical factors (median regional income with first-recorded therapy and imaging type, geographic region with these and with imaging frequency and use of tumor markers; < .0001).

Conclusion: Variability in US MBC care is explained by patient and disease factors and by nonclinical factors such as geographic region, suggesting that treatment decisions are influenced by local practice patterns and/or resources. A search engine designed to express complex electronic phenotypes from longitudinal patient records enables the identification of variability in patient care, helping to define disparities and areas for improvement.
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http://dx.doi.org/10.1200/CCI.21.00031DOI Listing
May 2021

Japanese subpopulation analysis of MONARCH 2: phase 3 study of abemaciclib plus fulvestrant for treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer that progressed on endocrine therapy.

Breast Cancer 2021 Apr 1. Epub 2021 Apr 1.

Breast Cancer Unit, Breast Surgery, Graduate School of Medicine, Kyoto University Hospital, Kyoto University, 54 Shogoin-Kawaracho, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: This was a Japanese subpopulation analysis of MONARCH 2, a double-blind, randomized, placebo-controlled, phase 3 study of abemaciclib plus fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC).

Methods: Eligible women had progressed on (neo)adjuvant endocrine therapy (ET), ≤ 12 months from end of adjuvant ET, or on first-line ET for ABC, and had not received chemotherapy for ABC. Patients were randomized 2:1 to receive abemaciclib or placebo plus fulvestrant. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), pharmacokinetics (PK), health-related quality of life (HRQoL), and safety.

Results: In Japan, 95 patients were randomized (abemaciclib, n = 64; placebo, n = 31). At final PFS analysis (February 14, 2017), median PFS was 21.2 and 14.3 months, respectively, in the abemaciclib and placebo groups (hazard ratio: 0.672; 95% confidence interval: 0.380-1.189). Abemaciclib had a higher objective response rate (37.5%) than placebo (12.9%). PK and safety profiles for Japanese patients were consistent with those of the overall population, without clinically meaningful differences across most HRQoL dimensions evaluated. The most frequent adverse events in the abemaciclib versus placebo groups were diarrhea (95.2 versus 25.8%), neutropenia (79.4 versus 0%), and leukopenia (66.7 versus 0%). At a second data cutoff (June 20, 2019), median OS was not reached with abemaciclib and 47.3 months with placebo (hazard ratio: 0.755; 95% confidence interval: 0.390-1.463).

Conclusions: Results of the Japanese subpopulation were consistent with the improved clinical outcomes and manageable safety profile observed in the overall population.

Clinical Trial Registration: NCT02107703; U.S. National Library of Medicine: https://clinicaltrials.gov/ct2/show/NCT02107703 .
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http://dx.doi.org/10.1007/s12282-021-01239-8DOI Listing
April 2021

Breast cancer patients' insurance status and residence zip code correlate with early discontinuation of endocrine therapy: An analysis of the ECOG-ACRIN TAILORx trial.

Cancer 2021 Apr 1. Epub 2021 Apr 1.

University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.

Background: Early discontinuation is a substantial barrier to the delivery of endocrine therapies (ETs) and may influence recurrence and survival. The authors investigated the association between early discontinuation of ET and social determinants of health, including insurance coverage and the neighborhood deprivation index (NDI), which was measured on the basis of patients' zip codes, in breast cancer.

Methods: In this retrospective analysis of a prospective randomized clinical trial (Trial Assigning Individualized Options for Treatment), women with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer who started ET within a year of study entry were included. Early discontinuation was calculated as stopping ET within 4 years of its start for reasons other than distant recurrence or death via Kaplan-Meier estimates. A Cox proportional hazards joint model was used to analyze the association between early discontinuation of ET and factors such as the study-entry insurance and NDI, with adjustments made for other variables.

Results: Of the included 9475 women (mean age, 55.6 years; White race, 84%), 58.0% had private insurance, whereas 11.7% had Medicare, 5.8% had Medicaid, 3.8% were self-pay, and 19.1% were treated at international sites. The early discontinuation rate was 12.3%. Compared with those with private insurance, patients with Medicaid (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.23-1.92) and self-pay patients (HR, 1.65; 95% CI, 1.25-2.17) had higher early discontinuation. Participants with a first-quartile NDI (highest deprivation) had a higher probability of discontinuation than those with a fourth-quartile NDI (lowest deprivation; HR, 1.34; 95% CI, 1.11-1.62).

Conclusions: Patients' insurance and zip code at study entry play roles in adherence to ET, with uninsured and underinsured patients having a high rate of treatment nonadherence. Early identification of patients at risk may improve adherence to therapy.

Lay Summary: In this retrospective analysis of 9475 women with breast cancer participating in a clinical trial (Trial Assigning Individualized Options for Treatment), Medicaid and self-pay patients (compared with those with private insurance) and those in the highest quartile of neighborhood deprivation scores (compared with those in the lowest quartile) had a higher probability of early discontinuation of endocrine therapy. These social determinants of health assume larger importance with the expected increase in unemployment rates and loss of insurance coverage in the aftermath of the coronavirus disease 2019 pandemic. Early identification of patients at risk and enrollment in insurance optimization programs may improve the persistence of therapy.
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http://dx.doi.org/10.1002/cncr.33527DOI Listing
April 2021

Y box binding protein 1 inhibition as a targeted therapy for ovarian cancer.

Cell Chem Biol 2021 Mar 9. Epub 2021 Mar 9.

Department of Radiation Oncology, Stanford University School of Medicine, Palo Alto, CA 94304, USA; Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University School of Medicine, Palo Alto, CA 94304, USA; Department of Cell, Development and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA; Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA. Electronic address:

Y box binding protein 1 (YB-1) is a multifunctional protein associated with tumor progression and the emergence of treatment resistance (TR). Here, we report an azopodophyllotoxin small molecule, SU056, that potently inhibits tumor growth and progression via YB-1 inhibition. This YB-1 inhibitor inhibits cell proliferation, resistance to apoptosis in ovarian cancer (OC) cells, and arrests in the G1 phase. Inhibitor treatment leads to enrichment of proteins associated with apoptosis and RNA degradation pathways while downregulating spliceosome pathway. In vivo, SU056 independently restrains OC progression and exerts a synergistic effect with paclitaxel to further reduce disease progression with no observable liver toxicity. Moreover, in vitro mechanistic studies showed delayed disease progression via inhibition of drug efflux and multidrug resistance 1, and significantly lower neurotoxicity as compared with etoposide. These data suggest that YB-1 inhibition may be an effective strategy to reduce OC progression, antagonize TR, and decrease patient mortality.
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http://dx.doi.org/10.1016/j.chembiol.2021.02.014DOI Listing
March 2021

Abemaciclib in combination with endocrine therapy for East Asian patients with HR+, HER2- advanced breast cancer: MONARCH 2 & 3 trials.

Cancer Sci 2021 Jun 1;112(6):2381-2392. Epub 2021 May 1.

Stanford University, Stanford, CA, USA.

This post hoc analysis of MONARCH 2 and MONARCH 3 assesses the efficacy, safety, and pharmacokinetics (PK) of abemaciclib in combination with endocrine therapy (ET) in East Asian patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. MONARCH 2 and MONARCH 3 are global, randomized, double-blind, phase 3 studies of abemaciclib/placebo + fulvestrant and abemaciclib/placebo + nonsteroidal aromatase inhibitor (NSAI, anastrozole or letrozole), respectively. The East Asian population comprised 212 (31.7%) of the 669 intent-to-treat (ITT) population in the MONARCH 2 trial and 144 (29.2%) of the 493 ITT patients in the MONARCH 3 trial. In the East Asian population, median progression-free survival (PFS) was significantly prolonged in the abemaciclib arm compared with placebo in both MONARCH 2 (hazard ratio [HR], 0.520; 95% confidence interval [CI], 0.362 to 0.747; P < .001; median: 21.2 vs 11.6 months) and MONARCH 3 (HR, 0.326; 95% CI, 0.200 to 0.531, P < .001; median: not reached vs 12.82 months). Diarrhea (MONARCH 2: 90%; MONARCH 3: 88%) and neutropenia (MONARCH 2: 68%; MONARCH 3: 58%) were the most frequent adverse events observed in the East Asian populations. Abemaciclib exposures and PK were similar in East Asians and the non-East Asian populations of both trials. Abemaciclib in combination with ET in the East Asian populations of MONARCH 2 and MONARCH 3 provided consistent results with the ITT populations, demonstrating improvements in efficacy with generally tolerable safety profiles for patients with HR+, HER2- advanced breast cancer.
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http://dx.doi.org/10.1111/cas.14877DOI Listing
June 2021

Liquid biopsy enters the clinic - implementation issues and future challenges.

Nat Rev Clin Oncol 2021 May 20;18(5):297-312. Epub 2021 Jan 20.

Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.

Historically, studies of disseminated tumour cells in bone marrow and circulating tumour cells in peripheral blood have provided crucial insights into cancer biology and the metastatic process. More recently, advances in the detection and characterization of circulating tumour DNA (ctDNA) have finally enabled the introduction of liquid biopsy assays into clinical practice. The FDA has already approved several single-gene assays and, more recently, multigene assays to detect genetic alterations in plasma cell-free DNA (cfDNA) for use as companion diagnostics matched to specific molecularly targeted therapies for cancer. These approvals mark a tipping point for the widespread use of liquid biopsy in the clinic, and mostly in patients with advanced-stage cancer. The next frontier for the clinical application of liquid biopsy is likely to be the systemic treatment of patients with 'ctDNA relapse', a term we introduce for ctDNA detection prior to imaging-detected relapse after curative-intent therapy for early stage disease. Cancer screening and diagnosis are other potential future applications. In this Perspective, we discuss key issues and gaps in technology, clinical trial methodologies and logistics for the eventual integration of liquid biopsy into the clinical workflow.
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http://dx.doi.org/10.1038/s41571-020-00457-xDOI Listing
May 2021

Safety and efficacy of abemaciclib plus endocrine therapy in older patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: an age-specific subgroup analysis of MONARCH 2 and 3 trials.

Breast Cancer Res Treat 2021 Apr 3;186(2):417-428. Epub 2021 Jan 3.

Stanford University School of Medicine, Stanford, CA, USA.

Purpose: Abemaciclib in combination with endocrine therapy (ET) has demonstrated significant efficacy benefits in HR+ , HER2- advanced breast cancer patients in the Phase 3 studies MONARCH 2 (fulvestrant as ET) and MONARCH 3 (letrozole or anastrozole as ET). Here, we report age-specific safety and efficacy outcomes.

Methods: Exploratory analyses of MONARCH 2 and 3 were performed for 3 age groups (<65, 65-74, and ≥75 years). For safety, data were pooled from both studies; for efficacy, a subgroup analysis of PFS was performed for each trial independently.

Results: Pooled safety data were available for 1152 patients. Clinically relevant diarrhea (Grade 2/3) was higher in older patients receiving abemaciclib + ET (<65, 39.5%; 65-74, 45.2%; ≥75, 55.4%) versus placebo + ET (<65, 6.8%; 65-74, 4.5%; ≥75, 16.0%). Nausea, decreased appetite, and venous thromboembolic events were all moderately higher in older patients. Neutropenia (Grade ≥ 3) did not differ as a function of age in the abemaciclib + ET arm (<65, 25.8%; 65-74, 27.4%; ≥75, 18.1%). Dose adjustments and discontinuation rates were slightly higher in older patients. Abemaciclib + ET improved PFS compared with placebo + ET independent of patient age, with no significant difference in abemaciclib treatment effect between the 3 age groups (MONARCH 2: interaction p-value, 0.695; MONARCH 3: interaction p-value, 0.634). Estimated hazard ratios ranged from 0.523-0.633 (MONARCH 2) and 0.480-0.635 (MONARCH 3).

Conclusions: While higher rates of adverse events were reported in older patients, they were manageable with dose adjustments and concomitant medication. Importantly, a consistent efficacy benefit was observed across all age groups.

Clinical Trial Registration: ClinicalTrials.gov: NCT02107703 (first posted April 8, 2014) and NCT02246621 (first posted September 23, 2014).
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http://dx.doi.org/10.1007/s10549-020-06029-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990838PMC
April 2021

Impact of insurance and neighborhood socioeconomic status on clinical outcomes in therapeutic clinical trials for breast cancer.

Cancer Med 2021 01 2;10(1):45-52. Epub 2020 Dec 2.

Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.

The objective of this study was to evaluate the impact of insurance and neighborhood SES (nSES) on chemotherapy completion and overall mortality among participants in breast cancer clinical trials. The data sources for this study were two adjuvant breast cancer trials (ECOG E1199 and E5103) collectively including 9790 women. Insurance status at trial registration was categorized into private, government (Medicaid, Medicare, and other government type insurance), and self-pay. An Agency for Healthcare Research Quality (AHRQ) nSES index was calculated using residential zip codes linked to county level data on occupation, income, poverty, wealth, education, and crowding. Logistic regression and Cox Proportional Hazard models estimated odds ratios (OR) for chemotherapy treatment completion and hazard ratios (HR) for mortality, respectively, for insurance status and nSES. The models adjusted for: race, age, tumor size, nodal status, hormone receptor status, and primary surgery. The majority of patients had private insurance at trial registration: E1199: 85.6% (4154/4854) and E5103: 82.4% (3987/4836); median SES index was 53.8 (range: 41.8-66.8) and 54.1 (range: 44.5-66.1), respectively. Patients with government insurance were less likely to complete chemotherapy treatment (E1199 OR (95%CI): 0.73 (0.57-0.94); E5103 0.76 (0.64-0.91)) and had an increased risk of death (E1199 HR (95%CI): 1.44 (1.22-1.70); E5103 1.29 (1.06-1.58)) compared to the privately insured patients. There was no association between nSES and chemotherapy completion or overall mortality. Patients with government insurance at trial registration appeared to face barriers in chemotherapy completion and had a higher overall mortality compared to their privately insured counterparts.
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http://dx.doi.org/10.1002/cam4.3542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826479PMC
January 2021

Novel Aza-podophyllotoxin derivative induces oxidative phosphorylation and cell death via AMPK activation in triple-negative breast cancer.

Br J Cancer 2021 02 3;124(3):604-615. Epub 2020 Nov 3.

Department of Radiation Oncology, Stanford University School of Medicine, Palo Alto, CA, 94304, USA.

Background: To circumvent Warburg effect, several clinical trials for different cancers are utilising a combinatorial approach using metabolic reprogramming and chemotherapeutic agents including metformin. The majority of these metabolic interventions work via indirectly activating AMP-activated protein kinase (AMPK) to alter cellular metabolism in favour of oxidative phosphorylation over aerobic glycolysis. The effect of these drugs is dependent on glycaemic and insulin conditions.  Therefore, development of small molecules, which can activate AMPK, irrespective of the energy state, may be a better approach for triple-negative breast cancer (TNBC) treatment.

Methods: Therapeutic effect of SU212 on TNBC cells was examined using in vitro and in vivo models.

Results: We developed and characterised the efficacy of novel AMPK activator (SU212) that selectively induces oxidative phosphorylation and decreases glycolysis in TNBC cells, while not affecting these pathways in normal cells.   SU212 accomplished this metabolic reprogramming by activating AMPK independent of energy stress and irrespective of the glycaemic/insulin state. This leads to mitotic phase arrest and apoptosis in TNBC cells. In vivo, SU212 inhibits tumour growth, cancer progression and metastasis.

Conclusions: SU212 directly activates AMPK in TNBC cells, but does not hamper glucose metabolism in normal cells. Our study provides compelling preclinical data for further development of SU212 for the treatment of TNBC.
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http://dx.doi.org/10.1038/s41416-020-01137-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851402PMC
February 2021

Race, Ethnicity, and Clinical Outcomes in Hormone Receptor-Positive, HER2-Negative, Node-Negative Breast Cancer in the Randomized TAILORx Trial.

J Natl Cancer Inst 2021 Apr;113(4):390-399

Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.

Background: Black race is associated with worse outcomes in early breast cancer. We evaluated clinicopathologic characteristics, the 21-gene recurrence score (RS), treatment delivered, and clinical outcomes by race and ethnicity among women who participated in the Trial Assigning Individualized Options for Treatment.

Methods: The association between clinical outcomes and race (White, Black, Asian, other or unknown) and ethnicity (Hispanic vs non-Hispanic) was examined using proportional hazards models. All P values are 2-sided.

Results: Of 9719 eligible women with hormone receptor-positive, HER2-negative, node-negative breast cancer, there were 8189 (84.3%) Whites, 693 (7.1%) Blacks, 405 (4.2%) Asians, and 432 (4.4%) with other or unknown race. Regarding ethnicity, 889 (9.1%) were Hispanic. There were no substantial differences in RS or ESR1, PGR, or HER2 RNA expression by race or ethnicity. After adjustment for other covariates, compared with White race, Black race was associated with higher distant recurrence rates (hazard ratio [HR] = 1.60, 95% confidence intervals [CI] = 1.07 to 2.41) and worse overall survival in the RS 11-25 cohort (HR = 1.51, 95% CI = 1.06 to 2.15) and entire population (HR = 1.41, 95% CI = 1.05 to 1.90). Hispanic ethnicity and Asian race were associated with better outcomes. There was no evidence of chemotherapy benefit for any racial or ethnic group in those with a RS of 11-25.

Conclusions: Black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy in the Trial Assigning Individualized Options for Treatment. Similar to Whites, Black women did not benefit from adjuvant chemotherapy if the 21-gene RS was 11-25. Further research is required to elucidate the basis for this racial disparity in prognosis.
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http://dx.doi.org/10.1093/jnci/djaa148DOI Listing
April 2021

Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 1: Late Recurrence: Current Understanding, Clinical Considerations.

JNCI Cancer Spectr 2019 Dec 10;3(4):pkz050. Epub 2019 Aug 10.

Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Sinai Health System, Toronto, ON, Canada.

Disease recurrence (locoregional, distant) exerts a significant clinical impact on the survival of estrogen receptor-positive breast cancer patients. Many of these recurrences occur late, more than 5 years after original diagnosis, and represent a major obstacle to the effective treatment of this disease. Indeed, methods to identify patients at risk of late recurrence and therapeutic strategies designed to avert or treat these recurrences are lacking. Therefore, an international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. In this article, the major issues surrounding late recurrence are defined and current approaches that may be applicable to this challenge are discussed. Specifically, diagnostic tests with potential utility in late-recurrence prediction are described as well as a variety of patient-related factors that may influence recurrence risk. Clinical and therapeutic approaches are also reviewed, with a focus on patient surveillance and the implementation of extended endocrine therapy in the context of late-recurrence prevention. Understanding and treating late recurrence in estrogen receptor-positive breast cancer is a major unmet clinical need. A concerted effort of basic and clinical research is required to confront late recurrence and improve disease management and patient survival.
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http://dx.doi.org/10.1093/jncics/pkz050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049988PMC
December 2019

Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 2: Approaches to Predict and Identify Late Recurrence, Research Directions.

JNCI Cancer Spectr 2019 Dec 10;3(4):pkz049. Epub 2019 Aug 10.

Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Sinai Health System, Toronto, ON, Canada.

Late disease recurrence (more than 5 years after initial diagnosis) represents a clinical challenge in the treatment and management of estrogen receptor-positive breast cancer (BC). An international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. The underlying biological causes of late recurrence are complex, with the processes governing cancer cell dormancy, including immunosurveillance, cell proliferation, angiogenesis, and cellular stemness, being integral to disease progression. These critical processes are described herein as well as their role in influencing risk of recurrence. Moreover, observational and interventional clinical trials are proposed, with a focus on methods to identify patients at risk of recurrence and possible strategies to combat this in patients with estrogen receptor-positive BC. Because the problem of late BC recurrence of great importance, recent advances in disease detection and patient monitoring should be incorporated into novel clinical trials to evaluate approaches to enhance patient management. Indeed, future research on these issues is planned and will offer new options for effective late recurrence treatment and prevention strategies.
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http://dx.doi.org/10.1093/jncics/pkz049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050024PMC
December 2019

Patient-Reported Cognitive Impairment Among Women With Early Breast Cancer Randomly Assigned to Endocrine Therapy Alone Versus Chemoendocrine Therapy: Results From TAILORx.

J Clin Oncol 2020 06 9;38(17):1875-1886. Epub 2020 Apr 9.

Northwestern University School of Medicine, Chicago, IL.

Purpose: Cancer-related cognitive impairment (CRCI) is common during adjuvant chemotherapy and may persist. TAILORx provided a novel opportunity to prospectively assess patient-reported cognitive impairment among women with early breast cancer who were randomly assigned to chemoendocrine therapy (CT+E) versus endocrine therapy alone (E), allowing us to quantify the unique contribution of chemotherapy to CRCI.

Methods: Women with a 21-gene recurrence score of 11 to 25 enrolled in TAILORX were randomly assigned to CT+E or E. Cognitive impairment was assessed among a subgroup of 552 evaluable women using the 37-item Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaire, administered at baseline, 3, 6, 12, 24, and 36 months. The FACT-Cog included the 20-item Perceived Cognitive Impairment (PCI) scale, our primary end point. Clinically meaningful changes were defined a priori and linear regression was used to model PCI scores on baseline PCI, treatment, and other factors.

Results: FACT-Cog PCI scores were significantly lower, indicating more impairment, at 3, 6, 12, 24, and 36 months compared with baseline for both groups. The magnitude of PCI change scores was greater for CT+E than E at 3 months, the prespecified primary trial end point, and at 6 months, but not at 12, 24, and 36 months. Tests of an interaction between menopausal status and treatment were nonsignificant.

Conclusion: Adjuvant CT+E is associated with significantly greater CRCI compared with E at 3 and 6 months. These differences abated over time, with no significant differences observed at 12 months and beyond. These findings indicate that chemotherapy produces early, but not sustained, cognitive impairment relative to E, providing reassurance to patients and clinicians in whom adjuvant chemotherapy is indicated to reduce recurrence risk.
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http://dx.doi.org/10.1200/JCO.19.01866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280048PMC
June 2020

Health-Related Quality of Life in MONARCH 2: Abemaciclib plus Fulvestrant in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer After Endocrine Therapy.

Oncologist 2020 02 24;25(2):e243-e251. Epub 2019 Oct 24.

Stanford University School of Medicine, Stanford, California, USA.

Background: In the phase III MONARCH 2 study (NCT02107703), abemaciclib plus fulvestrant significantly improved progression-free survival (PFS) versus placebo plus fulvestrant in patients with hormone receptor-positive (HR+), HER2-negative advanced breast cancer (ABC). This study assessed patient-reported pain, global health-related quality of life (HRQoL), functioning, and symptoms.

Materials And Methods: Abemaciclib or placebo (150 p.o. mg twice daily) plus fulvestrant (500 mg, per label) were randomly assigned (2:1). The modified Brief Pain Inventory, Short Form (mBPI-sf); European Organization for Research and Treatment of Cancer (EORTC) QoL Core 30 (QLQ-C30); and Breast Cancer Questionnaire (QLQ-BR23) assessed outcomes. Data were collected at baseline, cycle 2, every two cycles 3-13, thereafter at every three cycles, and 30 days postdiscontinuation. Longitudinal mixed regression and Cox proportional hazards models assessed postbaseline change and time to sustained deterioration (TTSD) by study arm.

Results: On-treatment HRQoL scores were consistently maintained from baseline and similar between arms. Patients in the abemaciclib arm (n = 446) experienced a 4.9-month delay in pain deterioration (mBPI-sf), compared with the control arm (n = 223), and significantly greater TTSD on the mBPI-sf and analgesic use (hazard ratio, 0.76; 95% CI, 0.59-0.98) and QLQ-C30 pain item (hazard ratio, 0.62; 95% CI, 0.48-0.79). TTSD for functioning and most symptoms significantly favored the abemaciclib arm, including fatigue, nausea and vomiting, and cognitive and social functioning. Only diarrhea significantly favored the control arm (hazard ratio, 1.60; 95% CI, 1.20-2.10).

Conclusion: HRQoL was maintained on abemaciclib plus fulvestrant. Alongside superior PFS and manageable safety profile, results support treatment with abemaciclib plus fulvestrant in a population of patients with endocrine-resistant HR+, HER2-negative ABC.

Implications For Practice: In MONARCH 2, abemaciclib plus fulvestrant demonstrated superior efficacy and a manageable safety profile for patients with in hormone receptor-positive (HR+), HER2-negative (-) advanced breast cancer (ABC). Impact on health-related quality of life (HRQoL) is important to consider, given the palliative nature of ABC treatment. In this study, abemaciclib plus fulvestrant, compared with placebo plus fulvestrant, significantly delayed sustained deterioration of pain and other patient-reported symptoms (including fatigue, nausea, vomiting), and social and cognitive functioning. Combined with demonstrated clinical benefit and tolerability, the stabilization of patient-reported symptoms and HRQoL further supports abemaciclib plus fulvestrant as a desirable treatment option in endocrine resistant, HR+, HER2- ABC.
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http://dx.doi.org/10.1634/theoncologist.2019-0551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011625PMC
February 2020

Using natural language processing to construct a metastatic breast cancer cohort from linked cancer registry and electronic medical records data.

JAMIA Open 2019 Dec 18;2(4):528-537. Epub 2019 Sep 18.

Department of Biomedical Data Science, Stanford University, Stanford, CA.

Objectives: Most population-based cancer databases lack information on metastatic recurrence. Electronic medical records (EMR) and cancer registries contain complementary information on cancer diagnosis, treatment and outcome, yet are rarely used synergistically. To construct a cohort of metastatic breast cancer (MBC) patients, we applied natural language processing techniques within a semisupervised machine learning framework to linked EMR-California Cancer Registry (CCR) data.

Materials And Methods: We studied all female patients treated at Stanford Health Care with an incident breast cancer diagnosis from 2000 to 2014. Our database consisted of structured fields and unstructured free-text clinical notes from EMR, linked to CCR, a component of the Surveillance, Epidemiology and End Results Program (SEER). We identified MBC patients from CCR and extracted information on distant recurrences from patient notes in EMR. Furthermore, we trained a regularized logistic regression model for recurrent MBC classification and evaluated its performance on a gold standard set of 146 patients.

Results: There were 11 459 breast cancer patients in total and the median follow-up time was 96.3 months. We identified 1886 MBC patients, 512 (27.1%) of whom were MBC patients and 1374 (72.9%) were recurrent MBC patients. Our final MBC classifier achieved an area under the receiver operating characteristic curve (AUC) of 0.917, with sensitivity 0.861, specificity 0.878, and accuracy 0.870.

Discussion And Conclusion: To enable population-based research on MBC, we developed a framework for retrospective case detection combining EMR and CCR data. Our classifier achieved good AUC, sensitivity, and specificity without expert-labeled examples.
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http://dx.doi.org/10.1093/jamiaopen/ooz040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994019PMC
December 2019

Patient familiarity with, understanding of, and preferences for clinical trial endpoints and terminology.

Cancer 2020 04 22;126(8):1605-1613. Epub 2020 Jan 22.

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.

Background: Although there is increased attention to designing and explaining clinical trials in ways that are clinically meaningful for patients, there is limited information on patient preferences, understanding, and perceptions of this content.

Methods: Maximum difference scaling (MaxDiff) methodology was used to develop a survey for assessing patients' understanding of 19 clinical terms and perceived importance of 9 endpoint surrogate phrases used in clinical trials and consent forms. The survey was administered electronically to individuals with metastatic breast cancer affiliated with the Metastatic Breast Cancer Alliance. Analyses were performed using Bayesian P values with statistical software.

Results: Among 503 respondents, 77% had a college degree, 70% were diagnosed with metastatic disease ≥2 years before survey completion, and 77% had received ≥2 lines of systemic therapy. Less than 35% of respondents reported understanding "fairly well" the terms symptomatic progression, duration of disease control, time to treatment cessation, and endpoints. Income level and time since onset of metastatic disease correlated with comprehension. Patients who had received ≥6 lines of therapy perceived that time until serious side effects (P < .001) and time on therapy (P < .001) were more important compared with those who had received only 1 line of therapy. Positively phrased parameters were associated with increased perceived importance.

Conclusions: Even among educated, heavily pretreated patients, many commonly used clinical research terms are poorly understood. Comprehension and the perceived importance of trial endpoints vary over the course of disease. These observations may inform the design, discussion, and reporting of clinical trials.
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http://dx.doi.org/10.1002/cncr.32730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276207PMC
April 2020

Gold Nanobipyramids as Second Near Infrared Optical Coherence Tomography Contrast Agents for Multiplexing Studies.

Nano Lett 2020 01 10;20(1):101-108. Epub 2019 Oct 10.

Department of Structural Biology , Stanford University , Stanford , California 94305 , United States.

Developing contrast-enhanced optical coherence tomography (OCT) techniques is important for specific imaging of tissue lesions, molecular imaging, cell-tracking, and highly sensitive microangiography and lymphangiography. Multiplexed OCT imaging in the second near-infrared (NIR-II) window is highly desirable since it allows simultaneous imaging and tracking of multiple biological events in high resolution with deeper tissue penetration . Here we demonstrate that gold nanobipyramids can function as OCT multiplexing contrast agents, allowing high-resolution imaging of two separate lymphatic flows occurring simultaneously from different drainage basins into the same lymph node in a live mouse. Contrast-enhanced multiplexed lymphangiography of a melanoma tumor shows that the peritumoral lymph flow upstream of the tumor is unidirectional, and tumor is accessible to such flow. Whereas the lymphatic drainage coming out from the tumor is multidirectional. We also demonstrate real-time tracking of the contrast agents draining from a melanoma tumor specifically to the sentinel lymph node of the tumor and the three-dimensional distribution of the contrast agents in the lymph node.
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http://dx.doi.org/10.1021/acs.nanolett.9b03344DOI Listing
January 2020

Clinical Outcomes in Early Breast Cancer With a High 21-Gene Recurrence Score of 26 to 100 Assigned to Adjuvant Chemotherapy Plus Endocrine Therapy: A Secondary Analysis of the TAILORx Randomized Clinical Trial.

JAMA Oncol 2020 03;6(3):367-374

Indiana University Hospital, Indianapolis.

Importance: A high 21-gene recurrence score (RS) by breast cancer assay is prognostic for distant recurrence of early breast cancer after local therapy and endocrine therapy alone, and for chemotherapy benefit.

Objective: To describe clinical outcomes for women with a high RS who received adjuvant chemotherapy plus endocrine therapy in the TAILORx trial, a population expected to have a high distant recurrence rate with endocrine therapy alone.

Design, Setting, And Participants: In this secondary analysis of data from a multicenter randomized clinical trial, 1389 women with hormone receptor-positive, ERBB2-negative, axillary node-negative breast cancer, and a high RS of 26 to 100 were prospectively assigned to receive adjuvant chemotherapy in addition to endocrine therapy. The analysis was conducted on May 12, 2019.

Interventions: The adjuvant chemotherapy regimen was selected by the treating physician.

Main Outcomes And Measures: Freedom from recurrence of breast cancer at a distant site, and freedom from recurrence, second primary cancer, and death (also known as invasive disease-free survival [IDFS]).

Results: Among the 9719 eligible women, with a mean age of 56 years (range 23-75 years), 1389 (14%) had a recurrence score of 26 to 100, of whom 598 (42%) had an RS of 26 to 30 and 791 (58%) had an RS of 31 to 100. The most common chemotherapy regimens included docetaxel/cyclophosphamide in 589 (42%), an anthracycline without a taxane in 334 (24%), an anthracycline and taxane in 244 (18%), cyclophosphamide/methotrexate/5-fluorouracil in 52 (4%), other regimens in 81 (6%), and no chemotherapy in 89 (6%). At 5 years, the estimated rate of freedom from recurrence of breast cancer at a distant site was 93.0% (standard error [SE], 0.8%), freedom of recurrence of breast cancer at a distant and/or local regional site 91.0% (SE, 0.8%), IDFS 87.6% (SE, 1.0%), and overall survival 95.9% (SE, 0.6%).

Conclusions And Relevance: The estimated rate of freedom from recurrence of breast cancer at a distant site in women with an RS of 26 to 100 treated largely with taxane and/or anthracycline-containing adjuvant chemotherapy regimens plus endocrine therapy in the prospective TAILORx trial was 93% at 5 years, an outcome better than expected with endocrine therapy alone in this population.

Trial Registration: ClinicalTrials.gov identifier: NCT00310180.
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http://dx.doi.org/10.1001/jamaoncol.2019.4794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777230PMC
March 2020

The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial.

JAMA Oncol 2020 Jan;6(1):116-124

Hospital Arnau Vilanova, Valencia, Spain.

Importance: Statistically significant overall survival (OS) benefits of CDK4 and CDK6 inhibitors in combination with fulvestrant for hormone receptor (HR)-positive, ERBB2 (formerly HER2)-negative advanced breast cancer (ABC) in patients regardless of menopausal status after prior endocrine therapy (ET) has not yet been demonstrated.

Objective: To compare the effect of abemaciclib plus fulvestrant vs placebo plus fulvestrant on OS at the prespecified interim of MONARCH 2 (338 events) in patients with HR-positive, ERBB2-negative advanced breast cancer that progressed during prior ET.

Design, Setting, And Participants: MONARCH 2 was a global, randomized, placebo-controlled, double-blind phase 3 trial of abemaciclib plus fulvestrant vs placebo plus fulvestrant for treatment of premenopausal or perimenopausal women (with ovarian suppression) and postmenopausal women with HR-positive, ERBB2-negative ABC that progressed during ET. Patients were enrolled between August 7, 2014, and December 29, 2015. Analyses for this report were conducted at the time of database lock on June 20, 2019.

Interventions: Patients were randomized 2:1 to receive abemaciclib or placebo, 150 mg, every 12 hours on a continuous schedule plus fulvestrant, 500 mg, per label. Randomization was stratified based on site of metastasis (visceral, bone only, or other) and resistance to prior ET (primary vs secondary).

Main Outcomes And Measures: The primary end point was investigator-assessed progression-free survival. Overall survival was a gated key secondary end point. The boundary P value for the interim analysis was .02.

Results: Of 669 women enrolled, 446 (median [range] age, 59 [32-91] years) were randomized to the abemaciclib plus fulvestrant arm and 223 (median [range] age, 62 [32-87] years) were randomized to the placebo plus fulvestrant arm. At the prespecified interim, 338 deaths (77% of the planned 441 at the final analysis) were observed in the intent-to-treat population, with a median OS of 46.7 months for abemaciclib plus fulvestrant and 37.3 months for placebo plus fulvestrant (hazard ratio [HR], 0.757; 95% CI, 0.606-0.945; P = .01). Improvement in OS was consistent across all stratification factors. Among stratification factors, more pronounced effects were observed in patients with visceral disease (HR, 0.675; 95% CI, 0.511-0.891) and primary resistance to prior ET (HR, 0.686; 95% CI, 0.451-1.043). Time to second disease progression (median, 23.1 months vs 20.6 months), time to chemotherapy (median, 50.2 months vs 22.1 months), and chemotherapy-free survival (median, 25.5 months vs 18.2 months) were also statistically significantly improved in the abemaciclib arm vs placebo arm. No new safety signals were observed for abemaciclib.

Conclusions And Relevance: Treatment with abemaciclib plus fulvestrant resulted in a statistically significant and clinically meaningful median OS improvement of 9.4 months for patients with HR-positive, ERBB2-negative ABC who progressed after prior ET regardless of menopausal status. Abemaciclib substantially delayed the receipt of subsequent chemotherapy.

Trial Registration: ClinicalTrials.gov identifier: NCT02107703.
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http://dx.doi.org/10.1001/jamaoncol.2019.4782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777264PMC
January 2020

Investigating circulating tumor cells and distant metastases in patient-derived orthotopic xenograft models of triple-negative breast cancer.

Breast Cancer Res 2019 08 28;21(1):98. Epub 2019 Aug 28.

Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.

Background: Circulating tumor cells (CTCs) represent a temporal "snapshot" of a patient's cancer and changes that occur during disease evolution. There is an extensive literature studying CTCs in breast cancer patients, and particularly in those with metastatic disease. In parallel, there is an increasing use of patient-derived models in preclinical investigations of human cancers. Yet studies are still limited demonstrating CTC shedding and metastasis formation in patient-derived models of breast cancer.

Methods: We used seven patient-derived orthotopic xenograft (PDOX) models generated from triple-negative breast cancer (TNBC) patients to study CTCs and distant metastases. Tumor fragments from PDOX tissue from each of the seven models were implanted into 57 NOD scid gamma (NSG) mice, and tumor growth and volume were monitored. Human CTC capture from mouse blood was first optimized on the marker-agnostic Vortex CTC isolation platform, and whole blood was processed from 37 PDOX tumor-bearing mice.

Results: Staining and imaging revealed the presence of CTCs in 32/37 (86%). The total number of CTCs varied between different PDOX tumor models and between individual mice bearing the same PDOX tumors. CTCs were heterogeneous and showed cytokeratin (CK) positive, vimentin (VIM) positive, and mixed CK/VIM phenotypes. Metastases were detected in the lung (20/57, 35%), liver (7/57, 12%), and brain (1/57, less than 2%). The seven different PDOX tumor models displayed varying degrees of metastatic potential, including one TNBC PDOX tumor model that failed to generate any detectable metastases (0/8 mice) despite having CTCs present in the blood of 5/5 tested, suggesting that CTCs from this particular PDOX tumor model may typify metastatic inefficiency.

Conclusion: PDOX tumor models that shed CTCs and develop distant metastases represent an important tool for investigating TNBC.
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http://dx.doi.org/10.1186/s13058-019-1182-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714238PMC
August 2019

Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer.

N Engl J Med 2019 06 3;380(25):2395-2405. Epub 2019 Jun 3.

From Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY (J.A.S., D.F.M.); Dana-Farber Cancer Institute, Boston (R.J.G.); University of Texas, San Antonio (P.M.R.); Sunnybrook Research Institute, Toronto (K.I.P.), and McMaster University, Hamilton, ON (T.J.W.) - both in Canada; Loyola University Medical Center, Maywood (K.S.A.), and Northwestern University, Chicago (L.I.W., V.G.K.) - both in Illinois; University of Michigan, Ann Arbor (D.F.H.); Virginia Commonwealth University School of Medicine and the Massey Cancer Center, Richmond (C.E.G.); University of North Carolina, Chapel Hill (E.C.D.), and Duke University Medical Center, Durham (J.A.O., J.A.) - both in North Carolina; Mayo Clinic, Jacksonville, FL (M.P.G.); National Institutes of Health, National Cancer Institute, Bethesda, MD (T.L.); Indiana University School of Medicine (S.S.B.) and Indiana University Hospital (G.W.S.), Indianapolis; Vince Lombardi Cancer Clinic, Two Rivers (T.J.S.), and Fox Valley Hematology and Oncology, Appleton (T.F.G.) - both in Wisconsin; Washington University, St. Louis (M.J.E.); the National Surgical Adjuvant Breast and Bowel Project Pathology Office (S.P.) and the University of Pittsburgh (A.M.B.), Pittsburgh; Emory University, Atlanta (W.C.W.); Cancer Trials Ireland, Dublin (M.M.K.); Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru (H.L.G.M.); Cancer Center of Kansas, Wichita (P.S.R.); Vanderbilt University, Nashville (I.A.M.); Rutgers Cancer Institute of New Jersey, New Brunswick (D.L.T.); and the University of Hawaii Cancer Center, Honolulu (J.L.B.).

Background: The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known.

Methods: We performed a prospective trial involving 9427 women with hormone-receptor-positive, human epidermal growth factor receptor 2-negative, axillary node-negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger.

Results: The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%).

Conclusions: Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.).
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http://dx.doi.org/10.1056/NEJMoa1904819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709671PMC
June 2019

Real-Time Detection of Circulating Tumor Cells in Living Animals Using Functionalized Large Gold Nanorods.

Nano Lett 2019 04 29;19(4):2334-2342. Epub 2019 Mar 29.

Department of Structural Biology , Stanford University , Stanford , California 94305 , United States.

Optical coherence tomography (OCT) can be utilized with significant speckle reduction techniques and highly scattering contrast agents for non-invasive, contrast-enhanced imaging of living tissues at the cellular scale. The advantages of reduced speckle noise and improved targeted contrast can be harnessed to track objects as small as 2 μm in vivo, which enables applications for cell tracking and quantification in living subjects. Here we demonstrate the use of large gold nanorods as contrast agents for detecting individual micron-sized polystyrene beads and single myeloma cells in blood circulation using speckle-modulating OCT. This report marks the first time that OCT has been used to detect individual cells within blood in vivo. This technical capability unlocks exciting opportunities for dynamic detection and quantification of tumor cells circulating in living subjects.
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http://dx.doi.org/10.1021/acs.nanolett.8b05005DOI Listing
April 2019

Targeting CXCR4-induced desmoplasia to improve checkpoint inhibition in breast cancer.

Authors:
George W Sledge

Proc Natl Acad Sci U S A 2019 03 22;116(11):4769-4771. Epub 2019 Feb 22.

Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305

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http://dx.doi.org/10.1073/pnas.1900368116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421464PMC
March 2019

Patients and Physicians in the Era of Modern Cancer Care.

Authors:
George W Sledge

JAMA 2019 Mar;321(9):829-830

Stanford University School of Medicine, Stanford, California.

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http://dx.doi.org/10.1001/jama.2018.17334DOI Listing
March 2019

Change in Survival in Metastatic Breast Cancer with Treatment Advances: Meta-Analysis and Systematic Review.

JNCI Cancer Spectr 2018 Nov 24;2(4):pky062. Epub 2018 Dec 24.

Department of Medicine, Stanford University School of Medicine, Stanford, CA.

Background: Metastatic breast cancer (MBC) treatment has changed substantially over time, but we do not know whether survival post-metastasis has improved at the population level.

Methods: We searched for studies of MBC patients that reported survival after metastasis in at least two time periods between 1970 and the present. We used meta-regression models to test for survival improvement over time in four disease groups: recurrent, recurrent estrogen (ER)-positive, recurrent ER-negative, and de novo stage IV. We performed sensitivity analyses based on bias in some studies that could lead earlier cohorts to include more aggressive cancers.

Results: There were 15 studies of recurrent MBC (N = 18 678 patients; 3073 ER-positive and 1239 ER-negative); meta-regression showed no survival improvement among patients recurring between 1980 and 1990, but median survival increased from 21 (95% confidence interval [CI] = 18 to 25) months to 38 (95% CI = 31 to 47) months from 1990 to 2010. For ER-positive MBC patients, median survival increased during 1990-2010 from 32 (95% CI = 23 to 43) to 57 (95% CI = 37 to 87) months, and for ER-negative MBC patients from 14 (95% CI = 11 to 19) to 33 (95% CI = 21 to 51) months. Among eight studies (N = 35 831) of de novo stage IV MBC, median survival increased during 1990-2010 from 20 (95% CI = 16 to 24) to 31 (95% CI = 24 to 39) months. Results did not change in sensitivity analyses.

Conclusion: By bridging studies over time, we demonstrated improvements in survival for recurrent and de novo stage IV MBC overall and across ER-defined subtypes since 1990. These results can inform patient-doctor discussions about MBC prognosis and therapy.
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http://dx.doi.org/10.1093/jncics/pky062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305243PMC
November 2018

Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy.

NPJ Breast Cancer 2018 18;4:41. Epub 2018 Dec 18.

8The Royal Marsden NHS Foundation Trust, London, UK.

CDK4 & 6 inhibitors have enhanced the effectiveness of endocrine therapy (ET) in patients with advanced breast cancer (ABC). This paper presents exploratory analyses examining patient and disease characteristics that may inform in whom and when abemaciclib should be initiated. MONARCH 2 and 3 enrolled women with HR+, HER2- ABC. In MONARCH 2, patients whose disease had progressed while receiving ET were administered fulvestrant+abemaciclib/placebo. In MONARCH 3, patients received a nonsteroidal aromatase inhibitor+abemaciclib/placebo as initial therapy for advanced disease. A combined analysis of the two studies was performed to determine significant prognostic factors. Efficacy results (PFS and ORR in patients with measurable disease) were examined for patient subgroups corresponding to each significant prognostic factor. Analysis of clinical factors confirmed the following to have prognostic value: bone-only disease, liver metastases, tumor grade, progesterone receptor status, performance status, treatment-free interval (TFI) from the end of adjuvant ET, and time from diagnosis to recurrence. Prognosis was poorer in patients with liver metastases, progesterone receptor-negative tumors, high grade tumors, or short TFI (<36 months). Benefit (PFS hazard ratio, ORR increase) from abemaciclib was observed in all patient subgroups. Patients with indicators of poor prognosis had the largest benefit from the addition of abemaciclib. However, in MONARCH 3, for patients with certain good prognostic factors (TFI ≥ 36 months, bone-only disease) ET achieved a median PFS of >20 months. These analyses identified prognostic factors and demonstrated that patients with poor prognostic factors derived the largest benefit from the addition of abemaciclib.
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http://dx.doi.org/10.1038/s41523-018-0094-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299082PMC
December 2018

Association of Circulating Tumor Cells With Late Recurrence of Estrogen Receptor-Positive Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial.

JAMA Oncol 2018 12;4(12):1700-1706

Department of Medicine, Division of Hematology/Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis.

Importance: Late recurrence 5 or more years after diagnosis accounts for at least one-half of all cases of recurrent hormone receptor-positive breast cancer.

Objective: To determine whether the presence of circulating tumor cells (CTCs) in a peripheral blood sample obtained approximately 5 years after diagnosis was associated with late clinical recurrence of operable human epidermal growth factor receptor 2-negative breast cancer.

Design, Setting, And Participants: This per-protocol secondary analysis of the Double-Blind Phase III Trial of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With Bevacizumab or Placebo in Patients With Lymph Node Positive and High Risk Lymph Node Negative Breast Cancer enrolled patients from 2007 to 2011 who were without clinical evidence of recurrence between 4.5 and 7.5 years after primary surgical treatment of human epidermal growth factor receptor 2-negative stage II-III breast cancer followed by adjuvant systemic therapy. Patients were enrolled in a subprotocol for secondary analysis from February 25, 2013, to July 29, 2016, after signing consent for the subprotocol. The analysis was performed in April 2018.

Interventions: A blood sample was obtained for identification and enumeration of CTCs.

Main Outcome And Measures: The association between a positive CTC assay result (at least 1 CTC per 7.5 mL of blood) and clinical recurrence.

Results: Among 547 women included in this analysis, the results of the CTC assay were positive for 18 of 353 with hormone receptor-positive disease (5.1% [95% CI, 3.0%-7.9%]); 23 of 353 patients (6.5% [95% CI, 4.2%-9.6%]) had a clinical recurrence. The recurrence rates per person-year of follow-up in the CTC-positive and CTC-negative groups were 21.4% (7 recurrences per 32.7 person-years) and 2.0% (16 recurrences per 796.3 person-years), respectively. In multivariate models including clinical covariates, a positive CTC assay result was associated with a 13.1-fold higher risk of recurrence (hazard ratio point estimate, 13.1; 95% CI, 4.7-36.3). Seven of 23 patients (30.4% [95% CI, 13.2%-52.9%]) with recurrence had a positive CTC assay result at a median of 2.8 years (range, 0.1-2.8 years) before clinical recurrence. The CTC assay result was also positive for 8 of 193 patients (4.1% [95% CI, 1.8%-8.0%]) with hormone receptor-negative disease, although only 1 patient (0.5% [95% CI, 0%-2.9%]) experienced disease recurrence (this patient was CTC negative).

Conclusions And Relevance: A single positive CTC assay result 5 years after diagnosis of hormone receptor-positive breast cancer provided independent prognostic information for late clinical recurrence, which provides proof of concept that liquid-based biomarkers may be used to risk stratify for late recurrence and guide therapy.

Trial Registration: ClinicalTrials.gov identifier: NCT00433511.
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http://dx.doi.org/10.1001/jamaoncol.2018.2574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385891PMC
December 2018

Double-Blind Phase III Trial of Adjuvant Chemotherapy With and Without Bevacizumab in Patients With Lymph Node-Positive and High-Risk Lymph Node-Negative Breast Cancer (E5103).

J Clin Oncol 2018 09 24;36(25):2621-2629. Epub 2018 Jul 24.

Kathy D. Miller, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Anne O'Neill, Dana-Farber Cancer Institute, Boston, MA; William Gradishar, Northwestern University, Chicago; Nguyet Anh Le-Lindqwister, Heartland Cancer Research National Cancer Institute Community Oncology Research Program, Peoria, IL; Timothy J. Hobday, Mayo Clinic, Rochester; Stuart Bloom, Abbott Northwestern Hospital, Minneapolis, MN; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia; Adam M. Brufsky, University of Pittsburgh, Pittsburgh, PA; Ingrid A. Mayer, Vanderbilt University, Nashville, TN; Amye J. Tevaarwerk, University of Wisconsin, Madison, WI; Joseph A. Sparano, Montefiore Hospital and Medical Center, Bronx; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Carolyn B. Hendricks, Association Community Clinical Oncology Program, Bethesda, MD; Donald W. Northfelt, Mayo Clinic, Scottsdale, AZ; and George W. Sledge JR, Stanford University, Stanford, CA.

Purpose Bevacizumab improves progression-free survival but not overall survival in patients with metastatic breast cancer. E5103 tested the effect of bevacizumab in the adjuvant setting in patients with human epidermal growth factor receptor 2-negative disease. Patients and Methods Patients were assigned 1:2:2 to receive placebo with doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (arm A), bevacizumab only during AC and paclitaxel (arm B), or bevacizumab during AC and paclitaxel followed by bevacizumab monotherapy for 10 cycles (arm C). Random assignment was stratified and bevacizumab dose adjusted for choice of AC schedule. Radiation and hormonal therapy were administered concurrently with bevacizumab in arm C. The primary end point was invasive disease-free survival (IDFS). Results Four thousand nine hundred ninety-four patients were enrolled. Median age was 52 years; 64% of patients were estrogen receptor positive, 27% were lymph node negative, and 78% received dose-dense AC. Chemotherapy-associated adverse events including myelosuppression and neuropathy were similar across all arms. Grade ≥ 3 hypertension was more common in bevacizumab-treated patients, but thrombosis, proteinuria, and hemorrhage were not. The cumulative incidence of clinical congestive heart failure at 15 months was 1.0%, 1.9%, and 3.0% in arms A, B, and C, respectively. Bevacizumab exposure was less than anticipated, with approximately 24% of patients in arm B and approximately 55% of patients in arm C discontinuing bevacizumab before completing planned therapy. Five-year IDFS was 77% (95% CI, 71% to 81%) in arm A, 76% (95% CI, 72% to 80%) in arm B, and 80% (95% CI, 77% to 83%) in arm C. Conclusion Incorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve IDFS or overall survival in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer. Longer duration bevacizumab therapy is unlikely to be feasible given the high rate of early discontinuation.
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http://dx.doi.org/10.1200/JCO.2018.79.2028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118403PMC
September 2018