Publications by authors named "Daniel F Hayes"

302 Publications

Evaluating Serum Thymidine Kinase 1 in Patients with Hormone Receptor-Positive Metastatic Breast Cancer Receiving First-line Endocrine Therapy in the SWOG S0226 Trial.

Clin Cancer Res 2021 Sep 14. Epub 2021 Sep 14.

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

Purpose: Serum thymidine kinase 1 (sTK1) activity is associated with poor prognosis in metastatic breast cancer (MBC). We assessed the prognostic effect of sTK1 in patients with hormone receptor-positive MBC treated on a prospective randomized trial of anastrozole (A) versus A plus fulvestrant (A + F).

Experimental Design: sTK1 was assessed in 1,726 serums [baseline (BL), cycles 2, 3, 4, and 7] using the DiviTum assay. A prespecified cutoff of ≥200 Du/L was considered high. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier, log-rank tests, and Cox regression.

Results: BL sTK1 was elevated in 171 (40%) of 432 patients. Patients with high versus low BL sTK1 had significantly worse PFS [median 11.2 vs. 17.3 months, HR = 1.76; 95% confidence interval (CI; 1.43-2.16); < 0.0001] and OS [median 30 vs. 58 months, HR = 2.38; 95% CI (1.91-2.98); < 0.0001]. OS was significantly better for patients with high sTK1 who did not have prior adjuvant tamoxifen and who received A + F versus A alone [median 46 vs. 21 months, HR = 0.58; 95% CI (0.38-0.87); = 0.0087]. Patients with low sTK1 had no difference in outcomes by therapy ( = 0.44). At serial timepoints, high versus low sTK1 had significantly worse subsequent PFS and OS [at cycle 2: PFS HR = 1.70, 95% CI (1.34-2.17); < 0.0001, OS HR = 2.51, 95% CI (1.93-3.26); < 0.0001].

Conclusions: High sTK1 at BL and subsequent timepoints is associated with worse prognosis in patients with MBC starting first-line endocrine therapy (ET). Patients with low sTK1 at BL have comparable outcomes on single-agent or combination ET.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1562DOI Listing
September 2021

Inertial focusing of circulating tumor cells in whole blood at high flow rates using the microfluidic CTCKey™ device for CTC enrichment.

Lab Chip 2021 09 14;21(18):3559-3572. Epub 2021 Sep 14.

Chemical Engineering, University of Michigan, 2800 Plymouth Rd., Ann Arbor, Michigan, USA.

Circulating tumor cells (CTCs) are extremely rare cells shed from tumors into the blood stream. These cells can provide valuable information about their tumor of origin and direct treatment decisions to improve patient outcomes. Current technologies isolate CTCs from a limited blood volume and often require pre-processing that leads to CTC loss, making it difficult to isolate enough CTCs to perform in-depth tumor analysis. Many inertial microfluidic devices have been developed to isolate CTCs at high flow rates, but they typically require either blood dilution, pre-processing to remove red blood cells, or a sheath buffer rather than being able to isolate cells directly from whole blood. To decrease the need for pre-processing while increasing CTC yield, we developed an inertial device, the CTCKey™, to focus CTCs in whole blood at high throughput yielding a concentrated product stream enriched for CTCs. The CTCKey™ consists of two sections to create CTC enriched blood that can be further processed using any CTC isolation device to selectively isolate the CTCs. A thorough analysis was performed using the MCF7 breast cancer cell line spiked into bovine serum albumin (BSA) solutions of varying concentrations, as well as whole blood to characterize the focusing patterns of the CTCKey™. At the optimal flow rate of 2.4 mL min, the CTCKey™ reduces the CTC containing blood volume by 78%; the CTCs from 1 mL of blood are now in 0.22 mL of blood. The CTCKey's™ ability to concentrate CTCs from a large original blood volume to a smaller, highly concentrated volume enables a much greater blood volume to be interrogated by downstream isolation and characterization methods despite their low volume input limitations.
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http://dx.doi.org/10.1039/d1lc00546dDOI Listing
September 2021

Circulating tumor cell number and endocrine therapy index in ER positive metastatic breast cancer patients.

NPJ Breast Cancer 2021 Jun 11;7(1):77. Epub 2021 Jun 11.

Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.

Circulating tumor cells (CTC) are prognostic in metastatic breast cancer (MBC). The CTC-endocrine therapy index (CTC-ETI), consisting of CTC-ER (estrogen receptor), BCL2, human epidermal growth factor receptor (HER2), and Ki67 expression, might predict resistance to endocrine therapy (ET) in patients with ER-positive MBC. One hundred twenty-one patients with ER-positive/HER2-negative MBC initiating a new ET after ≥1 lines of ET were enrolled in a prospective, multi-institutional clinical trial. CTC-ETI and clinical/imaging follow-up were performed at baseline and serial time points. Progression-free survival (PFS) and rapid progression (RP; determined at the 3-month time point) were primary endpoints. Associations with clinical outcomes used logrank and Fisher's exact tests. At baseline, 36% (38/107) of patients had ≥5 CTC/7.5 ml whole blood (WB). Patients with ≥5 vs. <5 CTC/7.5 ml WB had significantly worse PFS (median 3.3 vs. 5.9 months, P = 0.03). Elevated CTC at 1 month was associated with even worse PFS (1.9 vs. 5.0 months from the 1-month sample, P < 0.001). Low, intermediate, and high CTC-ETI were observed in 71 (66%), 8 (8%), and 28 (26%) patients, with median PFS of 6.9, 8.5, and 2.8 months, respectively (P = 0.008). Patients with high vs. low CTC and CTC-ETI more frequently experienced RP (CTC: 66% vs. 41%; P = 0.03; CTC-ETI: 79% vs. 40%; P = 0.002). In conclusion, CTC enumeration and the CTC-ETI assay are prognostic at baseline and follow-up in patients with ER-positive/HER2-negative MBC starting new ET. CTC at first follow-up might identify a group of patients with ER-positive MBC that could forego ET, but CTC-ETI did not contribute further.
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http://dx.doi.org/10.1038/s41523-021-00281-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196036PMC
June 2021

Genome-wide association study of letrozole plasma concentrations identifies non-exonic variants that may affect CYP2A6 metabolic activity.

Pharmacogenet Genomics 2021 07;31(5):116-123

Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, University of Michigan, Ann Arbor, Michigan.

Objectives: Letrozole is a nonsteroidal aromatase inhibitor used to treat hormone-receptor-positive breast cancer. Variability in letrozole efficacy and toxicity may be partially attributable to variable systemic drug exposure, which may be influenced by germline variants in the enzymes responsible for letrozole metabolism, including cytochrome P450 2A6 (CYP2A6). The objective of this genome-wide association study (GWAS) was to identify polymorphisms associated with steady-state letrozole concentrations.

Methods: The Exemestane and Letrozole Pharmacogenetics (ELPh) Study randomized postmenopausal patients with hormone-receptor-positive nonmetastatic breast cancer to letrozole or exemestane treatment. Germline DNA was collected pretreatment and blood samples were collected after 1 or 3 months of treatment to measure steady-state letrozole (and exemestane) plasma concentrations via HPLC/MS. Genome-wide genotyping was conducted on the Infinium Global Screening Array (>650 000 variants) followed by imputation. The association of each germline variant with age- and BMI-adjusted letrozole concentrations was tested in self-reported white patients via linear regression assuming an additive genetic model.

Results: There were 228 patients who met the study-specific inclusion criteria and had both DNA and letrozole concentration data for this GWAS. The association for one genotyped polymorphism (rs7937) with letrozole concentration surpassed genome-wide significance (P = 5.26 × 10-10), explaining 13% of the variability in untransformed steady-state letrozole concentrations. Imputation around rs7937 and in silico analyses identified rs56113850, a variant in the CYP2A6 intron that may affect CYP2A6 expression and activity. rs7937 was associated with age- and BMI-adjusted letrozole levels even after adjusting for genotype-predicted CYP2A6 metabolic phenotype (P = 3.86 × 10-10).

Conclusion: Our GWAS findings confirm that steady-state letrozole plasma concentrations are partially determined by germline polymorphisms that affect CYP2A6 activity, including variants near rs7937 such as the intronic rs56113850 variant. Further research is needed to confirm whether rs56113850 directly affects CYP2A6 activity and to integrate nonexonic variants into CYP2A6 phenotypic activity prediction systems.
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http://dx.doi.org/10.1097/FPC.0000000000000429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185249PMC
July 2021

Improving Oncology-Pathology Collaboration in Resource-Limited Settings: An American Society of Clinical Oncology/College of American Pathologists Initiative.

Am Soc Clin Oncol Educ Book 2021 Mar;41:199-220

University of Michigan Rogel Cancer Center, Ann Arbor MI.

Accurate pathologic evaluation is essential for proper diagnosis and treatment of patients with cancer. ASCO and the College of American Pathologists have successfully collaborated over the last 15 years to improve collaboration between clinical oncologists and pathologists and to standardize pathologic assay techniques. Cancer is an increasingly recognized societal burden in low- and middle-income countries. In 2015, ASCO and the College of American Pathologists implemented an initiative to identify countries that could benefit from peer insights by jointly convening an international workshop among members of both organizations and pathologists and clinical oncologists from Haiti, Honduras, Vietnam, and Uganda. Honduras was chosen as a pilot site, and representatives of ASCO, the College of American Pathologists, and the Honduras pathology and clinical oncology communities have identified areas in which collaboration might be productive. Multiple barriers, including high poverty levels, poor cancer awareness educational programs, lack of human resources, and delayed diagnosis and treatment, have resulted in a higher cancer mortality rate in Honduras compared with high/moderate-income countries and are shared by other low-income countries. ASCO and the College of American Pathologists member faculty supported a symposium led by Honduras colleagues for interested Honduran pathologists and oncologists. The Honduran communities are now working to establish national resource-appropriate guidelines for both pathology and clinical oncology. Taken together, these efforts indicate that barriers to meet the needs of the clinical oncologists in a low-income country such as Honduras are challenging but not insurmountable.
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http://dx.doi.org/10.1200/EDBK_320037DOI Listing
March 2021

Response to Zhang and Yang.

J Natl Cancer Inst 2021 May 18. Epub 2021 May 18.

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

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http://dx.doi.org/10.1093/jnci/djab094DOI Listing
May 2021

Assessment of Clinical Benefit of Integrative Genomic Profiling in Advanced Solid Tumors.

JAMA Oncol 2021 Apr;7(4):525-533

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor.

Importance: Use of next-generation sequencing (NGS) to identify clinically actionable genomic targets has been incorporated into routine clinical practice in the management of advanced solid tumors; however, the clinical utility of this testing remains uncertain.

Objective: To determine which patients derived the greatest degree of clinical benefit from NGS profiling.

Design, Setting, And Participants: Patients in this cohort study underwent fresh tumor biopsy and blood sample collection for genomic profiling of paired tumor and normal DNA (whole-exome or targeted-exome capture with analysis of 1700 genes) and tumor transcriptome (RNA) sequencing. Somatic and germline genomic alterations were annotated and classified according to degree of clinical actionability. Results were returned to treating oncologists. Data were collected from May 1, 2011, to February 28, 2018, and analyzed from May 1, 2011, to April 30, 2020.

Main Outcomes And Measures: Patients' subsequent therapy and treatment response were extracted from the medical record to determine clinical benefit rate from NGS-directed therapy at 6 months and exceptional responses lasting 12 months or longer.

Results: During the study period, NGS was attempted on tumors from 1138 patients and was successful in 1015 (89.2%) (MET1000 cohort) (538 men [53.0%]; mean [SD] age, 57.7 [13.3] years). Potentially clinically actionable genomic alterations were discovered in 817 patients (80.5%). Of these, 132 patients (16.2%) received sequencing-directed therapy, and 49 had clinical benefit (37.1%). Exceptional responses were observed in 26 patients (19.7% of treated patients). Pathogenic germline variants (PGVs) were identified in 160 patients (15.8% of cohort), including 49 PGVs (4.8% of cohort) with therapeutic relevance. For 55 patients with carcinoma of unknown primary origin, NGS identified the primary site in 28 (50.9%), and sequencing-directed therapy in 13 patients resulted in clinical benefit in 7 instances (53.8%), including 5 exceptional responses.

Conclusions And Relevance: The high rate of therapeutically relevant PGVs identified across diverse cancer types supports a recommendation for directed germline testing in all patients with advanced cancer. The high frequency of therapeutically relevant somatic and germline findings in patients with carcinoma of unknown primary origin and other rare cancers supports the use of comprehensive NGS profiling as a component of standard of care for these disease entities.
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http://dx.doi.org/10.1001/jamaoncol.2020.7987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907987PMC
April 2021

Assessment of Ki67 in Breast Cancer: Updated Recommendations From the International Ki67 in Breast Cancer Working Group.

J Natl Cancer Inst 2021 Jul;113(7):808-819

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

Ki67 immunohistochemistry (IHC), commonly used as a proliferation marker in breast cancer, has limited value for treatment decisions due to questionable analytical validity. The International Ki67 in Breast Cancer Working Group (IKWG) consensus meeting, held in October 2019, assessed the current evidence for Ki67 IHC analytical validity and clinical utility in breast cancer, including the series of scoring studies the IKWG conducted on centrally stained tissues. Consensus observations and recommendations are: 1) as for estrogen receptor and HER2 testing, preanalytical handling considerations are critical; 2) a standardized visual scoring method has been established and is recommended for adoption; 3) participation in and evaluation of quality assurance and quality control programs is recommended to maintain analytical validity; and 4) the IKWG accepted that Ki67 IHC as a prognostic marker in breast cancer has clinical validity but concluded that clinical utility is evident only for prognosis estimation in anatomically favorable estrogen receptor-positive and HER2-negative patients to identify those who do not need adjuvant chemotherapy. In this T1-2, N0-1 patient group, the IKWG consensus is that Ki67 5% or less, or 30% or more, can be used to estimate prognosis. In conclusion, analytical validity of Ki67 IHC can be reached with careful attention to preanalytical issues and calibrated standardized visual scoring. Currently, clinical utility of Ki67 IHC in breast cancer care remains limited to prognosis assessment in stage I or II breast cancer. Further development of automated scoring might help to overcome some current limitations.
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http://dx.doi.org/10.1093/jnci/djaa201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487652PMC
July 2021

Defining Clinical Utility of Tumor Biomarker Tests: A Clinician's Viewpoint.

Authors:
Daniel F Hayes

J Clin Oncol 2021 01 16;39(3):238-248. Epub 2020 Dec 16.

Stuart B. Padnos Professor of Breast Cancer Research, University of Michigan Rogel Cancer Center, Ann Arbor, MI.

Tumor biomarker tests (TBTs) are used to guide therapeutic strategies for patients with cancer. However, the regulatory environment for TBTs in the United States is inconsistent and, in general, TBTs are poorly valued. The National Academy of Medicine has recommended that TBTs should not be used in general practice until they are shown to have analytical validity and clinical utility. The latter term, first coined by the Evaluation of Genomic Applications in Practice and Prevention Initiative, has been widely stated but is indeterminately defined. In considering whether a TBT has clinical utility, several factors need to be considered: (1) What is the intended use of the TBT? (2) What are the end points that are used to determine clinical utility? (3) How substantial does the difference in end points between groups defined by the TBT need to be to determine therapeutic strategies? (4) What is the risk tolerance of the stakeholders? and (5) Who are the stakeholders that make the decision? For all these factors, the data used to consider clinical utility must be derived from level I evidence studies. In conclusion, there is no strict definition of clinical utility for a TBT. However, consideration of these factors will lead to more objective conclusions. Doing so will facilitate value-based decisions regarding whether a TBT should be used to guide patient care.
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http://dx.doi.org/10.1200/JCO.20.01572DOI Listing
January 2021

Osteonecrosis of the jaw risk factors in bisphosphonate-treated patients with metastatic cancer.

Oral Dis 2020 Dec 4. Epub 2020 Dec 4.

Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

Background: A case-control study was performed to define clinical and genetic risk factors associated with osteonecrosis of the jaw in patients with metastatic cancer treated with bisphosphonates.

Methods: Clinical data and tissues were collected from patients treated with bisphosphonates for metastatic bone disease who were diagnosed with osteonecrosis of the jaw (cases) and matched controls. Clinical data included patient, behavioral, disease, and treatment information. Genetic polymorphisms in CYP2C8 (rs1934951) and other candidate genes were genotyped. Odds ratios from conditional logistic regression models were examined to identify clinical and genetic characteristics associated with case or control status.

Results: The study population consisted of 76 cases and 126 controls. In the final multivariable clinical model, patients with osteonecrosis of the jaw were less likely to have received pamidronate than zoledronic acid (odds ratio = 0.18, 95% Confidence interval: 0.03-0.97, p = .047) and more likely to have been exposed to bevacizumab (OR = 5.15, 95% CI: 1.67-15.95, p = .005). The exploratory genetic analyses suggested a protective effect for VEGFC rs2333496 and risk effects for VEGFC rs7664413 and PPARG rs1152003.

Conclusions: We observed patients with ONJ were more likely to have been exposed to bevacizumab and zoledronic and identified potential genetic predictors that require validation prior to clinical translation.
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http://dx.doi.org/10.1111/odi.13746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284838PMC
December 2020

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 04;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

Genetic variation in Charcot-Marie-Tooth genes contributes to sensitivity to paclitaxel-induced peripheral neuropathy.

Pharmacogenomics 2020 08 23;21(12):841-851. Epub 2020 Jul 23.

University of Michigan Rogel Cancer Center, Ann Arbor, MI 48109.

This study explored whether inherited variants in genes causing the hereditary neuropathy condition Charcot-Marie-Tooth disease are associated with sensitivity to paclitaxel-induced peripheral neuropathy (PN). Hereditary neuropathy genes previously associated with risk of paclitaxel-induced PN were sequenced in paclitaxel-treated patients. Eight putative genetic predictors in five hereditary neuropathy genes (, , ,  and ) were tested for association with PN sensitivity after accounting for systemic exposure and clinical variables. rs7833751, a proxy for rs7001034, decreased PN sensitivity (additive model, β = -0.41; 95% CI: -0.66 to -0.17; p = 0.0011). None of the other genetic predictors were associated with PN sensitivity. Our results support prior evidence that rs7001034 is protective of PN and may be useful for individualizing paclitaxel treatment to prevent PN.
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http://dx.doi.org/10.2217/pgs-2020-0053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444626PMC
August 2020

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

Correction to: Targeted degradation of activating estrogen receptor α ligand-binding domain mutations in human breast cancer.

Breast Cancer Res Treat 2020 04;180(3):623

The University of Michigan Rogel Cancer Center, Ann Arbor, USA.

In the original publication of the article, the spelling of the sixth author's given name was incorrect. The corrected author name should read as "Wadie David". The original article has been corrected.
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http://dx.doi.org/10.1007/s10549-020-05594-6DOI Listing
April 2020

Vitamin D deficiency increases severity of paclitaxel-induced peripheral neuropathy.

Breast Cancer Res Treat 2020 Apr 12;180(3):707-714. Epub 2020 Mar 12.

Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI, 48109, USA.

Purpose: Approximately 25% of patients receiving weekly paclitaxel for breast cancer require treatment disruptions to avoid severe, irreversible peripheral neuropathy (PN). Vitamin insufficiencies are PN risk factors in many diseases, but their relevance to chemotherapy-induced PN is unknown.

Methods: We investigated whether baseline insufficiency of vitamin D, vitamin B12, folate, or homocysteine increased PN in patients with breast cancer receiving weekly paclitaxel in a retrospective analysis of a prospective observational study. Patient-reported PN was collected at baseline and during treatment on the Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy (CIPN20). The primary analysis tested associations between vitamin deficiency and the maximum increase from baseline in the CIPN20 sensory subscale (ΔCIPN8). Secondary analyses tested for association with PN-induced treatment disruptions and adjusted associations for treatment and clinical variables.

Results: 25-hydroxy-vitamin D was the only nutrient with sufficient deficiency (< 20 ng/mL) for analysis (15/37 = 41%). Vitamin D-deficient patients had a greater mean PN increase than non-deficient patients (ΔCIPN8 ± SD, 36 ± 23 vs. 16 ± 16, p = 0.003) and a non-significant, approximately threefold increase in risk of treatment disruption (OR 2.98, 95% CI [0.72, 12.34], p = 0.16). In multivariable models adjusted for clinical and treatment variables, baseline vitamin D level was inversely associated with PN (β = - 0.04, p = 0.02).

Conclusion: Pre-treatment vitamin D deficiency was associated with PN in women receiving weekly paclitaxel for breast cancer. Vitamin D deficiency may be an easily detected PN risk factor that could be resolved prior to treatment to prevent PN, avoid treatment disruptions, and improve treatment outcomes.
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http://dx.doi.org/10.1007/s10549-020-05584-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945004PMC
April 2020

Completing the Translation.

Oncologist 2020 03 16;25(3):183-185. Epub 2019 Oct 16.

University of Michigan Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA.

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http://dx.doi.org/10.1634/theoncologist.2019-0650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066685PMC
March 2020

Targeted degradation of activating estrogen receptor α ligand-binding domain mutations in human breast cancer.

Breast Cancer Res Treat 2020 Apr 17;180(3):611-622. Epub 2020 Feb 17.

The University of Michigan Rogel Cancer Center, Ann Arbor, USA.

Purpose: Studies have identified several estrogen receptor α (ERα) ligand-binding domain (LBD) somatic mutations in endocrine therapy resistant, metastatic ER-positive breast cancers. The most common mutations, Tyr537Ser (Y537S) and Asp538Gly (D538G), are detected in ~ 30% of endocrine resistant metastatic breast cancer patients. These ESR1 mutations induce the agonist conformation of ERα, confer an estrogen-independent phenotype, and promote drug resistance to antiestrogens.

Methods: ER-positive, estrogen-dependent MCF-7 cells were engineered to express either the Y537S or D538G mutants using CRISPR knock-in (cY537S and cD538G). These cells were used to screen several estrogen receptor degrader (ERD) compounds synthesized using the Proteolysis Targeting Chimeras (PROTAC) method to induce degradation of ERα via the ubiquitin-proteasome pathway.

Results: Wild-type MCF-7 and ERα LBD mutant cells were treated with ERD-148 (10 pM-1 µM) and assayed for cellular proliferation using the PrestoBlue cell viability assay. ERD-148 attenuated ER-dependent growth with IC values of 0.8, 10.5, and 6.1 nM in MCF-7, cY537S, and cD538G cells, respectively. Western blot analysis showed that MCF-7 cells treated with 1 nM ERD-148 for 24 h exhibited reduced ERα protein expression as compared to the mutants. The ER-regulated gene, GREB1, demonstrated significant downregulation in parental and mutant cells after 24 h of ERD-148 treatment at 10 nM. Growth of the ER-negative, estrogen-independent MDA-MB-231 breast cancer cells was not inhibited by ERD-148 at the ~ IC observed in the ER-positive cells.

Conclusion: ERD-148 inhibits the growth of ER-positive breast cancer cells via downregulating ERα with comparable potency to Fulvestrant with marginal non-specific toxicity.
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http://dx.doi.org/10.1007/s10549-020-05564-yDOI Listing
April 2020

Tumour-derived extracellular vesicles in blood of metastatic cancer patients associate with overall survival.

Br J Cancer 2020 03 15;122(6):801-811. Epub 2020 Jan 15.

Department of Medical Cell BioPhysics, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.

Background: Circulating tumour cells (CTCs) in blood associate with overall survival (OS) of cancer patients, but they are detected in extremely low numbers. Large tumour-derived extracellular vesicles (tdEVs) in castration-resistant prostate cancer (CRPC) patients are present at around 20 times higher frequencies than CTCs and have equivalent prognostic power. In this study, we explored the presence of tdEVs in other cancers and their association with OS.

Methods: The open-source ACCEPT software was used to automatically enumerate tdEVs in digitally stored CellSearch® images obtained from previously reported CTC studies evaluating OS in 190 CRPC, 450 metastatic colorectal cancer (mCRC), 179 metastatic breast cancer (MBC) and 137 non-small cell lung cancer (NSCLC) patients before the initiation of a new treatment.

Results: Presence of unfavourable CTCs and tdEVs is predictive of OS, with respective hazard ratios (HRs) of 2.4 and 2.2 in CRPC, 2.7 and 2.2 in MBC, 2.3 and 1.9 in mCRC and 2.0 and 2.4 in NSCLC, respectively.

Conclusions: tdEVs have equivalent prognostic value as CTCs in the investigated metastatic cancers. CRPC, mCRC, and MBC (but not NSCLC) patients with favourable CTC counts can be further prognostically stratified using tdEVs. Our data suggest that tdEVs could be used in clinical decision-making.
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http://dx.doi.org/10.1038/s41416-019-0726-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078322PMC
March 2020

Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update.

J Clin Oncol 2020 04 13;38(12):1346-1366. Epub 2020 Jan 13.

Johns Hopkins University, Baltimore, MD.

Purpose: To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists estrogen (ER) and progesterone receptor (PgR) testing in breast cancer guideline.

Methods: A multidisciplinary international Expert Panel was convened to update the clinical practice guideline recommendations informed by a systematic review of the medical literature.

Recommendations: The Expert Panel continues to recommend ER testing of invasive breast cancers by validated immunohistochemistry as the standard for predicting which patients may benefit from endocrine therapy, and no other assays are recommended for this purpose. Breast cancer samples with 1% to 100% of tumor nuclei positive should be interpreted as ER positive. However, the Expert Panel acknowledges that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive. Samples with these results should be reported using a new reporting category, ER Low Positive, with a recommended comment. A sample is considered ER negative if < 1% or 0% of tumor cell nuclei are immunoreactive. Additional strategies recommended to promote optimal performance, interpretation, and reporting of cases with an initial low to no ER staining result include establishing a laboratory-specific standard operating procedure describing additional steps used by the laboratory to confirm/adjudicate results. The status of controls should be reported for cases with 0% to 10% staining. Similar principles apply to PgR testing, which is used primarily for prognostic purposes in the setting of an ER-positive cancer. Testing of ductal carcinoma in situ (DCIS) for ER is recommended to determine potential benefit of endocrine therapies to reduce risk of future breast cancer, while testing DCIS for PgR is considered optional. Additional information can be found at www.asco.org/breast-cancer-guidelines.
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http://dx.doi.org/10.1200/JCO.19.02309DOI Listing
April 2020

Estrogen and Progesterone Receptor Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Guideline Update.

Arch Pathol Lab Med 2020 05 13;144(5):545-563. Epub 2020 Jan 13.

Johns Hopkins University, Baltimore, MD.

Purpose.—: To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer guideline.

Methods.—: A multidisciplinary international Expert Panel was convened to update the clinical practice guideline recommendations informed by a systematic review of the medical literature.

Recommendations.—: The Expert Panel continues to recommend ER testing of invasive breast cancers by validated immunohistochemistry as the standard for predicting which patients may benefit from endocrine therapy, and no other assays are recommended for this purpose. Breast cancer samples with 1% to 100% of tumor nuclei positive should be interpreted as ER positive. However, the Expert Panel acknowledges that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive. Samples with these results should be reported using a new reporting category, ER Low Positive, with a recommended comment. A sample is considered ER negative if < 1% or 0% of tumor cell nuclei are immunoreactive. Additional strategies recommended to promote optimal performance, interpretation, and reporting of cases with an initial low to no ER staining result include establishing a laboratory-specific standard operating procedure describing additional steps used by the laboratory to confirm/adjudicate results. The status of controls should be reported for cases with 0% to 10% staining. Similar principles apply to PgR testing, which is used primarily for prognostic purposes in the setting of an ER-positive cancer. Testing of ductal carcinoma in situ (DCIS) for ER is recommended to determine potential benefit of endocrine therapies to reduce risk of future breast cancer, while testing DCIS for PgR is considered optional. Additional information can be found at www.asco.org/breast-cancer-guidelines .
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http://dx.doi.org/10.5858/arpa.2019-0904-SADOI Listing
May 2020

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

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

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

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

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

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

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

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

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

Progress in the Treatment of Breast Cancer. Reply.

Authors:
Daniel F Hayes

N Engl J Med 2020 01;382(2):e4

University of Michigan Rogel Cancer Center, Ann Arbor, MI

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http://dx.doi.org/10.1056/NEJMc1915045DOI Listing
January 2020

Pharmacogenomics and Endocrine Therapy in Breast Cancer.

J Clin Oncol 2020 02 27;38(6):525-528. Epub 2019 Dec 27.

University of Michigan Medical School, Ann Arbor, MI.

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http://dx.doi.org/10.1200/JCO.19.03119DOI Listing
February 2020

Genetic variation in EPHA contributes to sensitivity to paclitaxel-induced peripheral neuropathy.

Br J Clin Pharmacol 2020 05 4;86(5):880-890. Epub 2020 Feb 4.

Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, USA.

Aims: Chemotherapy-induced peripheral neuropathy (PN) is a treatment limiting toxicity of paclitaxel. We evaluated if EPHA genetic variation (EPHA4, EPHA5, EPHA6, and EPHA8) is associated with PN sensitivity by accounting for variability in systemic paclitaxel exposure (time above threshold).

Methods: Germline DNA from 60 patients with breast cancer was sequenced. PN was measured using the 8-item sensory subscale (CIPN8) of the patient-reported CIPN20. Associations for 3 genetic models were tested by incorporating genetics into previously published PN prediction models integrating measured paclitaxel exposure and cumulative treatment. Significant associations were then tested for association with PN-related treatment disruption.

Results: EPHA5 rs7349683 (minor allele frequency = 0.32) was associated with increased PN sensitivity (β-coefficient = 0.39, 95% confidence interval 0.11-0.67, p = 0.007). Setting a maximum tolerable threshold of CIPN8 = 30, optimal paclitaxel exposure target is shorter for rs7349683 homozygous (11.6 h) than heterozygous (12.6 h) or wild-type (13.6 h) patients. Total number of missense variants (median = 0, range 0-2) was associated with decreased PN sensitivity (β-coefficient: -0.42, 95% confidence interval -0.72 to -0.12, P = .006). No association with treatment disruption was detected for the total number of missense variants or rs7349683.

Conclusion: Isolating toxicity sensitivity by accounting for exposure is a novel approach, and rs7349683 represents a promising marker for PN sensitivity that may be used to individualize paclitaxel treatment.
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http://dx.doi.org/10.1111/bcp.14192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163383PMC
May 2020

Phase III Randomized Trial of Bisphosphonates as Adjuvant Therapy in Breast Cancer: S0307.

J Natl Cancer Inst 2020 07;112(7):698-707

The University of Texas MD Anderson Cancer Center, Houston, TX.

Background: Adjuvant bisphosphonates, when given in a low-estrogen environment, can decrease breast cancer recurrence and death. Treatment guidelines include recommendations for adjuvant bisphosphonates in postmenopausal patients. SWOG/Alliance/Canadian Cancer Trials Group/ECOG-ACRIN/NRG Oncology study S0307 compared the efficacy of three bisphosphonates in early-stage breast cancer.

Methods: Patients with stage I-III breast cancer were randomly assigned to 3 years of intravenous zoledronic acid, oral clodronate, or oral ibandronate. The primary endpoint was disease-free survival (DFS) with overall survival as a secondary outcome. All statistical tests were two-sided.

Results: A total of 6097 patients enrolled. Median age was 52.7 years. Prior to being randomly assigned, 73.2% patients indicated preference for oral vs intravenous formulation. DFS did not differ across arms in a log-rank test (P = .49); 5-year DFS was 88.3% (zoledronic acid: 95% confidence interval [CI] = 86.9% to 89.6%), 87.6% (clodronate: 95% CI = 86.1% to 88.9%), and 87.4% (ibandronate: 95% CI = 85.6% to 88.9%). Additionally, 5-year overall survival did not differ between arms (log rank P = .50) and was 92.6% (zoledronic acid: 95% CI = 91.4% to 93.6%), 92.4% (clodronate: 95% CI = 91.2% to 93.5%), and 92.9% (ibandronate: 95% CI = 91.5% to 94.1%). Bone as first site of recurrence did not differ between arms (P = .93). Analyses based on age and tumor subtypes showed no treatment differences. Grade 3/4 toxicity was 8.8% (zoledronic acid), 8.3% (clodronate), and 10.5% (ibandronate). Osteonecrosis of the jaw was highest for zoledronic acid (1.26%) compared with clodronate (0.36%) and ibandronate (0.77%).

Conclusions: We found no evidence of differences in efficacy by type of bisphosphonate, either in overall analysis or subgroups. Despite an increased rate of osteonecrosis of the jaw with zoledronic acid, overall toxicity grade differed little across arms. Given that patients expressed preference for oral formulation, efforts to make oral agents available in the United States should be considered.
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http://dx.doi.org/10.1093/jnci/djz215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357327PMC
July 2020

Validation of the DNA Damage Immune Response Signature in Patients With Triple-Negative Breast Cancer From the SWOG 9313c Trial.

J Clin Oncol 2019 12 28;37(36):3484-3492. Epub 2019 Oct 28.

University of Michigan, Ann Arbor, MI.

Purpose: To independently validate two biomarkers, a 44-gene DNA damage immune response (DDIR) signature and stromal tumor-infiltrating lymphocytes (sTILs), as prognostic markers in patients with triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG 9313.

Methods: Four hundred twenty-five centrally determined patient cases with TNBC from S9313 were identified. DDIR signature was performed on RNA isolated from formalin-fixed paraffin-embedded tumor tissue, and samples were classified as DDIR negative or positive using predefined cutoffs. Evaluation of sTILs was performed as described previously. Markers were tested for prognostic value for disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment, nodal status, and tumor size.

Results: Among 425 patients with TNBC, 33% were node positive. DDIR was tested successfully in 90% of patients (381 of 425), 62% of which were DDIR signature positive. DDIR signature positivity was associated with improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.92; = .015) and OS (HR, 0.61; 95% CI, 0.43 to 0.89; = .010). sTILs density assessment was available in 99% of patients and was associated with improved DFS (HR, 0.70; 95% CI, 0.51 to 0.96; = .026 for sTILs density ≥ 20% < 20%) and OS (HR, 0.59; 95% CI, 0.41 to 0.85; = .004 for sTILs density ≥ 20% < 20%). DDIR signature score and sTILs density were moderately correlated ( = 0.60), which precluded statistical significance for DFS in a joint model. Three-year DFS and OS in a subgroup of patients with DDIR positivity and T1c/T2N0 disease were 88% and 94%, respectively.

Conclusion: The prognostic role of sTILs and DDIR in early-stage TNBC was confirmed. DDIR signature conferred improved prognosis in two thirds of patients with TNBC treated with adjuvant AC. DDIR signature has the potential to stratify outcome and to identify patients with less projected benefit after AC chemotherapy.
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http://dx.doi.org/10.1200/JCO.19.00693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194448PMC
December 2019

Clinical Applications of Circulating Tumor Cells in Breast Cancer.

Recent Results Cancer Res 2020 ;215:147-160

Department of Internal Medicine, Breast Oncology Program of the Comprehensive Cancer Center, University of Michigan Health System, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109-5942, USA.

The development of metastatic disease accounts for the vast majority of cancer-related deaths in solid tumor malignancies. Distant metastases primarily develop as a result of tumor cell dissemination through the circulatory system.
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http://dx.doi.org/10.1007/978-3-030-26439-0_8DOI Listing
October 2019
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