Publications by authors named "Larry Norton"

245 Publications

Clonal hematopoiesis is associated with risk of severe Covid-19.

Nat Commun 2021 10 13;12(1):5975. Epub 2021 Oct 13.

Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15-2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15-3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22-3.30, p = 6×10) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15-2.13, p = 5×10). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.
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http://dx.doi.org/10.1038/s41467-021-26138-6DOI Listing
October 2021

The clinical behavior and genomic features of the so-called adenoid cystic carcinomas of the solid variant with basaloid features.

Mod Pathol 2021 Oct 1. Epub 2021 Oct 1.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Classic adenoid cystic carcinomas (C-AdCCs) of the breast are rare, relatively indolent forms of triple negative cancers, characterized by recurrent MYB or MYBL1 genetic alterations. Solid and basaloid adenoid cystic carcinoma (SB-AdCC) is considered a rare variant of AdCC yet to be fully characterized. Here, we sought to determine the clinical behavior and repertoire of genetic alterations of SB-AdCCs. Clinicopathologic data were collected on a cohort of 104 breast AdCCs (75 C-AdCCs and 29 SB-AdCCs). MYB expression was assessed by immunohistochemistry and MYB-NFIB and MYBL1 gene rearrangements were investigated by fluorescent in-situ hybridization. AdCCs lacking MYB/MYBL1 rearrangements were subjected to RNA-sequencing. Targeted sequencing data were available for 9 cases. The invasive disease-free survival (IDFS) and overall survival (OS) were assessed in C-AdCC and SB-AdCC. SB-AdCCs have higher histologic grade, and more frequent nodal and distant metastases than C-AdCCs. MYB/MYBL1 rearrangements were significantly less frequent in SB-AdCC than C-AdCC (3/14, 21% vs 17/20, 85% P < 0.05), despite the frequent MYB expression (9/14, 64%). In SB-AdCCs lacking MYB rearrangements, CREBBP, KMT2C, and NOTCH1 alterations were observed in 2 of 4 cases. SB-AdCCs displayed a shorter IDFS than C-AdCCs (46.5 vs 151.8 months, respectively, P < 0.001), independent of stage. In summary, SB-AdCCs are a molecularly heterogeneous but clinically aggressive group of tumors. Less than 25% of SB-AdCCs display the genomic features of C-AdCC. Defining whether these tumors represent a single entity or a collection of different cancer types with a similar basaloid histologic appearance is warranted.
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http://dx.doi.org/10.1038/s41379-021-00931-6DOI Listing
October 2021

The impact of scaling up access to treatment and imaging modalities on global disparities in breast cancer survival: a simulation-based analysis.

Lancet Oncol 2021 09 17;22(9):1301-1311. Epub 2021 Aug 17.

Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.

Background: Female breast cancer is the most commonly diagnosed cancer in the world, with wide variations in reported survival by country. Women in low-income and middle-income countries (LMICs) in particular face several barriers to breast cancer services, including diagnostics and treatment. We aimed to estimate the potential impact of scaling up the availability of treatment and imaging modalities on breast cancer survival globally, together with improvements in quality of care.

Methods: For this simulation-based analysis, we used a microsimulation model of global cancer survival, which accounts for the availability and stage-specific survival impact of specific treatment modalities (chemotherapy, radiotherapy, surgery, and targeted therapy), imaging modalities (ultrasound, x-ray, CT, MRI, PET, and single-photon emission computed tomography [SPECT]), and quality of cancer care, to simulate 5-year net survival for women with newly diagnosed breast cancer in 200 countries and territories in 2018. We calibrated the model to empirical data on 5-year net breast cancer survival in 2010-14 from CONCORD-3. We evaluated the potential impact of scaling up specific imaging and treatment modalities and quality of care to the mean level of high-income countries, individually and in combination. We ran 1000 simulations for each policy intervention and report the means and 95% uncertainty intervals (UIs) for all model outcomes.

Findings: We estimate that global 5-year net survival for women diagnosed with breast cancer in 2018 was 67·9% (95% UI 62·9-73·4) overall, with an almost 25-times difference between low-income (3·5% [0·4-10·0]) and high-income (87·0% [85·6-88·4]) countries. Among individual treatment modalities, scaling up access to surgery alone was estimated to yield the largest survival gains globally (2·7% [95% UI 0·4-8·3]), and scaling up CT alone would have the largest global impact among imaging modalities (0·5% [0·0-2·0]). Scaling up a package of traditional modalities (surgery, chemotherapy, radiotherapy, ultrasound, and x-ray) could improve global 5-year net survival to 75·6% (95% UI 70·6-79·4), with survival in low-income countries improving from 3·5% (0·4-10·0) to 28·6% (4·9-60·1). Adding concurrent improvements in quality of care could further improve global 5-year net survival to 78·2% (95% UI 74·9-80·4), with a substantial impact in low-income countries, improving net survival to 55·3% (42·2-67·8). Comprehensive scale-up of access to all modalities and improvements in quality of care could improve global 5-year net survival to 82·3% (95% UI 79·3-85·0).

Interpretation: Comprehensive scale-up of treatment and imaging modalities, and improvements in quality of care could improve global 5-year net breast cancer survival by nearly 15 percentage points. Scale-up of traditional modalities and quality-of-care improvements could achieve 70% of these total potential gains, with substantial impact in LMICs, providing a more feasible pathway to improving breast cancer survival in these settings even without the benefits of future investments in targeted therapy and advanced imaging.

Funding: Harvard T H Chan School of Public Health, and National Cancer Institute P30 Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center.
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http://dx.doi.org/10.1016/S1470-2045(21)00403-4DOI Listing
September 2021

Poor response to neoadjuvant chemotherapy in metaplastic breast carcinoma.

NPJ Breast Cancer 2021 Jul 22;7(1):96. Epub 2021 Jul 22.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Metaplastic breast carcinoma (MpBC) is a rare special histologic subtype of breast carcinoma characterized by the presence of squamous and/or mesenchymal differentiation. Most MpBCs are of triple-negative phenotype and neoadjuvant chemotherapy (NAC) is frequently utilized in patients with MpBC. The aim of this study was to evaluate response to NAC in a retrospective cohort of MpBCs. We identified 44 patients with MpBC treated with NAC at our center between 2002 and 2018. Median age was 48 years, 86% were clinical stage II-III, and 36% were clinically node-positive. Most (80%) MpBCs were triple-negative or low (1-10%) hormonal receptor positive and HER2 negative on pre-NAC biopsy. While on NAC, 49% showed no clinical response or clinico-radiological progression. Matrix-producing subtype was associated with clinico-radiological response (p = 0.0036). Post NAC, two patients initially ineligible for breast-conserving surgery (BCS) were downstaged to be eligible for BCS, whereas three patients potentially eligible for BCS before treatment became ineligible due to disease progression. Only one (2%) patient had a pathologic complete response (pCR). Among the 16 patients presenting with biopsy-proven clinical node-positive disease, 3 (19%) had nodal pCR. Axillary lymph node dissection was avoided in 3 (19%) patients who had successful axillary downstaging. Residual cancer burden (RCB) was assessed in 22 patients and was significantly associated with disease-free survival and overall survival. We observed a poor response or even disease progression on NAC among patients with MpBC, suggesting that NAC should be reserved for patients with inoperable MpBC.
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http://dx.doi.org/10.1038/s41523-021-00302-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298632PMC
July 2021

In Memoriam: José Baselga's Journey in Cancer Medicine.

Clin Cancer Res 2021 06;27(12):3499-3502

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

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http://dx.doi.org/10.1158/1078-0432.CCR-21-1624DOI Listing
June 2021

Anti-tumor effects of an ID antagonist with no observed acquired resistance.

NPJ Breast Cancer 2021 May 24;7(1):58. Epub 2021 May 24.

Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

ID proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. ID proteins inhibit basic-HLH transcription factors often blocking differentiation and sustaining proliferation. A small-molecule, AGX51, targets ID proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impairs cell growth and viability that results from an increase in reactive oxygen species (ROS) production upon ID degradation. In mouse models, AGX51 treatment suppresses breast cancer colonization in the lung, regresses the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduces tumor burden in sporadic colorectal neoplasia. Furthermore, in cells and mice, we fail to observe acquired resistance to AGX51 likely the result of the inability to mutate the binding pocket without loss of ID function and efficient degradation of the ID proteins. Thus, AGX51 is a first-in-class compound that antagonizes ID proteins, shows strong anti-tumor effects and may be further developed for the management of multiple cancers.
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http://dx.doi.org/10.1038/s41523-021-00266-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144414PMC
May 2021

TERT promoter hotspot mutations and gene amplification in metaplastic breast cancer.

NPJ Breast Cancer 2021 Apr 16;7(1):43. Epub 2021 Apr 16.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Metaplastic breast cancers (MBCs) are characterized by complex genomes, which seem to vary according to their histologic subtype. TERT promoter hotspot mutations and gene amplification are rare in common forms of breast cancer, but present in a subset of phyllodes tumors. Here, we sought to determine the frequency of genetic alterations affecting TERT in a cohort of 60 MBCs with distinct predominant metaplastic components (squamous, 23%; spindle, 27%; osseous, 8%; chondroid, 42%), and to compare the repertoire of genetic alterations of MBCs according to the presence of TERT promoter hotspot mutations or gene amplification. Forty-four MBCs were subjected to: whole-exome sequencing (WES; n = 27) or targeted sequencing of 341-468 cancer-related genes (n = 17); 16 MBCs were subjected to Sanger sequencing of the TERT promoter, TP53 and selected exons of PIK3CA, HRAS, and BRAF. TERT promoter hotspot mutations (n = 9) and TERT gene amplification (n = 1) were found in 10 of the 60 MBCs analyzed, respectively. These TERT alterations were less frequently found in MBCs with predominant chondroid differentiation than in other MBC subtypes (p = 0.01, Fisher's exact test) and were mutually exclusive with TP53 mutations (p < 0.001, CoMEt). In addition, a comparative analysis of the MBCs subjected to WES or targeted cancer gene sequencing (n = 44) revealed that MBCs harboring TERT promoter hotspot mutations or gene amplification (n = 6) more frequently harbored PIK3CA than TERT wild-type MBCs (n = 38; p = 0.001; Fisher's exact test). In conclusion, TERT somatic genetic alterations are found in a subset of TP53 wild-type MBCs with squamous/spindle differentiation, highlighting the genetic diversity of these cancers.
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http://dx.doi.org/10.1038/s41523-021-00250-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052452PMC
April 2021

Accuracy of Magnetic Resonance Imaging-Guided Biopsy to Verify Breast Cancer Pathologic Complete Response After Neoadjuvant Chemotherapy: A Nonrandomized Controlled Trial.

JAMA Netw Open 2021 01 4;4(1):e2034045. Epub 2021 Jan 4.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: After neoadjuvant chemotherapy (NAC), pathologic complete response (pCR) is an optimal outcome and a surrogate end point for improved disease-free and overall survival. To date, surgical resection remains the only reliable method for diagnosing pCR.

Objective: To evaluate the accuracy of magnetic resonance imaging (MRI)-guided biopsy for diagnosing a pCR after NAC compared with reference-standard surgical resection.

Design, Setting, And Participants: Single-arm, phase 1, nonrandomized controlled trial in a single tertiary care cancer center from September 26, 2017, to July 29, 2019. The median follow-up was 1.26 years (interquartile range, 0.85-1.59 years). Data analysis was performed in November 2019. Eligible patients had (1) stage IA to IIIC biopsy-proven operable invasive breast cancer; (2) standard-of-care NAC; (3) MRI before and after NAC, with imaging complete response defined as no residual enhancement on post-NAC MRI; and (4) definitive surgery. Patients were excluded if they were younger than 18 years, had a medical reason precluding study participation, or had a prior history of breast cancer.

Interventions: Post-NAC MRI-guided biopsy without the use of intravenous contrast of the tumor bed before definitive surgery.

Main Outcomes And Measures: The primary end point was the negative predictive value of MRI-guided biopsy, with true-negative defined as negative results of the biopsy (ie, no residual cancer) corresponding to a surgical pCR. Accuracy, sensitivity, positive predictive value, and specificity were also calculated. Two clinical definitions of pCR were independently evaluated: definition 1 was no residual invasive cancer; definition 2, no residual invasive or in situ cancer.

Results: Twenty of 23 patients (87%) had evaluable data (median [interquartile range] age, 51.5 [39.0-57.5] years; 20 women [100%]; 13 White patients [65%]). Of the 20 patients, pre-NAC median tumor size on MRI was 3.0 cm (interquartile range, 2.0-5.0 cm). Nineteen of 20 patients (95%) had invasive ductal carcinoma; 15 of 20 (75%) had stage II cancer; 11 of 20 (55%) had ERBB2 (formerly HER2 or HER2/neu)-positive cancer; and 6 of 20 (30%) had triple-negative cancer. Surgical pathology demonstrated a pCR in 13 of 20 (65%) patients and no pCR in 7 of 20 patients (35%) when pCR definition 1 was used. Results of MRI-guided biopsy had a negative predictive value of 92.8% (95% CI, 66.2%-99.8%), with accuracy of 95% (95% CI, 75.1%-99.9%), sensitivity of 85.8% (95% CI, 42.0%-99.6%), positive predictive value of 100%, and specificity of 100% for pCR definition 1. Only 1 patient had a false-negative MRI-guided biopsy result (surgical pathology showed <0.02 cm of residual invasive cancer).

Conclusions And Relevance: This study's results suggest that the accuracy of MRI-guided biopsy to diagnose a post-NAC pCR approaches that of reference-standard surgical resection. MRI-guided biopsy may be a viable alternative to surgical resection for this population after NAC, which supports the need for further investigation.

Trial Registration: ClinicalTrials.gov Identifier: NCT03289195.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.34045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811182PMC
January 2021

Comparative Effectiveness Research Needs to Consider Optimal Dosing and Scheduling.

J Clin Oncol 2021 01 17;39(3):253-254. Epub 2020 Dec 17.

Andrew D. Seidman, MD, Elisa de Stanchina, PhD, and Larry Norton, MD, Memorial Sloan Kettering Cancer Center, New York, NY and Aki Morikawa, MD, University of Michigan, Ann Arbor, MI.

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http://dx.doi.org/10.1200/JCO.20.02355DOI Listing
January 2021

Clonal hematopoiesis is associated with risk of severe Covid-19.

medRxiv 2020 Nov 27. Epub 2020 Nov 27.

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 515 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we found that CH was associated with severe Covid-19 outcomes (OR=1.9, 95%=1.2-2.9, p=0.01). We further explored the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH was significantly associated with risk of (HR=2.0, 95% CI: 1.2-3.3, p=6×10 ) and infections (HR=1.5, 95% CI=1.1-2.1, p=5×10 ). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.
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http://dx.doi.org/10.1101/2020.11.25.20233163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709186PMC
November 2020

Fractional SIR epidemiological models.

Sci Rep 2020 11 30;10(1):20882. Epub 2020 Nov 30.

Depts of Computer Science and Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, 11794, USA.

The purpose of this work is to make a case for epidemiological models with fractional exponent in the contribution of sub-populations to the incidence rate. More specifically, we question the standard assumption in the literature on epidemiological models, where the incidence rate dictating propagation of infections is taken to be proportional to the product between the infected and susceptible sub-populations; a model that relies on strong mixing between the two groups and widespread contact between members of the groups. We contend, that contact between infected and susceptible individuals, especially during the early phases of an epidemic, takes place over a (possibly diffused) boundary between the respective sub-populations. As a result, the rate of transmission depends on the product of fractional powers instead. The intuition relies on the fact that infection grows in geographically concentrated cells, in contrast to the standard product model that relies on complete mixing of the susceptible to infected sub-populations. We validate the hypothesis of fractional exponents (1) by numerical simulation for disease propagation in graphs imposing a local structure to allowed disease transmissions and (2) by fitting the model to the JHU CSSE COVID-19 Data for the period Jan-22-20 to April-30-20, for the countries of Italy, Germany, France, and Spain.
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http://dx.doi.org/10.1038/s41598-020-77849-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705759PMC
November 2020

Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Nat Genet 2020 11 26;52(11):1219-1226. Epub 2020 Oct 26.

Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.
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http://dx.doi.org/10.1038/s41588-020-00710-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891089PMC
November 2020

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

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

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

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

The genetic landscape of metaplastic breast cancers and uterine carcinosarcomas.

Mol Oncol 2021 04 19;15(4):1024-1039. Epub 2021 Feb 19.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Metaplastic breast carcinoma (MBC) and uterine carcinosarcoma (UCS) are rare aggressive cancers, characterized by an admixture of adenocarcinoma and areas displaying mesenchymal/sarcomatoid differentiation. We sought to define whether MBCs and UCSs harbor similar patterns of genetic alterations, and whether the different histologic components of MBCs and UCSs are clonally related. Whole-exome sequencing (WES) data from MBCs (n = 35) and UCSs (n = 57, The Cancer Genome Atlas) were reanalyzed to define somatic genetic alterations, altered signaling pathways, mutational signatures, and genomic features of homologous recombination DNA repair deficiency (HRD). In addition, the carcinomatous and sarcomatous components of an additional cohort of MBCs (n = 11) and UCSs (n = 6) were microdissected separately and subjected to WES, and their clonal relatedness was assessed. MBCs and UCSs harbored recurrent genetic alterations affecting TP53, PIK3CA, and PTEN, similar patterns of gene copy number alterations, and an enrichment in alterations affecting the epithelial-to-mesenchymal transition (EMT)-related Wnt and Notch signaling pathways. Differences were observed, however, including a significantly higher prevalence of FAT3 and FAT1 somatic mutations in MBCs compared to UCSs, and conversely, UCSs significantly more frequently harbored somatic mutations affecting FBXW7 and PPP2R1A as well as HER2 amplification than MBCs. Genomic features of HRD and biallelic alterations affecting bona fide HRD-related genes were found to be more prevalent in MBCs than in UCSs. The distinct histologic components of MBCs and UCSs were clonally related in all cases, with the sarcoma component likely stemming from a minor subclone of the carcinoma component in the samples with interpretable chronology of clonal evolution. Despite the similar histologic features and pathways affected by genetic alterations, UCSs differ from MBCs on the basis of FBXW7 and PPP2R1A mutations, HER2 amplification, and lack of HRD, supporting the notion that these entities are more than mere phenocopies of the same tumor type in different anatomical sites.
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http://dx.doi.org/10.1002/1878-0261.12813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024717PMC
April 2021

Alterations in and promote clinical resistance to alpelisib plus aromatase inhibitors.

Nat Cancer 2020 Apr 23;1(4):382-393. Epub 2020 Mar 23.

Human Oncology and Pathogenesis Program, MSKCC, New York, NY.

Alpelisib is a selective inhibitor of PI3Kα, shown to improve outcomes for mutant, hormone receptor positive (HR+) metastatic breast cancers (MBC) when combined with antiestrogen therapy. To uncover mechanisms of resistance, we conducted a detailed, longitudinal analysis of tumor and plasma circulating tumor DNA among such patients from a phase I/II trial combining alpelisib with an aromatase inhibitor (AI) (NCT01870505). The trial's primary objective was to establish safety with maculopapular rash emerging as the most common grade 3 adverse event (33%). Among 44 evaluable patients, the observed clinical benefit rate was 52%. Correlating genetic alterations with outcome, we identified loss-of-function mutations in 25% of patients with resistance. activating mutations also expanded in number and allele fraction during treatment and were associated with resistance. These data indicate that genomic alterations that mediate resistance to alpelisib or antiestrogen may promote disease progression and highlight loss as a recurrent mechanism of resistance to PI3Kα inhibition.
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http://dx.doi.org/10.1038/s43018-020-0047-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450824PMC
April 2020

Clinical and pathologic features associated with PD-L1 (SP142) expression in stromal tumor-infiltrating immune cells of triple-negative breast carcinoma.

Mod Pathol 2020 11 1;33(11):2221-2232. Epub 2020 Jul 1.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

The Ventana PD-L1 SP142 immunohistochemistry (IHC) assay is the FDA-approved companion diagnostic assay for atezolizumab therapy selection for patients with PD-L1-positive locally advanced or metastatic triple-negative breast carcinoma (TNBC). We aimed to elucidate clinical, pathologic, and molecular features associated with PD-L1 expression in TNBCs. Clinical, pathologic, and next-generation sequencing (NGS)-based molecular data for TNBCs tested with PD-L1 (SP142) IHC at our institution between 11/2018 and 12/2019 were retrieved and reviewed. PD-L1 positivity was defined as ≥1% IC staining. Patients with metastatic TNBC treated at first line with atezolizumab regimens were evaluated for treatment response and for time to treatment failure (TTF). Among 156 TNBCs, PD-L1 was positive in 47.4% of cases. Primary TNBCs were significantly more frequently PD-L1 positive, compared with recurrent/metastatic samples (p = 0.002). PD-L1-positive TNBCs had increased stromal IC, compared with PD-L1-negative samples (p < 0.001). The repertoire of somatic genetic alterations of PD-L1-positive and PD-L1-negative TNBCs was similar. Matched primary and recurrent/metastatic TNBC samples were available for eight patients, in whom four had discordant results. Thirty patients with metastatic TNBC were treated with atezolizumab regimens, with treatment failure occurring in 16 patients and a median TTF of 5.1 months in this early evaluation. The findings of this study show stromal ICs in primary TNBCs are more likely to show PD-L1 positivity than in recurrent or metastatic samples. This information should guide selection of samples suitable for testing. Further studies are needed to identify other features associated with PD-L1-positive breast carcinomas and clinical benefit of treatment.
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http://dx.doi.org/10.1038/s41379-020-0606-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234788PMC
November 2020

Fractional SIR Epidemiological Models.

medRxiv 2020 Apr 30. Epub 2020 Apr 30.

Departments of Computer Science and Applied Mathematics & Statistics Stony Brook University Stony Brook, NY 11794.

The purpose of this work is to make a case for epidemiological models with fractional exponent in the contribution of sub-populations to the transmission rate. More specifically, we question the standard assumption in the literature on epidemiological models, where the transmission rate dictating propagation of infections is taken to be proportional to the product between the infected and susceptible sub-populations; a model that relies on strong mixing between the two groups and widespread contact between members of the groups. We content, that contact between infected and susceptible individuals, especially during the early phases of an epidemic, takes place over a (possibly diffused) boundary between the respective sub-populations. As a result, the rate of transmission depends on the product of fractional powers instead. The intuition relies on the fact that infection grows in geographically concentrated cells, in contrast to the standard product model that relies on complete mixing of the susceptible to infected sub-populations. We validate the hypothesis of fractional exponents i) by numerical simulation for disease propagation in graphs imposing a local structure to allowed disease transmissions and ii) by fitting the model to a COVID-19 data set provided by John Hopkins University (JHUCSSE) for the period Jan-31-20 to Mar-24-20, for the countries of Italy, Germany, Iran, and France.
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http://dx.doi.org/10.1101/2020.04.28.20083865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273264PMC
April 2020

Optimizing Radiation Therapy to Boost Systemic Immune Responses in Breast Cancer: A Critical Review for Breast Radiation Oncologists.

Int J Radiat Oncol Biol Phys 2020 09 14;108(1):227-241. Epub 2020 May 14.

Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Immunotherapy using immune checkpoint blockade has revolutionized the treatment of many types of cancer. Radiation therapy (RT)-particularly when delivered at high doses using newer techniques-may be capable of generating systemic antitumor effects when combined with immunotherapy in breast cancer. These systemic effects might be due to the local immune-priming effects of RT resulting in the expansion and circulation of effector immune cells to distant sites. Although this concept merits further exploration, several challenges need to be overcome. One is an understanding of how the heterogeneity of breast cancers may relate to tumor immunogenicity. Another concerns the need to develop knowledge and expertise in delivery, sequencing, and timing of RT with immunotherapy. Clinical trials addressing these issues are under way. We here review and discuss the particular opportunities and issues regarding this topic, including the design of informative clinical and translational studies.
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http://dx.doi.org/10.1016/j.ijrobp.2020.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646202PMC
September 2020

First-in-Human Trial of Epichaperome-Targeted PET in Patients with Cancer.

Clin Cancer Res 2020 10 4;26(19):5178-5187. Epub 2020 May 4.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: I-PU-H71 is an investigational first-in-class radiologic agent specific for imaging tumor epichaperome formations. The intracellular epichaperome forms under cellular stress and is a clinically validated oncotherapeutic target. We conducted a first-in-human study of microdose I-PU-H71 for PET to study biodistribution, pharmacokinetics, metabolism, and safety; and the feasibility of epichaperome-targeted tumor imaging.

Experimental Design: Adult patients with cancer ( = 30) received I-PU-H71 tracer (201±12 MBq, <25 μg) intravenous bolus followed by PET/CT scans and blood radioassays.

Results: I-PU-H71 PET detected tumors of different cancer types (breast, lymphoma, neuroblastoma, genitourinary, gynecologic, sarcoma, and pancreas). I-PU-H71 was retained by tumors for several days while it cleared rapidly from bones, healthy soft tissues, and blood. Radiation dosimetry is favorable and patients suffered no adverse effects.

Conclusions: Our first-in-human results demonstrate the safety and feasibility of noninvasive detection of tumor epichaperomes using I-PU-H71 PET, supporting clinical development of PU-H71 and other epichaperome-targeted therapeutics.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541604PMC
October 2020

Whole-exome analysis of metaplastic breast carcinomas with extensive osseous differentiation.

Histopathology 2020 Aug;77(2):321-326

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Aims: Metaplastic breast carcinoma (MBC) is a rare type of triple-negative breast cancer that shows vast histological and genetic heterogeneity. Osseous differentiation can be found in different subtypes of MBC. Whether MBCs with osseous differentiation are underpinned by specific genetic alterations has yet to be defined. The aim of this study was to investigate the repertoire of somatic mutations and copy number alterations (CNAs) in three MBCs with extensive osseous differentiation.

Methods And Results: Tumour and normal DNA samples from three MBCs with extensive osseous differentiation were subjected to whole-exome sequencing. Somatic mutations, CNAs and mutational signatures were determined by use of a validated bioinformatics pipeline. Our analyses revealed clonal TP53 hotspot mutations associated with loss of heterozygosity of the wild-type allele coupled with mutations affecting genes related to the Wnt and/or the phosphoinositide 3-kinase-AKT-mammalian target of rapamycin pathways in all cases analysed. All cases showed a dominant mutational signature 1, with two cases showing a secondary signature 3 in addition to other features of homologous recombination DNA repair defects. The oncostatin M receptor gene, which plays a role in mesenchymal differentiation and bone formation, was found to be mutated in two MBCs with extensive osseous differentiation and in none of 35 previously published 35 MBCs.

Conclusion: Our findings suggest that MBCs with osseous differentiation have somatic mutations similar to those of other forms of MBC.
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http://dx.doi.org/10.1111/his.14088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518240PMC
August 2020

Efficacy and Safety of Gemcitabine With Trastuzumab and Pertuzumab After Prior Pertuzumab-Based Therapy Among Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: A Phase 2 Clinical Trial.

JAMA Netw Open 2019 11 1;2(11):e1916211. Epub 2019 Nov 1.

Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Taxanes with trastuzumab and pertuzumab for initial treatment of human epidermal growth factor receptor 2 (ERBB2, formerly HER2)-positive metastatic breast cancer is associated with improved progression-free survival (PFS) and overall survival. While continued use of trastuzumab in therapeutic combinations after disease progression is standard, the efficacy of continuing pertuzumab is unknown.

Objective: To evaluate the efficacy and safety of pertuzumab in combination with gemcitabine and trastuzumab after prior treatment with pertuzumab for ERBB2-positive metastatic breast cancer.

Design, Setting, And Participants: This is a phase 2 single-arm clinical trial of dual anti-ERBB2 therapy after prior treatment with pertuzumab. The study took place at a single academic center from March 2015 to April 2017 among women with ERBB2-positive metastatic breast cancer, prior pertuzumab-based treatment, and 3 or fewer prior chemotherapy regimens. Data were analyzed between January 2019 and March 2019.

Intervention: Treatment consisted of gemcitabine, 1200 mg/m2 (later amended to 1000 mg/m2) on days 1 and 8 every 3 weeks, plus trastuzumab (8-mg/kg loading dose, then 6 mg/kg) and pertuzumab (840-mg loading dose, then 420 mg) once every 3 weeks.

Main Outcomes And Measures: The primary end point was 3-month PFS. Based on prior trials, a target rate of 70% or higher was selected as the promising progression-free rate at 3 months. Secondary outcomes included safety, tolerability, and overall survival.

Results: A total of 45 patients (median [range] age, 57.1 [31.7-77.2] years) were enrolled; 22 (49%) were treated in the second-line setting, and 23 (51%) were treated in the third-line setting or beyond. Of these, 22 (49%) received prior trastuzumab emtansine (T-DM1). At a median (range) follow-up of 27.6 (8.3-36.0) months, 3-month PFS was 73.3% (95% CI, 61.5%-87.5%). Overall, median PFS was 5.5 months (95% CI, 5.4-8.2 months). Treatment was well tolerated, with no occurrences of febrile neutropenia or symptomatic left ventricular systolic dysfunction.

Conclusions And Relevance: In this phase 2 trial, treatment with gemcitabine, trastuzumab, and pertuzumab after prior pertuzumab-based therapy for ERBB2-positive metastatic breast cancer was associated with a 3-month PFS rate of 73.3% and was well tolerated. Continuation of pertuzumab beyond progression was associated with apparent clinical benefit.

Trial Registration: ClinicalTrials.gov identifier: NCT02252887.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.16211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902832PMC
November 2019

Multisystem Toxicity in Cancer: Lessons from NASA's Countermeasures Program.

Cell 2019 11;179(5):1003-1009

Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.

Astronauts and cancer patients are subject to similar multisystem physiological toxicities. Over the past sixty years, NASA developed a state-of-the-art countermeasures program (CMP) to characterize and mitigate the physiological consequences of spaceflight. Here, we propose a NASA-modeled CMP to elucidate and abrogate physiological toxicities in patients with cancer.
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http://dx.doi.org/10.1016/j.cell.2019.10.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380275PMC
November 2019

Paradigms for Precision Medicine in Epichaperome Cancer Therapy.

Cancer Cell 2019 11 24;36(5):559-573.e7. Epub 2019 Oct 24.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Program in Molecular Pharmacology, Sloan Kettering Institute, New York, NY 10065, USA.

Alterations in protein-protein interaction networks are at the core of malignant transformation but have yet to be translated into appropriate diagnostic tools. We make use of the kinetic selectivity properties of an imaging probe to visualize and measure the epichaperome, a pathologic protein-protein interaction network. We are able to assay and image epichaperome networks in cancer and their engagement by inhibitor in patients' tumors at single-lesion resolution in real time, and demonstrate that quantitative evaluation at the level of individual tumors can be used to optimize dose and schedule selection. We thus provide preclinical and clinical evidence in the use of this theranostic platform for precision medicine targeting of the aberrant properties of protein networks.
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http://dx.doi.org/10.1016/j.ccell.2019.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996250PMC
November 2019

Impact of the 2018 American Society of Clinical Oncology/College of American Pathologists HER2 Guideline Updates on HER2 Assessment in Breast Cancer With Equivocal HER2 Immunohistochemistry Results With Focus on Cases With /CEP17 Ratio <2.0 and Average Copy Number ≥4.0 and <6.0.

Arch Pathol Lab Med 2020 05 24;144(5):597-601. Epub 2019 Oct 24.

From the Departments of Pathology (Drs Hoda, Brogi, Xu, Ross, and Wen and Ms Ventura), Medicine (Drs Dang, Robson, and Norton), and Surgery (Dr Morrow), Memorial Sloan Kettering Cancer Center, New York, New York.

Context.—: The American Society of Clinical Oncology/College of American Pathologists HER2 testing guideline in breast cancer was updated in 2018 to address issues on interpretation of uncommon results using dual-probe in situ hybridization according to the 2013 guideline.

Objective.—: To assess impact of the 2018 guideline on breast cancer with equivocal HER2 immunohistochemistry results.

Design.—: We retrospectively reviewed fluorescence in situ hybridization (FISH) data (/CEP17 ratio and average copy number per cell) of HER2 immunohistochemistry-equivocal (2+ or 1+ to 2+) breast cancers at our center between January 2014 and May 2018 and compared FISH results according to 2013 and 2018 guidelines.

Results.—: A total of 1666 FISH results from 1421 patients with equivocal HER2 immunohistochemistry were reviewed. Based on the 2013 guideline, FISH results were amplified in 346 cases (20.8%), equivocal in 242 (14.5%), and nonamplified in 1078 (64.7%). Using the 2018 guideline, 258 cases (16%) were reclassified, including 242 previously equivocal test results (15%) and 16 previously positive results (1%) reclassified as negative. The subset of 2013 HER2-equivocal and 2018 HER2-nonamplified cases with /CEP17 ratio lower than 2.0 and average copy number 4.0 or higher and lower than 6.0 showed higher incidence of micropapillary morphology compared with HER2-amplified cases. Despite most patients in this group not receiving HER2-targeted treatment, 96% had no evidence of disease at follow-up.

Conclusions.—: The 2018 guideline eliminated FISH-equivocal cases by reclassifying HER2-equivocal cases and cases with nonclassical amplification without HER2 overexpression as HER2 negative. As a consequence, we observed a considerable increase in FISH-negative cases and a slight decrease in FISH-positive cases.
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http://dx.doi.org/10.5858/arpa.2019-0307-OADOI Listing
May 2020

A Small-Molecule Pan-Id Antagonist Inhibits Pathologic Ocular Neovascularization.

Cell Rep 2019 10;29(1):62-75.e7

Structural Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Id helix-loop-helix (HLH) proteins (Id1-4) bind E protein bHLH transcription factors, preventing them from forming active transcription complexes that drive changes in cell states. Id proteins are primarily expressed during development to inhibit differentiation, but they become re-expressed in adult tissues in diseases of the vasculature and cancer. We show that the genetic loss of Id1/Id3 reduces ocular neovascularization in mouse models of wet age-related macular degeneration (AMD) and retinopathy of prematurity (ROP). An in silico screen identifies AGX51, a small-molecule Id antagonist. AGX51 inhibits the Id1-E47 interaction, leading to ubiquitin-mediated degradation of Ids, cell growth arrest, and reduced viability. AGX51 is well-tolerated in mice and phenocopies the genetic loss of Id expression in AMD and ROP models by inhibiting retinal neovascularization. Thus, AGX51 is a first-in-class compound that antagonizes an interaction formerly considered undruggable and that may have utility in the management of multiple diseases.
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http://dx.doi.org/10.1016/j.celrep.2019.08.073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896334PMC
October 2019

Evaluating Clonal Hematopoiesis in Tumor-Infiltrating Leukocytes in Breast Cancer and Secondary Hematologic Malignancies.

J Natl Cancer Inst 2020 01;112(1):107-110

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Chemotherapy and radiation therapy are the foundations of adjuvant therapy for early-stage breast cancer. As a complication of cytotoxic regimens, breast cancer patients are at risk for therapy-related myeloid neoplasms (t-MNs). These t-MNs are commonly refractory to antileukemic therapies and result in poor patient outcomes. We previously demonstrated that somatic mutations in leukemia-related genes are present in the tumor-infiltrating leukocytes (TILeuks) of a subset of early breast cancers. Here, we performed genomic analysis of microdissected breast cancer tumor cells and TILeuks from seven breast cancer patients who subsequently developed leukemia. In four patients, mutations present in the leukemia were detected in breast cancer TILeuks. This finding suggests that TILeuks in the primary breast cancer may harbor the ancestor of the future leukemogenic clone. Additional research is warranted to ascertain whether infiltrating mutant TILeuks could constitute a biomarker for the development of t-MN and to determine the functional consequences of mutant TILeuks.
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http://dx.doi.org/10.1093/jnci/djz157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690564PMC
January 2020

Homologous recombination DNA repair defects in associated breast cancers.

NPJ Breast Cancer 2019 8;5:23. Epub 2019 Aug 8.

20Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY USA.

Mono-allelic germline pathogenic variants in the () gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in -associated breast cancers (BCs), and whether -associated BCs display bi-allelic inactivation of and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic germline mutations were analyzed by whole-exome sequencing (WES,  = 16) or targeted capture massively parallel sequencing (410 cancer genes,  = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. -associated BCs were found to be heterogeneous at the genetic level, with (29%), (21%), (21%), and (17%) being the genes most frequently affected by somatic mutations. Bi-allelic inactivation was found in 16 of the 24 cases (67%), either through LOH ( = 11) or second somatic mutations ( = 5) of the wild-type allele. High LST scores were found in all 12 -associated BCs with bi-allelic inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic inactivation in -associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of -associated BCs without bi-allelic inactivation lack genomic features of HRD.
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http://dx.doi.org/10.1038/s41523-019-0115-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687719PMC
August 2019

The Landscape of Somatic Genetic Alterations in Breast Cancers from Germline Mutation Carriers.

JNCI Cancer Spectr 2019 Jun 27;3(2):pkz027. Epub 2019 Apr 27.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.

Pathogenic germline variants in checkpoint kinase 2 (), which plays pivotal roles in DNA damage response and cell cycle regulation, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic and genomic characteristics of 33 BCs from germline mutation carriers (16 high-risk variants and 17 low-risk p.Ile157Thr variants). -associated BCs from patients with high-risk germline variants were largely hormone receptor-positive (87%, 13/15), and 81% (13/16) exhibited loss of heterozygosity (LOH) of the wild-type allele. Conversely, -associated BCs from patients with the low-risk p.Ile157Thr variant displayed less-frequent loss of heterozygosity (5/17, 29%) and higher levels of CHEK2 protein expression than those with high-risk germline variants. -associated BCs lacked a dominant mutational signature 3, a genomics feature of homologous recombination DNA repair deficiency (HRD). Our findings indicate that -associated BCs are generally hormone receptor-positive and lack HRD-related mutational signatures, recapitulating the features of -associated BCs. Specific germline variants may have a distinct impact on tumor biology.
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http://dx.doi.org/10.1093/jncics/pkz027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649818PMC
June 2019

Randomized Trial of Standard Adjuvant Chemotherapy Regimens Versus Capecitabine in Older Women With Early Breast Cancer: 10-Year Update of the CALGB 49907 Trial.

J Clin Oncol 2019 09 24;37(26):2338-2348. Epub 2019 Jul 24.

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

Purpose: Older women with breast cancer remain under-represented in clinical trials. The Cancer and Leukemia Group B 49907 trial focused on women age 65 years and older. We previously reported the primary analysis after a median follow-up of 2.4 years. Standard adjuvant chemotherapy showed significant improvements in recurrence-free survival (RFS) and overall survival compared with capecitabine. We now update results at a median follow-up of 11.4 years.

Patients And Methods: Patients age 65 years or older with early breast cancer were randomly assigned to either standard adjuvant chemotherapy (physician's choice of either cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide and doxorubicin) or capecitabine. An adaptive Bayesian design was used to determine sample size and test noninferiority of capecitabine. The primary end point was RFS.

Results: The design stopped accrual with 633 patients at its first sample size assessment. RFS remains significantly longer for patients treated with standard chemotherapy. At 10 years, in patients treated with standard chemotherapy versus capecitabine, the RFS rates were 56% and 50%, respectively (hazard ratio [HR], 0.80; = .03); breast cancer-specific survival rates were 88% and 82%, respectively (HR, 0.62; = .03); and overall survival rates were 62% and 56%, respectively (HR, 0.84; = .16). With longer follow-up, standard chemotherapy remains superior to capecitabine among hormone receptor-negative patients (HR, 0.66; = .02), but not among hormone receptor-positive patients (HR, 0.89; = .43). Overall, 43.9% of patients have died (13.1% from breast cancer, 16.4% from causes other than breast cancer, and 14.1% from unknown causes). Second nonbreast cancers occurred in 14.1% of patients.

Conclusion: With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor-negative disease. Competing risks in this older population dilute overall survival benefits.
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http://dx.doi.org/10.1200/JCO.19.00647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900836PMC
September 2019
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