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Molecular subtype and tumor characteristics of breast cancer metastases as assessed by gene expression significantly influence patient post-relapse survival.

ABSTRACT: BACKGROUND:We and others have recently shown that tumor characteristics are altered throughout tumor progression. These findings emphasize the need for re-examination of tumor characteristics at relapse and have led to recommendations from ESMO and the Swedish Breast Cancer group. Here, we aim to determine whether tumor characteristics and molecular subtypes in breast cancer metastases confer clinically relevant prognostic information for patients. PATIENTS AND METHODS:The translational aspect of the Swedish multicenter randomized trial called TEX included 111 patients with at least one biopsy from a morphologically confirmed locoregional or distant breast cancer metastasis diagnosed from December 2002 until June 2007. All patients had detailed clinical information, complete follow-up, and metastasis gene expression information (Affymetrix array GPL10379). We assessed the previously published gene expression modules describing biological processes [proliferation, apoptosis, human epidermal receptor 2 (HER2) and estrogen (ER) signaling, tumor invasion, immune response, and angiogenesis] and pathways (Ras, MAPK, PTEN, AKT-MTOR, PI3KCA, IGF1, Src, Myc, E2F3, and ?-catenin) and the intrinsic subtypes (PAM50). Furthermore, by contrasting genes expressed in the metastases in relation to survival, we derived a poor metastasis survival signature. RESULTS:A significant reduction in post-relapse breast cancer-specific survival was associated with low-ER receptor signaling and apoptosis gene module scores, and high AKT-MTOR, Ras, and ?-catenin module scores. Similarly, intrinsic subtyping of the metastases provided statistically significant post-relapse survival information with the worst survival outcome in the basal-like [hazard ratio (HR) 3.7; 95% confidence interval (CI) 1.3-10.9] and HER2-enriched (HR 4.4; 95% CI 1.5-12.8) subtypes compared with the luminal A subtype. Overall, 25% of the metastases were basal-like, 32% HER2-enriched, 10% luminal A, 28% luminal B, and 5% normal-like. CONCLUSIONS:We show that tumor characteristics and molecular subtypes of breast cancer metastases significantly influence post-relapse patient survival, emphasizing that molecular investigations at relapse provide prognostic and clinically relevant information. CLINICALTRIALS.GOV: This is the translational part of the Swedish multicenter and randomized trial TEX, clinicaltrials.gov identifier nct01433614 (http://www.clinicaltrials.gov/ct2/show/nct01433614).

SUBMITTER: Tobin NP

PROVIDER: S-EPMC4269343 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Molecular subtype and tumor characteristics of breast cancer metastases as assessed by gene expression significantly influence patient post-relapse survival.

Tobin N P NP Harrell J C JC Lövrot J J Egyhazi Brage S S Frostvik Stolt M M Carlsson L L Einbeigi Z Z Linderholm B B Loman N N Malmberg M M Walz T T Fernö M M Perou C M CM Bergh J J Hatschek T T Lindström L S LS

Annals of oncology : official journal of the European Society for Medical Oncology 20141031 1

<h4>Background</h4>We and others have recently shown that tumor characteristics are altered throughout tumor progression. These findings emphasize the need for re-examination of tumor characteristics at relapse and have led to recommendations from ESMO and the Swedish Breast Cancer group. Here, we aim to determine whether tumor characteristics and molecular subtypes in breast cancer metastases confer clinically relevant prognostic information for patients.<h4>Patients and methods</h4>The transla ...[more]

PMID: 25361981

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Project description:Background and objectivesOutcomes-based research rarely focuses on patients with ESRD caused by GN. The hypotheses were that the GN subtype would clinically discriminate patient groups and independently associate with survival after ESRD therapy initiation.Design, setting, participants, & measurementsData were extracted from the US Renal Data System for adult patients with incident (1996-2011) ESRD attributed to six GN subtypes: FSGS, IgA nephropathy (IgAN), membranous nephropathy, membranoproliferative glomeruonephritis, lupus nephritis (LN), and vasculitis. ESRD attributed to diabetes and autosomal dominant polycystic kidney disease served as non-GN comparators. Unadjusted and adjusted mortality hazard ratios (aHRs) with 95% confidence intervals (95% CIs) were estimated using Cox regression (reference, IgAN). Models sequentially adjusted for sociodemographic (model 2), comorbidity/laboratory (model 3), and ESRD treatment modality (model 4) variables.ResultsAmong 84,301 patients with ESRD attributed to GN, the median age ranged from 39 (LN) to 66 (vasculitis) years, male sex ranged from 18% (LN) to 68% (IgAN), and black race ranged from 7% (IgAN) to 49% (LN). Patients with IgAN had the fewest comorbidities and lowest use of hemodialysis (70.1%). After a median follow-up of 2.5 (interquartile range, 1.0-4.9) years, crude mortality was lowest in IgAN (3.7 deaths/100 person years). Compared to IgAN, adjusted mortality was highest in LN (model 4 aHR=1.75; 95% CI, 1.68 to 1.83) and in diabetes (aHR=1.73; 95% CI, 1.67 to 1.79), and was also higher in all other GN subtypes (membranous nephropathy: aHR=1.23; 95% CI, 1.17 to 1.29; FSGS: aHR=1.37; 95% CI, 1.32 to 1.42; membranoproliferative GN: aHR=1.38; 95% CI, 1.31 to 1.45; vasculitis: aHR=1.51; 95% CI, 1.45 to 1.58) and in autosomal dominant polycystic kidney disease (aHR=1.22; 95% CI, 1.18 to 1.27).ConclusionsThis study exposes substantial heterogeneity across GN subtypes at ESRD therapy initiation and identifies independent associations between GN subtype and post-ESRD mortality. These survival discrepancies warrant further study, and the utility of current research practice to group GN subtypes together when evaluating ESRD outcomes should be questioned.

Project description:BackgroundMost endocrinologists encounter patients who are dissatisfied with their current hypothyroidism therapy and request combination therapy with either liothyronine (LT3) or thyroid extract.MethodsA survey of American Thyroid Association members was conducted in 2017. Respondents were presented with 13 scenarios describing patients with hypothyroidism and were asked to choose among six therapeutic options. The index patient was satisfied taking levothyroxine (LT4) therapy. Twelve variations introduced parameters that potentially provide reasons for considering combination therapy (presence of symptoms, low serum triiodothyronine concentration, documentation of deiodinase polymorphisms). Therapeutic options included (i) continuing LT4, (ii) increasing LT4, (iii) adding LT3 to a reduced LT4 dose, (iv) adding LT3 to the current LT4 dose, (v) replacing LT4 with thyroid extract, and (vi) replacing LT4 with LT3. Repeated-measures logistic regression analysis was performed to examine both the prescribing of LT4 (options i and ii) versus all other therapies and the choice of continuing LT4 (option i) versus either increasing LT4 (option ii), adding LT3 (options iii and iv), or replacing LT4 with thyroid extract or LT3 (options v and vi).ResultsOf the 389 survey respondents, 363 physicians prescribed therapy for hypothyroidism. For the index patient, 98% of physicians continued current LT4 therapy. However, as the patient scenario incorporated other patient characteristics, physicians opted to increase LT4 dose or prescribe other therapies. The tendency to prescribe alternative therapies was powerfully increased by patient symptoms (odds ratio = 25.6 [confidence interval 9-73], p < 0.0001). Older age and the presence of a comorbidity reduced the likelihood that an alternative therapy was prescribed (p = 0.0002 and <0.0001, respectively). All other characteristics, except athyreotic status, patient sex, and body mass index, significantly increased the likelihood that alternative therapies would be prescribed in multivariate analyses (p < 0.0001).ConclusionsEven with the acknowledged limitations of survey methodology, this analysis appears to show a marked increase in the willingness of physicians to prescribe combination therapy in specific circumstances. If current prescribing patterns do incorporate the use of therapies other than LT4, there is a critical need for more research into the benefits and risks of these therapies.

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Molecular subtype and tumor characteristics of breast cancer metastases as assessed by gene expression significantly influence patient post-relapse survival.

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Molecular subtype and tumor characteristics of breast cancer metastases as assessed by gene expression significantly influence patient post-relapse survival.

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