Multigene assays for molecular subtypes and biomarkers can aid management of early invasive breast cancer. Using RNA-sequencing we aimed to develop single-sample predictor (SSP) models for clinical markers, subtypes, and risk of recurrence (ROR). A cohort of 7743 patients was divided into training and test set. We trained SSPs for subtypes and ROR assigned by nearest-centroid (NC) methods and SSPs for biomarkers from histopathology. Classifications were compared with Prosigna in two external cohorts (ABiM, n = 100 and OSLO2-EMIT0, n = 103). Prognostic value was assessed using distant recurrence-free interval. Agreement between SSP and NC for PAM50 (five subtypes) was high (85%, Kappa = 0.78) for Subtype (four subtypes) very high (90%, Kappa = 0.84) and for ROR risk category high (84%, Kappa = 0.75, weighted Kappa = 0.90). Prognostic value was assessed as equivalent and clinically relevant. Agreement with histopathology was very high or high for receptor status, while moderate for Ki67 status and poor for Nottingham histological grade. SSP and Prosigna concordance was high for subtype (OSLO-EMIT0 83%, Kappa = 0.73 and ABiM 80%, Kappa = 0.72) and moderate and high for ROR risk category (68 and 84%, Kappa = 0.50 and 0.70, weighted Kappa = 0.70 and 0.78). Pooled concordance for emulated treatment recommendation dichotomized for chemotherapy was high (85%, Kappa = 0.66). Retrospective evaluation suggested that SSP application could change chemotherapy recommendations for up to 17% of postmenopausal ER+/HER2-/N0 patients with balanced escalation and de-escalation. Results suggest that NC and SSP models are interchangeable on a group-level and nearly so on a patient level and that SSP models can be derived to closely match clinical tests.

Background. There is still no complete agreement about the proper treatment of differentiated thyroid cancer (DTC). Material and methods. All patients (nϭ130) with DTC in a defi ned population, treated with surgery between 1985 and 1999, were carefully followed up (median 13.1 years). Fifty three were operated with subtotal and 77 with total thyroidectomy. Twenty seven percent of the patients in the subtotal group and 56% of those in the total thyroidectomy group had postoperative radioiodine ablation. Thirty nine patients had papillary cancers incidentally detected during surgery for benign disorders (median size 7 (1-30) mm). Living patients answered the Swedish version of the SF-36 health survey. Results. Eleven of 106 patients considered tumour-free after primary surgery developed recurrences during follow-up. Fifteen patients (12%) died from DTC but only one within stage I-II (1.2%). No patient below 50 years of age at diagnosis died from DTC. Only three of 29 patients with isolated loco-regional spreading of their disease at the time of diagnosis have died from thyroid cancer. There was no statistically signifi cant difference in the 10 year cancer-specifi c survival rate between those operated with subtotal or total thyroidectomy -irrespective of stage. Survival rate was signifi cantly better for papillary than for follicular cancer. Mental and physical quality of life among patients treated for DTC were similar to the healthy Swedish population. Conclusions. Patients with DTC stage I-II (according to TNM) or low-risk (according to AMES) have an excellent prognosis. Treatment as well as follow-up should not be exaggerated.

BackgroundMultigene expression assays for molecular subtypes and biomarkers can aid clinical management of early breast cancer. Based on RNA-sequencing we aimed to develop robust single-sample predictor (SSP) models for conventional clinical markers as well as molecular intrinsic subtype and risk of recurrence (ROR) that provide clinically relevant prognostic stratification.MethodsA uniformly accrued breast cancer cohort of 7743 patients with RNA-sequencing data from fresh tissue was divided into a training set (n=5250) and a reserved test set (n=2412). We trained SSPs for PAM50 molecular subtypes and ROR assigned by nearest-centroid (NC) methods and SSPs for conventional clinical markers from histopathology data. Additionally, SSP classifications were compared with Prosigna in two external clinical series (ABiM, n=100 and OSLO2-EMIT0, n=103 cases).ResultsIn the test set, agreement between SSP and NC classifications for PAM50 (five subtypes) and Subtype (four subtypes) was high (85%, Kappa=0.78) and very high (90%, Kappa=0.84) respectively. Accuracy for ROR risk category was high (84%, Kappa=0.75, weighted Kappa=0.90). The prognostic value for SSP and NC classification was assessed as equivalent and added clinically relevant prognostic information. Agreement for SSP and histopathology was very high or high for receptor status, while moderate and poor for Ki67 status and Nottingham histological grade (NHG), respectively. SSP concordance with Prosigna was high for subtype (OSLO=83% and ABiM=80%, Kappa=0.73 and 0.72, respectively) and moderate and high for ROR risk category (68% and 84%, Kappa=0.50 and 0.70, weighted Kappa=0.70 and 0.78). In pooled analysis, concordance between SSP and Prosigna for emulated treatment recommendation dichotomized for chemotherapy (yes vs. no) was high (85%, Kappa=0.66). In postmenopausal ER+/ HER2-/N0 patients SSP application suggested changed treatment recommendations for up to 17% of patients, with nearly balanced escalation and de-escalation of therapy.ConclusionsRobust SSP models, mimicking histopathological variables, PAM50, and ROR classifications can be derived from RNA-sequencing that closely matches clinical tests. Agreement and outcome analyses suggest that NC and SSP models are interchangeable on a group-level and nearly so on a patient level. Retrospective evaluation in ER+/HER2-/ N0 early breast cancer suggested that molecular testing could lead to a changed therapy recommendation for about one-fifth of patients.