Abstract P1-06-02: Mismatch repair protein loss in breast cancer: Clinicopathological associations in a large British Columbia cohort
Notice bibliographique
Résumé
Abstract Background: Alterations to mismatched repair (MMR) pathways are a known cause of cancer (particularly colorectal and endometrial). Recently, the FDA approved pembrolizumab for use in MMR-deficient (MMRD) cancers of any type, and the diagnosis can be made by immunohistochemistry (IHC) or genomic methods. In breast cancer, mutational process analyses indicate MMRD occurs in about 2% of breast cancer (Cancer Res; 77; 4755-62, 2017) and recent functional studies have shown associations with resistance to endocrine therapy and sensitivity to CDK4/6 inhibitors (Cancer Discov; 7; 1168-83, 2017). To date, insufficient cases have been assembled to power meaningful associative or survival studies. Herein, the strong correlation between IHC-determined loss of MLH1, PMS2, MSH2 or MSH6 and genomic evidence allowed the assessment of MMRD on a large tissue microarray (TMA) series linked to detailed biomarkers and long-term outcome data. Methods: IHC markers MLH1, PMS2, MSH2 and MSH6 were optimized on the Ventana automated stainer for application to breast cancer TMAs. The patient cohort consists of females from British Columbia diagnosed with primary invasive breast carcinoma in 1986-1992, referred to the British Columbia Cancer Agency for treatment and follow-up. TMA blocks were sectioned and stained. Slides were scored by a pathologist and only nuclear positivity was evaluated positive. Loss of nuclear positivity for any one of the four tested marker defined MMRD. Clinicopathological associations were tested by Chi-square, and survival by Kaplan-Meier plot with log rank test. Result: 1635 cases were interpretable for all MMR markers. 31 cases (1.9%) met criteria for MMRD. 6 cases had paired losses (4 MLH1-PMS2 loss, 2 MSH2-MSH6 loss) and the remaining 25 cases had singular MMR loss (11 PMS2 loss, 10 MLH1 loss, 3 MSH6 loss, 1 MSH2 loss). Deficiency of the the MutL complex (MLH1/PMS2) predominated over the MutS complex (MSH2/MSH6). Among the demographic and pathological variables assessed – age, grade, tumour size, lymphovascular invasion, nodal and menstrual status – high grade is associated with MMRD (p=0.014). In terms of biomarker, MMRD is significantly associated with PR negativity (p=0.003) and PD-L1 expression (p=0.049), but not with ER, Her2, Ki67, or basal breast cancer IHC markers, nor does MMRD significantly correlate with any of the established major intrinsic subtypes of breast cancer. Tumor infiltrating lymphocyte (TIL) counts are higher in MMRD cases (p=0.009). Although statistically not significant (small numbers), Kaplan-Meier plots of survival analysis demonstrated a trend for MMR loss to be associated with decreased breast cancer disease-specific and overall survival. Conclusion: This large series assessed by IHC corroborates findings from smaller genomic series that MMRD is present in about 2% of breast cancers. MMRD tumors are more likely to be high grade, low PR and immunologically active (higher PD-L1 expression and TIL counts). MMR deficiency is present across all major molecular subtypes (luminal, HER2, basal). Given the efficacy of PD1/PDL1 targeting agents in MMR deficient tumors of other types, evidence for the activity of these agents in MMR deficient breast cancers should be actively sought. Citation Format: Cheng AS, Leung SC, Gao D, Anurag M, Nielsen T, Ellis MJ. Mismatch repair protein loss in breast cancer: Clinicopathological associations in a large British Columbia cohort [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-06-02.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,002 |
| Études des sciences et des technologies | 0,002 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».