Metformin to treat breast cancer: an application of the prevalent new-user design for observational studies with no active comparator
Notice bibliographique
Résumé
OBJECTIVES: Numerous observational studies have reported significant reductions in cancer outcomes, including breast cancer in women, with metformin use. However, most studies were affected by immortal time bias. We assessed whether metformin use in women diagnosed with breast cancer is associated with lower breast cancer-related and all-cause mortality and illustrate the impact of immortal time bias on the results. STUDY DESIGN AND SETTING: The Clinical Practice Research Datalink was used to identify a base cohort of all women with a new diagnosis of breast cancer and with type 2 diabetes, at least 18 years of age, between 1998 and 2020. We employed the prevalent new-user design to match metformin initiators 1:1 with nonusers on a prior diabetes diagnosis and time-conditional propensity scores. We also used the naïve approach that introduces immortal time when classifying metformin users. Hazard ratios (HRs) and 95% CIs of all-cause and breast cancer-related death were estimated. RESULTS: The base cohort included 13,314 women newly diagnosed with breast cancer and with type 2 diabetes, before (n = 4761) and after (n = 8553) their breast cancer diagnosis, of which 5047 initiated metformin during follow-up. The prevalent new-user design included 4923 metformin initiators and 4923 matched nonusers. The HRs of breast cancer-related and all-cause mortality were 1.12 (95% CI: 0.98-1.28) and 0.96 (95% CI: 0.89-1.05), respectively. The naïve approach, among women with diabetes at cohort entry, which included 1354 metformin users and 3407 metformin nonusers, resulted in adjusted HRs of 0.45 (95% CI: 0.40-0.50) and 0.58 (95% CI: 0.54-0.62) for breast cancer and all-cause mortality. CONCLUSION: In this study, the use of metformin was not associated with a reduced risk of breast cancer-related and all-cause mortality. Using the flawed approach not accounting for immortal time bias, we confirmed the implausible beneficial effects of metformin on breast cancer and all-cause mortality reported in previous studies. PLAIN LANGUAGE SUMMARY: Observational studies have reported that the antidiabetic drug metformin can increase the survival of women with breast cancer. However, these studies were shown to have a flaw in their analysis, called "immoral time bias", known to exaggerate the benefit of a drug. We used a cohort of over 13,000 women with breast cancer to investigate the effectiveness of metformin on reducing mortality in women with breast cancer, using both the flawed and a correct time-matched approach. Using the flawed approach, we confirmed the implausible beneficial effects of metformin on breast cancer-related and on all-cause mortality reported in previous studies. Using the correct time-matched approach, we found that the use of metformin was not associated with these beneficial effects, confirming the impact of the flaw.
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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 | 0,170 | 0,163 |
| Méta-épidémiologie (sens strict) | 0,003 | 0,002 |
| Méta-épidémiologie (sens large) | 0,007 | 0,012 |
| Bibliométrie | 0,003 | 0,002 |
| Études des sciences et des technologies | 0,003 | 0,003 |
| Communication savante | 0,003 | 0,003 |
| Science ouverte | 0,005 | 0,004 |
| Intégrité de la recherche | 0,006 | 0,004 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,006 | 0,000 |
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 ».