Abstract S1-08: High risk premenopausal luminal A breast cancer patients derive no benefit from adjuvant chemotherapy: Results from DBCG77B randomized trial
Bibliographic record
Abstract
Abstract Aim: To determine the predictive value of intrinsic subtypes for response to adjuvant chemotherapy using specimens from a randomized clinical trial. Background: Several studies have shown distinct clinical profiles of intrinsic breast cancer subtypes. The Luminal A subtype has a favorable prognosis with higher survival rate and lower recurrence in comparison to other breast cancer subtypes (luminal B, HER2 and basal-like). In addition, there is mounting evidence suggesting that intrinsic breast cancer subtypes differ in their responsiveness to adjuvant chemotherapy. Based on these data, we hypothesized that Luminal A breast cancer patients derive no benefit from adjuvant chemotherapy whereas other intrinsic subtypes do. Randomized breast cancer trials with a no chemotherapy arm and available tissues are rare, but represent the best materials to test for markers predicting chemotherapy benefit. The 77B clinical trial from the Danish Breast Cancer Cooperative Group (DBCG) offers a unique opportunity to test such hypotheses as it randomized 1146 premenopausal women, who had positive axillary lymph nodes or tumors >5 cm, to two chemotherapy arms (single-agent oral cyclophosphamide, or cyclophosphamide-methotrexate-fluorouracil (CMF)), and two no chemotherapy arms (levamisole, or no agent). All arms included radiotherapy but no endocrine therapy. Methods: We performed a full intrinsic subtype analysis on the 709 breast cancers available from DBCG77B on tissue microarrays using previously published, locked-down immunohistochemical (IHC) methods and intrinsic subtype definitions based on ER, PR, HER2, Ki67 and basal markers (Prat et al. JCO 2014). Biomarker scoring was performed in Vancouver by researchers with no access to the clinical database. A full statistical plan was prespecified in the Material Transfer Agreement and executed accordingly by the DBCG Statistical Office. 10-year invasive disease-free survival (IDFS) was the primary end point in DBCG77B; overall survival was also a predefined endpoint. The primary hypothesis was to assess interaction between benefit of chemotherapy (chemotherapy yes vs no) and subtype (Luminal A vs non-luminal A). This was analyzed in multivariate Cox proportional hazards models using the Wald test for interaction. Results: 709 patients had tissue available and completed IHC intrinsic subtyping. The effect of chemotherapy in this subset of patients was similar to the original trial: hazard ratio 0.56, favoring chemotherapy for 10-yr IDFS. IHC classified 165 as luminal A, 319 luminal B, 58 HER2E and 91 as triple negative (including 82 core basal). Patients with luminal A breast tumors did not benefit from chemotherapy (HR = 1.07, 95% CI = 0.53-2.14, p = 0.86), whereas patients with non-luminal A subtypes did (HR = 0.50, 95% CI = 0.38-0.66, p < 0.001). This heterogeneity was statistically significant (p=0.048). A similar trend for 25-yr OS was seen, although not significant. Conclusions: In a formal prospective-retrospective analysis of the DBCG 77B study randomizing women to adjuvant cyclophosphamide-based chemotherapy vs. no chemotherapy arms, patients with non-luminal A breast tumors (defined by IHC), but not luminal A tumors, benefit from adjuvant chemotherapy. Citation Format: Nielsen TO, Jensen [lrm] M-B, Gao D, Leung S, Burugu S, Liu S, Tykjær Jørgensen CL, Balslev E, Ejlertsen B. High risk premenopausal luminal A breast cancer patients derive no benefit from adjuvant chemotherapy: Results from DBCG77B randomized trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S1-08.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.004 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.003 | 0.003 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.010 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".