Shc proteins predict outcome in treatment-naïve breast cancer patients: Do they also predict chemotherapy benefit?
Bibliographic record
Abstract
PR-9 Background: Better predictors of adjuvant chemotherapy benefit would improve clinical management of breast cancer patients. The Shc proteins, implicated in many pathways associated with aggressive cancers, can be measured in tumors by the OncoPlanTM immunohistochemical test, which reports on phosphorylated (PY)-Shc and an inhibitory form of the protein, p66 Shc. Previous studies have shown that OncoPlan is a strong predictor of disease outcome. Here we report on the ability of p66 Shc to identify those patients most likely to benefit from chemotherapy.Methods: Population-based primary invasive tumors from 2380 women from BC were arrayed in TMA format (no adjuvant therapy=1663; chemotherapy=717; relapsed=854; died of disease=501; 13yrs median follow-up). Shc staining was scored on a continuous 0-5 scale by two pathologists, blinded to patient data.Results: In 1663 patients not receiving chemotherapy prior to first relapse, p66 Shc as a continuous variable had strong ability to predict relapse-free survival (RFS) (hazard ratio (HR) = 0.64, 95% CI 0.44-0.93, P = 0.018) and disease-specific survival (DSS) (HR = 0.47, 95% CI 0.30-0.75, P = 0.001) in multivariate Cox models adjusted for nodal status, Her2 and ER status, age, tumor size and grade. In contrast, p66 Shc did not predict outcome in chemotherapy-treated patients (RFS HR = 1.06, 95% CI 0.67-1.65, P = 0.81; DSS HR = 1.00 95% CI 0.61-1.67, P = 0.98). This suggested that p66 Shc levels predicted tumor responsiveness to chemotherapy. To test this hypothesis, we examined chemotherapy9s protective ability in patients subgrouped by p66 Shc levels, using fully adjusted Cox model.The 60% of patients classified as high risk by OncoPlan (low p66 Shc levels) were strongly protected by chemotherapy (RFS HR = 0.53, 95% CI 0.38-0.75, P = 0.0001; DSS HR = 0.51, 95% CI 0.34-0.74, P = 0.001), whereas for the 40% of patients classified as low risk by OncoPlan, chemotherapy appeared to be a hazard (RFS HR = 1.2, 95% CI 0.79-1.8, P = 0.41; DSS HR = 1.9, 95% CI 1.15-3.02, P = 0.01). For the total population of patients, chemotherapy appeared to be protective (RFS HR = 0.74, 95% CI 0.59-94, P = 0.01; DSS HR = 0.81, 95% CI 0.62-1.05, P = 0.12).By drug, high risk patients were protected by AC (DSS HR = 0.31, 95% CI 0.017-0.57, P 1.5, P > 0.10).Conclusions: These data suggest that p66 Shc levels in primary tumors identify patients with a low risk profile who will derive little benefit from chemotherapy and also patients with a high risk profile, who will derive the most benefit.Supported in part by a Susan G. Komen Breast Cancer Foundation grant
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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 | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".