Biomarker Profiles in Trastuzumab (T) Refractory HER2+ Inflammatory Breast Cancer (IBC) That Predict for Survival Benefit from Lapatinib (L) Monotherapy.
Bibliographic record
Abstract
Abstract Background:L is a reversible, oral small molecule inhibitor of EGFR and HER2. L demonstrated an objective response rate (ORR) of 39%, a median progression free survival (PFS) of 14.6 weeks and a median overall survival (OS) of 11.2 months in a monotherapy Phase II study of 126 patients (pts) with HER2+ IBC (Kaufman et al. Lancet Oncology, 2009). In the initial cohort of pts we reported an association between response to L and coexpression of pHER3 with pHER2 (Johnston et al, J Clin Oncol, 2008 26; 1066-72). In this study we measured a series of biomarkers in tumor biopsies obtained before the start of treatment and evaluated their association with parameters of clinical benefit to L in relation to prior T.Methods:Core needle biopsies were obtained pretreatment, preserved in phosphatase inhibitor buffer, fixed in formalin and embedded in paraffin. Baseline expression of total and activated EGFR, HER2, HER3 and downstream markers, as well as markers specific to IBC were determined by standard IHC techniques yielding manual and optical density (OD) scores. 94/126 pts received prior T treatment before beginning L treatment, while 32 patients were T naive. The baseline expression of each marker was tested for association with ORR, PFS and OS using proportional hazards and logistic regression models.Results:OD IHC data indicated pEGFR and TGFα had statistically significant association with OS and PFS in pts treated with prior T. pHER3 also appeared to be associated with OS, although was not statistically significant. Higher levels of these biomarkers were associated with decreased hazard of progression or death. Correlation between OD and manual scores (0,1,2,3) were highly significant for these markers (R=0.80, p<0.0001). These markers were not significant when tested against ORR.[table 1] OSPFSORRpEGFR (N=56)P<0.0001, HR=0.45P=0.0192,HR=0.66P=0.2721,OR=1.44pHER3 (N=71)P=0.0634, HR=0.74P=0.1256, HR=0.78P=0.0920, OR=1.72TGFα (N=57)P=0.0019, HR=0.95P=0.0386, HR=0.97P=0.8211, OR=1.05HR; Hazard Ratio, OR; Odds Ratio (odds of response)When we evaluated the same panel of biomarkers in T naïve pts, higher levels of HER2 expression were significantly associated with improved ORR (p=0.0186) and a trend towards significance with OS (p=0.0674). Furthermore, higher levels of pAKT (p=0.0068) and pERK (p=0.006) were significantly associated with improved OS.Discussion:L monotherapy is clinically active in the treatment of relapsed/refractory HER2+ IBC. Higher levels of pEGFR and TGFa by IHC are significantly associated with improved OS and PFS but not ORR in patients with prior T therapy. In contrast, T naïve pts, higher levels of pAKT and pERK showed a significant association with OS. Thus, different biomarker profiles may predict benefit in T naïve vs T-refractory pts benefiting from L monotherapy in HER2+ IBC. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 706.
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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 | 0.000 | 0.001 |
| 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 | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".