TEST:

OncoSignal™

The findings from this window-of-opportunity study highlight the need for larger cohort analyses to validate these initial observations and further investigate the clinical impact of these racial differences in breast cancer biology and treatment response.

Conclusion The OncoSIGNal test provides a robust and quantitative method to characterize low ER and HER2 1+ IHC breast cancer samples. In addition to detecting and quantifying the relevant cell signaling pathways, the mRNA markers can be used to elucidate the results of low ER and HER2 1+ IHC staining, enabling the identification of patients who may benefit from targeted therapy.

We show that we are able to quantitatively measure the capacity of drugs to inhibit activity of the PI3K pathway and correlate its activity directly to biological response. Pathway activity measurement is more predictive for the cell growth inhibition than measurement of KI-67 mRNA expression. Clinical studies are in progress to evaluate the value of measuring pathway activity as predictive biomarker for response to PI3K, AKT or mTOR inhibitors in patients.

Higher Ki67 gene expression was associated with recurrences (p=0.042) Increased PI3K pathway activity, independent of PIK3CA mutations, may play a role in the recurrence of early-stage breast cancer with low and intermediate 21-gene RS. Pathway analysis can help to identify high-risk patients in this setting.

"The InnoSIGN team...during the San Antonio Breast Cancer Symposium (SABCS), from Wednesday December 6 to Friday 8 December, 2023...An abstract by NYU-Langone and two abstracts by InnoSIGN have been selected for poster presentation in the scientific program."

"The InnoSIGN team is excited to meet you at this year’s AMP Annual Meeting & Expo in Salt Lake City, US, from Tuesday November 14 to Saturday 18 November, 2023...Applications of OncoSIGNal pathway profiling platform in breast cancer and bladder cancer will be presented at the InnoSIGN corporate workshop..."

"...InnoSIGN Inc...announces the offering of its OncoSIGNal pathway profiling platform for clinical use as a Laboratory Developed Test (LDT) through InnoSIGN’s high-complexity CLIA laboratory...OncoSIGNal is the first platform identifying the tumor-driving cell signaling pathways in tumor tissue."

Based on the two week Ki67-IHC, patients were randomized (Ki67 ≥1%) to receive either Letrozole + Ribociclib or standard chemotherapy until surgery, or continued (Ki67 < 1%) Letrozole mono therapy. Positive ER staining does not always relate to a high ER pathway activity, possibly explaining that not all patients respond equally well to ER inhibition therapy. Activation of hormonal pathways (ER, but also AR) appear to be predictive for early (2 weeks) response towards Letrozole as assessed by Ki67 staining. Involvement of non-hormonal pathways is associated with less effective response towards Letrozole alone.

Compared to ER positive primary tumors we observed in metastatic ER positive tumors less frequent activation of the ER and more frequent activation of the PI3K pathway, suggesting that the latter pathway is associated with a more aggressive tumor phenotype. The triple negative subtype is characterized predominantly by activation of the PI3K, MAPK, AR and/or HH pathways, which may create new options for personalized targeted therapy of this subtype. OncoSIGNal can be used to determine the tumor driving signaling pathways in breast cancer patients, guiding selection of personalized targeted therapies.

Our observation suggests that distinct biomarkers may be differently suited to predict response to PI3K inhibitors in TNBC. This may include expanding the number of patients for which PI3K/Akt pathway inhibition might be a therapeutic option, as well as explaining the lack of response in PI3K mutated tumors.

Our data suggest that RNA expression-based pathway activity and DNA mutational and methylation analyses provide complementary information about the molecular landscape of TNBC. PI3K mutations are early drivers and lead to distinct DNA methylation signatures; however, they are not associated with increased PI3K pathway activity by RNA expression. In contrast, TNBC without PI3K mutations may show activation of the PI3K pathway in the absence of PI3K/Akt mutations.

The OncoSignal seven-pathway LDT test (ER, AR, PI3K, MAPK, Hedgehog, TGF- β, and Notch) is a robust and reliable method to quantify signaling pathway activity. By comparing with reference ranges from non-malignant tissues, the test can be used to identify tumor driving pathways. This opens new options for selection of targeted therapies for hard-to-treat breast cancer patients.