Oncotarget recently published “Predictive biomarkers for sacituzumab govitecan efficacy in Trop-2-expressing triple-negative breast cancer” which reported that the authors investigated whether Trop-2-expression and homologous recombination repair of SN-38-mediated double-strand DNA breaks play a role in the sensitivity of triple-negative breast cancer to SG.
Further, two Trop-2-transfectants of MDA-MB-231, C13, and C39, were treated in mice with SG to determine whether increasing Trop-2 expression improves SG efficacy.
SG mediated >2-fold increase in Rad51 in MDA-MB-231 but had no effect in SK-MES-1 or HCC1806, resulting in lower levels of dsDNA breaks in MDA-MB-231. SG and saline produced similar effects in parental MDA-MB-231 tumor-bearing mice.
However, in mice bearing higher Trop-2-expressing C13 and C39 tumors after Trop-2 transfection, SG provided a significant survival benefit, even compared to irinotecan.
These results suggest that SG could provide better clinical benefit than irinotecan in patients with HRR-proficient tumors expressing high levels of Trop-2, as well as to patients with HRR-deficient tumors expressing low/moderate levels of Trop-2.
SG could provide better clinical benefit than irinotecan in patients with HRR-proficient tumors expressing high levels of Trop-2, as well as to patients with HRR-deficient tumors expressing low/moderate levels of Trop-2
Dr. Thomas M. Cardillo from Immunomedics, Inc said, “In recent years, there has been an increased focus on personalized cancer therapy.“
SG demonstrated significant clinical benefit across a range of solid tumors, including metastatic TNBC, hormone-positive breast cancer, small-cell lung cancer, non-small-cell lung cancer, and metastatic urothelial carcinomas.
It remains unclear from these results whether the overriding mechanism for SG sensitivity in these various tumor models is Trop-2 expression or defective HRR pathways, or their combination.
Herein, the Oncotarget authors examined the HRR response in MDA-MB-231, being unresponsive to SG, including upregulation of Rad51 and levels of dsDNA breaks mediated by SG exposure, and compared it to that of SG-sensitive tumor lines to elucidate the role that this pathway plays in protecting cells from SG-mediated dsDNA breaks.
Additionally, MDA-MB-231 cells transfected to express higher levels of Trop-2 were assessed in vivo for SG antitumor effects in comparison to parental tumors with low Trop-2 expression.
However, this does not rule out SG being active in tumors with low Trop-2 expression and deficiencies in HRR.
The Cardillo Research Team concluded in their >Oncotarget Research Paper that, these data strongly support the hypothesis that as a biomarker, high surface Trop-2 expression on a patient’s tumor may be predictive of a positive clinical outcome for SG therapy.
Further, there are secondary biomarkers that may need to be considered for those patients with low/moderate Trop-2 expression or those with high Trop-2 expression that failed previous irinotecan therapy for reasons other than acquired resistance.
Moreover, while high expression of Trop-2 was found to be a primary biomarker for SG efficacy, it should not be a limiting factor, because other secondary biomarkers coupled with Trop-2 expression may likewise be predictive of clinical benefit.
For these reasons, future clinical trials will need to comprehensively examine potential biomarkers, in addition to Trop-2 expression, to generate a profile that will better identify those patients likely to benefit from SG therapy.
Full text – https:/
Correspondence to – Thomas M. Cardillo – [email protected]
Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.
To learn more about Oncotarget, please visit https:/
SoundCloud – https:/
Facebook – https:/
Twitter – https:/
LinkedIn – https:/
Pinterest – https:/
Reddit – https:/
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
Help us to become independent in PANDEMIC COVID-19. Contribute to diligent Authors.