IMAGE: Increased Trop-2 expression in MDA-MB-231 tumors overcomes resistance to SG but not irinotecan. NCr athymic nu/nu mice were injected s.c. with either MDA-MB-231 parental cells (parental), MDA-MB-231 clone 13 (C13)... view more
Credit: Correspondence to - Thomas M. Cardillo - tcardillo@immunomedics.com
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.
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Correspondence to - Thomas M. Cardillo - tcardillo@immunomedics.com
Keywords - sacituzumab govitecan, Trop-2, biomarker, RAD51, triple-negative breast cancer
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