Ghanshyam Yadav, MD, resident physician, Baylor College of Medicine, discusses the differences between type 1 and type 2 uterine cancer. 

Type 1 uterine cancer is associated with a favorable prognosis, says Yadav. Conversely, patients with type 2 cancer have a poor prognosis. Though rare, 50% to 70% of patients who have type 2 disease have extrauterine spread compared with 4% of patients with type 1 disease. 

Type 2 cancer accounts for 40% of uterine cancer deaths despite the rarity of the disease, says Yadav.

Uterine cancer also tends to be resistant to chemotherapy. Therefore, there is a lot of work being done to develop novel targeted therapies, says Yadav. Targeting 

 alterations could be a potential strategy as the target is expressed in a proportion of patients with uterine cancer, Yadav concludes. 

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Ghanshyam Yadav, MD, discusses the differences between type 1 and type 2 uterine cancer. 
 

Dr. Yadav on Differences in Type 1 and Type 2 Uterine Cancer

Ghanshyam Yadav, MD, resident physician, Baylor College of Medicine, discusses research surrounding the combination of the PARP inhibitor olaparib (Lynparza) and the pan-HER TKI neratinib (Nerlynx), which proved to be highly synergistic and had significant activity in preclinical models of HER2-positive uterine serous carcinoma.

Yadav and his team began to hypothesize about the combination after reading a paper on breast cancer that determined PI3K inhibition also changes the 

mutation. Previously, these 2 pathways were thought to look entirely different. Neratinib inhibits the HER/ERBB2 pathway and olaparib inhibits the DNA damage repair pathway; however, Yadav and his team started to hypothesize whether there was a connection between the two pathways, which led to this investigation.

In the study, it was found that once the cell is treated with a PARP inhibitor, HER2 expression increases on the cell surface, providing more targets for neratinib, Yadav explains. Then, when these cells were treated with neratinib, there was an increase in PARP expression, suggesting more DNA damage, says Yadav. When PARP is taken away, more DNA is damaged, which is why the combination is synergistic. When the combination was tested on mice, there was a significantly longer survival and statistically significant differences in tumor growth in one of the cell lines, Yadav concludes.

Ghanshyam Yadav, MD, discusses research surrounding the combination of the PARP inhibitor olaparib and the pan-HER TKI neratinib, which proved to be highly synergistic and had significant activity in preclinical models of HER2-positive uterine serous carcinoma.

Dr. Yadav on the Olaparib/Neratinib Combo in HER2+ Uterine Serous Carcinoma

Ghanshyam Yadav, MD, first-year resident, Baylor College of Medicine, discusses the synergy of a novel combination in the treatment of patients with HER2-overexpressing uterine serous carcinoma.

Across tumor types, there has been significant interest in targeting cell surface receptors, which led researchers to explore the combination of the PARP inhibitor olaparib (Lynparza) and the TKI neratinib (Nerlynx) in this patient population. Recent data in the breast cancer realm suggested that inhibiting 

, a downstream molecule in that pathway, also had activity in 

. Researchers were hopeful that a similar, synergistic effect would occur with the combination of olaparib and neratinib in HER2-overexpressing uterine serous carcinoma.

Initially, treatment with a PARP inhibitor led to increased HER2 expression on the cell surface, so study investigators were hopeful that adding a HER2-targeted agent would be useful, Yadav says. Subsequently, investigators realized neratinib also increased PAR, the active part of PARP, proving that the agents act synergistically. Notably, Yadav adds, this benefit appears to be limited to cases of HER2 overexpression—the combination was tried in cell lines with low HER2 expression, and they did not find the same results.

Dr. Yadav on the Synergy of a Novel Combination in Uterine Serous Carcinoma

Ghanshyam Yadav, MD, first-year resident, Baylor College of Medicine, discusses the combination of olaparib (Lynparza) and neratinib (Nerlyx) in patients with HER2-overexpressing uterine serous carcinoma.

Uterine serous carcinoma is highly resistant to chemotherapy, says Yadav. A lot of research is examining cell-surface targeting. Much of the research Yadav has done has involved using TKIs in uterine serous cancers. Yadav and colleagues hypothesized that combining a TKI, which targets the ERBB2 pathway, with olaparib, which targets the DNA damage repair pathway, could have synergistic activity in this patient population.

Treatment with a PARP inhibitor was found to increase the HER2 expression on the surface of the cells, providing more of a target for neratinib, explains Yadav. Moreover, cells that had been treated with neratinib increased the active component of PARP. In the mouse study, the combination proved to be synergistic with significantly longer survival benefit and a statistically significant difference in tumor growth in one of the cell lines, says Yadav.

Ghanshyam Yadav, MD

Articles

Dr. Yadav on Differences in Type 1 and Type 2 Uterine Cancer

Dr. Yadav on the Olaparib/Neratinib Combo in HER2+ Uterine Serous Carcinoma

Dr. Yadav on the Synergy of a Novel Combination in Uterine Serous Carcinoma

Dr. Yadav on Olaparib/Neratinib in HER2-Overexpressing Uterine Serous Carcinoma