Publications Update # 84

Last updated on Dec 14, 2024

Non-Medical Topic of the Week

This is a fantastic performance, and it's so fitting that it was Yo-Yo Ma performing at the re-opening of the Notre Dame in Paris.

Yo-Yo Ma is the best cellist in the world. If you watch the video, what fascinates me is his state of flow, which you can discern from his facial expression. Yo-Yo has been doing this since he was seven. When doing your 1000th hysterectomy, how do you sustain a level of interest that puts you in a flow state? It turns out that I was not the only person grappling with this question. Adam Grant had the same question and interviewed Yo-Yo Ma last year.

And in case you are obsessed with the Notre-Dame, read this amazing article from NYT discussing its rebirth

Ovarian Cancer

Real World Analysis of FR-alpha

This study answers a lot of questions I have been asking every time we do folate receptor testing in patients with platinum-resistant ovarian cancer. Some key points include:

FRα was positive in 36.3% of cases, strongly associated with high-grade serous histology and higher positivity in primary tumor sites (44.4% vs. 32.5% in metastatic sites).
Testing showed discordant results in 1/3rd of the cases, highlighting tumor heterogeneity and the need for standardized protocols.
The timing of specimen collection didn’t impact FRα positivity, supporting its value across disease progression. Perhaps testing the debulking specimens early on might make sense.

Endometrial Cancer

Why do we add CDK-4/6 inhibitors to estrogen receptor blockers (fulvestrant) or aromatase inhibitors? Here is a video explaining the rationale:

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This video is a part of GYOEDU Board Review Series.

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Did you know many fellows subscribe to the GYOEDU Board Review Series to enhance their learning? Learn more about it here: GYOEDU BOARD REVIEW Video Series

Two studies recently published explore the role of CDK4/6 inhibitors in endometrial cancer:

MSK Fulvestrant-Abemaciclib Phase 2 Study

This is a single-arm study with no comparator arm. Two important things to note from this article:

The majority of the responses were seen in patients with NSMP tumor profiles.
No responses were observed in copy number–high/ TP53abnormal endometrial cancers.
The median progression-free survival was 9.0 months.
The objective response rate was 44%, with a median duration of response of 15.6 months.

Study Summary

Fulvestrant + Abemaciclib

The combination of abemaciclib and fulvestrant shows promising efficacy and manageable toxicity in HR-positive advanced or recurrent endometrial cancer, especially in CN-L/NSMP tumors

GYOEDU PlusShitanshu Uppal

PALEO Trial

In this study, the investigators compared letrozole with Palbociclib to a combination of Letrozole and placebo. The study shows that the addition of palbociclib significantly improves progression-free survival as well as disease control rate. Here is the study summary.

Study Summary

PALEO Trial: Palbociclib + Letrozole in Endometrial Cancer

The combination of palbociclib and letrozole significantly improved PFS compared to placebo with letrozole. However, it was associated with higher hematologic toxicities, particularly neutropenia.

GYOEDU PlusShitanshu Uppal

Comparison: PALEO Trial vs. MSK Fulvestrant-Abemaciclib Phase 2Study

Although the MSK phase II study is very small compared to the PALEO study and has no comparator arm, it shows a higher response rate (see the table below). The key difference between the two studies is the estrogen blockade strategy. Fulvestrant is an estrogen receptor alpha blocker compared to the aromatase inhibition of Letrozole.

Attribute	PALEO Trial	Fulvestrant-Abemaciclib Study
Disease Site	Advanced/recurrent endometrial cancer (ER-positive)	Advanced/recurrent endometrial cancer (HR-positive)
Study Design	Double-blind, placebo-controlled, randomized Phase II	Single-arm Phase II
Primary Endpoint	Progression-free survival (PFS)	Objective response rate (ORR)
Number of Patients	73 treated (36 in palbociclib–letrozole, 37 in placebo–letrozole)	27 enrolled, 25 evaluable
Experimental Arm	Palbociclib (125 mg, days 1–21, 28-day cycle) + Letrozole (2.5 mg daily)	Fulvestrant (500 mg IM, monthly with 2-week loading dose) + Abemaciclib (150 mg orally, twice daily)
Control Arm	Placebo (days 1–21, 28-day cycle) + Letrozole (2.5 mg daily)	None (single-arm study)
Median PFS	8.3 months (95% CI, 4.6–11.2)	NA
Median ORR	9% (palbociclib + letrozole) vs 16% (placebo + letrozole)	44% (11/25 patients)
Disease Control Rate	64% (palbociclib + letrozole) vs 38% (placebo + letrozole)	NA
Top Adverse Event	Neutropenia: 67% (Grade ≥3: 44%)	Neutropenia: 26% (Grade ≥3)
Grade ≥3 Adverse Events (%)	67% (palbociclib + letrozole) vs 30% (placebo + letrozole)	Neutropenia: 26%, Anemia: 19%
Subgroup Outcomes	Enhanced benefit in patients with measurable disease and fewer prior therapies	Responses primarily in CN-L/NSMP tumors, one in MSI-H tumor; none in CN-H/TP53abn
Conclusions	Significant improvement in PFS with palbociclib + letrozole, warrants further phase III trials	Promising efficacy, especially in specific molecular subtypes, supports further trials
Limitations	Small sample size, heterogeneous prior treatments, no OS benefit	Single-arm design, small sample size, no long-term survival outcomes

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