At the genetic consultation special meeting, Professor Wu Ming from Peking Union Medical College Hospital of the Chinese Academy of Medical Sciences brought us a special report on "New Progress in Genetic Testing of Gynecological Tumors".

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Academic frontiers, within reach! The importance of

molecular detection in tumor treatment is becoming increasingly prominent. PARPi maintenance therapy has brought 56 ​​months of progression-free survival (PFS) to ovarian cancer patients, but its first-line treatment relies on BRCA/HRD testing. In other gynecological tumors, the exploration of the new biomarker also pointed out the direction for treatment.

2022 Gynecological Oncology Professional Committee of the China Anti-Cancer Association and the 19th National Gynecological Oncology Academic Conference were held online from September 15 to 18, 2022. At the genetic consultation special meeting, Professor Wu Ming from Peking Union Medical College Hospital of the Chinese Academy of Medical Sciences brought us a special report on "New Progress in Genetic Testing of Gynecological Tumors".

Currently, there are 8 known DNA damage responses and repair mechanisms, among which , homologous recombinant repair (HRR) pathway variants are related to the occurrence of multiple cancers.

HRR is a very accurate DNA double-strand break repair method. When the HRR pathway mutates, it causes homologous recombination defects (HRD), resulting in gene instability, and thus the occurrence of various cancers.

In clinical practice, the HRD detection ratio of tumor samples before and after neoadjuvant chemotherapy is also a topic of concern to everyone. After tumor chemotherapy, some tumors will disappear, and some patients can even obtain complete remission (CR). How to do genetic testing at this time?

2022 SGO Conference has a poster (139.5) compared the HRD scores of ovarian cancer samples of different pathological types to study the HRD scores.

study found that:

① In the resection samples with CRS score 2-3, the HRD detection failure rate is higher, the sample with CRS score 1 is 2-3 times, and the sample with biopsy samples are 3 times;

② In patients with ovarian cancer with different pathological subtypes, HRD detection is feasible;

③ Patients with certain characteristics have a higher proportion of HRD, such as high-grade serous carcinoma, carcinosarcoma, CRS2-3, etc.

Professor Wu Ming said: Considering that after neoadjuvant chemotherapy, the CRS2-3 samples have a higher proportion of tumors, resulting in failure of HRD detection. is therefore recommended to perform puncture and send test before neoadjuvant chemotherapy. Similarly, it is not recommended to send cytology samples such as ascites.

As we all know, Ki67 can reflect the proliferation activity of tumor cells and to a certain extent reflect the degree of malignancy. The 2022 European Society of Oncology Annual Meeting (ESMO) Conference released an abstract (NO.590). This study found that Ki67 expression levels are related to maintenance treatment of PARPi in patients with BRCAwt platinum-sensitive relapse (PSR) ovarian cancer.

study found that

① Patients with high Ki67 expression had better efficacy with PARPi; patients with high Ki67 expression had better survival.

2022 The American Society of Gynecological Oncology Annual Meeting (SGO) Scientific Plenary Session II published an article (#102) on the dynamic monitoring of circulating tumor DNA (ctDNA) PARP inhibitor resistance. This study was conducted to predict the effect of PARP inhibitor response by monitoring the continuous circulation tumor DNA (ctDNA).

ctDNA monitoring of gene changes before and after PARP inhibitor treatment:

study found that

mutant genes will change before and after PARPi treatment, including HRD-related genes, cell cycle-related genes, and specific genes after treatment.

BRCA reply mutation diagram:

It is well known that BRCA reply mutation is an important reason for drug resistance during the use of PARPi.

study found that:

① The overall tumor mutation burden increased, including genes that regulate the cell cycle;

② BRCA recovery mutations can be identified through ct-DNA;

③ For patients with PARPi progression, continuous collection and monitoring of ct-DNA can provide useful clues for personalized treatment.

Circulating tumor DNA (ct-DNA) detection is a liquid biopsy method that can be obtained through peripheral blood. ctDNA can reflect the current patient's condition and continuously monitor the condition. The genetic testing of tissue samples can only reflect the patient's operation at that time and cannot reflect the patient's current situation.

2022 An abstract (NO.588) study on the value of ct-DNA detection in the prognosis of ovarian cancer was published at the ESMO conference.

study results found that the consistency between tissue and blood tests was 91.1%. One patient had ct-DNA positive but the tissue test was negative, and six patients had tissue positive but the college ct-DNA negative; patients with ct-DNA residuals six months after chemotherapy had poor prognosis.

study found that

ct-DNA detection can be used for ovarian cancer prognosis evaluation .

If ct-DNA is monitored for mutant gene conversion (blue curve) during treatment, the prognosis is the best; if ct-DNA monitoring results continue to be positive (red curve), the prognosis is the worst; if ct-DNA negative conversion (green curve) the prognosis will also become worse.

2022 An article on the genomic map of low-grade serous carcinoma (LGSOC) and its impact on clinical clinical outcomes (#246).

The author of this article used first-generation serous serous carcinoma (LGSOC) to detect low-grade serous carcinoma (LGSOC). The study found that LGSOC has a MAPK signaling pathway mutation, with a mutation rate of up to 50%. The most common one is KRAS mutation, which has an excellent prognosis (median OS = 106.8 months). The investigator further studied the genomic map of LGSOC through NGS, and the research results were consistent with the research results of first-generation sequencing.

study results:

results show that the median PFS and median OS in patients with MAPK pathway mutation (red curve) were greater than the median PFS and median OS in patients without MAPK pathway mutation (blue curve).

Research conclusions of this article:

① LGSOC patients carrying MAPK pathway mutations have significant benefits of PFS and OS;

② Women aged 35 years old have worse prognosis than women aged ≥35 years old;

③ Women without MAPK mutations have relatively poor prognosis and need better treatment methods.

2022 SGO Science plenary meeting shared a study related to the additional benefits of PPP2R1A functional deletion mutation and immune checkpoint inhibitors in the treatment of ovarian clear cell carcinoma (#365).

study found that the overall survival (OS) of patients with ovarian clear cell carcinoma with PPP2R1A mutation (red dotted line) longer than those of patients with ovarian clear cell carcinoma without PPP2R1A mutation (blue curve). results show that patients with PPP2R1A mutations can significantly benefit from immunotherapy.

left picture: Based on the ARID1A mutation, the OS of patients with PPP2R1A mutation (red dotted line) was longer than those without PPP2R1A mutation (blue curve), and there was a significant statistical difference; right picture: Based on the ARID1A mutation, the OS of patients with ARID1A mutation (red dotted line) were both shorter than those without ARID1A mutation (blue curve).

results show that the impact of PPP2R1A mutation on survival has nothing to do with the common ARID1A mutation in ovarian clear cell carcinoma. As long as the PPP2R1A mutation is present, patients can significantly benefit from the treatment of immunosuppressor .

left picture: In immunotherapy, the OS with PPP2R1A mutation (red curve) was significantly longer than the OS without PPP2R1A mutation (blue curve); right picture: In other therapies, the OS with PPP2R1A mutation (red curve) was obviously shorter than the OS without PPP2R1A mutation (blue curve).

results show that in other cancers treated with immune checkpoint blockers (ICB), PPP2R1A mutation is also related to prolonged survival. Patients receiving other therapies will not benefit from the presence of PPP2R1A mutations.

Research conclusions of this article:

① Function-deletion PPP2R1A mutation is related to the additional benefits of ICB treatment in patients with ovarian clear cell carcinoma (OCCC);

② Compared with ARID1A, PPP2R1A is more suitable as a biomarker for the benefit of ICB treatment, and it may be a new therapeutic target;

③ During the treatment process, remission may occur again after the first progress.

Source of this article: Medical Pathology Channel

Author of this article: Hong Meiling

Review expert: Professor Dong Lin Chinese Academy of Medical Sciences Cancer Hospital

Editor in charge: Sweet

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