Among ovarian cancer patients, about 15% have germline BRCA mutations, about 25% have tumor BRCA mutations (including germline + system), and about 50% have homologous recombination repair deficiency (HRD). BRCA-negative and/or HRD-negative patients have a relatively poor prognosis because they are less sensitive to platinum drugs and PARPi that cause DNA fragmentation than BRCA-positive patients. Gratifyingly, the results of the PRIMA study confirmed [1] that for patients with negative HRD, niraparib can also reduce the risk of disease progression or death by 32%. Based on this evidence-based basis, this HRD-negative patient was treated with niraparib as first-line maintenance therapy, and the data as of January 2022 have shown no recurrence for 1 year. This article details the diagnosis and treatment process of this case and the inspiration brought by the good efficacy of niraparib.
Professor Guo Peng
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Sun Yat-sen University
Graduated from Peking Union Medical College ; Doctor of Medicine; Proficient in the diagnosis and treatment of common, frequently-occurring and complex and difficult diseases in obstetrics and gynecology, especially for gynecological malignancies He has certain clinical experience in the diagnosis and comprehensive treatment of tumors such as cervical cancer, endometrial cancer, and ovarian cancer.
01 Case review
Basic information
Patient, female, 54 years old. Past history: 8 years ago, a cervical conization was performed in another hospital, the details are unknown; an intestinal polypectomy was performed, and there was a history of allergy to penicillin.
treatment went through the first stage of
✔: neoadjuvant chemotherapy (NACT) + intermittent cytoreductive surgery (IDS) + postoperative chemotherapy
2020-05-14 The patient suffered from "abdominal distension for more than 4 months and worsened for more than 1 month" Admit me to our hospital. More than 4 months ago, I had pain in the right lower abdomen without obvious triggers, which was a persistent dull pain. In the past 2 years, ecchymoses tended to appear after bumps.
General physical examination: the abdomen is flat and soft, with tenderness in the right lower quadrant, rebound tenderness , and remainder (-).
Auxiliary examination:
Blood routine and rheumatic immune disease-related examinations (2020-05-15) found no significant abnormalities.
The bone marrow proliferates actively, the proportion of granulocytes is normal, and the proportion of erythroid is increased. It can be seen that there are many megakaryocytes and platelets .
PET-CT (2020-05-15) 1. The metabolism in and around the appendix is active, and no obvious nodules or masses are found; 2. The local fat spaces in the middle and lower abdomen are blurred and scattered with spots of increased density, and the pelvic peritoneum is not clear. Regular thickening; 3. Enlarged lymph nodes behind the right internal mammary and right iliac vessels, approximately 1.5×1.6cm in size; 4. The lower end of the esophagus is metabolically active, so esophagoscopy may be recommended.
gastroscopy and colonoscopy showed no abnormalities.
tumor marker (2020-05-15): CA125 107.10U/ml; CA15-3 44.50U/mL.
Gynecological color ultrasound (2020-05-15) shows uterine fibroids .
Figure 1 Gynecological color ultrasound (2020-05-15)
CT (2020-06-02): 1. It is considered that appendicitis is highly likely, the boundaries of the adjacent intestinal tubes are unclear, and the possibility of adhesions has not been ruled out; 2. Peritonitis in the middle and lower abdominal cavity, medium There are multiple lymph node shadows in the lower abdominal cavity and right side of the iliac blood vessels, and the possibility of inflammatory lymph nodes is considered.
2020-06-04 Laparoscopic exploration was performed, and intraoperative frozen pathology showed: (omental nodule, left ovary) malignant tumors, pending IHC. Total abdominal hysterectomy + double adnexectomy + omentectomy + right hemicolectomy + resection of diaphragm, mesentery and pelvic floor nodules were performed. After the operation, the residual tumor was 1cm.
Postoperative pathology: 1. (Greater omentum) Multifocal adenocarcinoma infiltration was seen in the omentum tissue, consistent with metastatic cancer ; 2. (General tumor) was seen in the muscular and serosal layers of the appendix, small intestine and colon. Poorly differentiated adenocarcinoma with infiltration. immunohistochemistry : No. 2K wax block cancer cell PAX-8 (+), CK7 (+), WT1 (+), CR (-), MC (-), Vimentin (-), CDX-2 (-) , CK20 (-), M-CEA (-), P53 about 10% (+). Combined with the HE morphology and immunohistochemistry results, the lesion was consistent with poorly differentiated adenocarcinoma, and the ovarian origin was considered. 3. (uterus and right ovary) poorly differentiated adenocarcinoma was seen in the ovarian tissue, and the cancer tissue involved the fallopian tube wall; uterine multiple leiomyomas chronic cervicitis and atrophic endometrium. No cancer was found in the cervical canal and bilateral parametrial tissue; 4. (Left abdominal wall nodule) There was cancer tissue infiltration in the fibrous tissue , which was consistent with metastatic cancer.
Diagnosis: 1. Ovarian poorly differentiated adenocarcinoma stage IVB (internal mammary lymph node metastasis) 2. Chronic appendicitis 3. Abnormal coagulation function (secondary) 4. Uterine fibroids.
After 6 courses of chemotherapy (2019-06-30 to 2020-10-29): nab-paclitaxel 260mg/m + carboplatin AUC=5-6 (iv.drip).
After re-evaluation after NACT, tumor marker levels decreased: CA125 4.80U/ml, HE4 32.90pmol/L.
Figure 2 Tumor marker change curve
Efficacy evaluation: PET-CT results (2020-12-23): Soft tissue nodules at the lower edge of the right lobe of the liver (close to the colon anastomosis), metabolically active, SUVmax is 4.9, planned Tumor metastasis, reexamination is recommended; there are several slightly larger lymph nodes in the mesenteric area of the right lower abdomen, the larger ones are about 1.0cm×0.6cm, with clear borders, some FDG uptake is slightly increased, SUVmax is 1.6, reexamination is recommended.
patient’s genetic test result: HRD negative.
✔ Phase II: PARPi first-line maintenance treatment
2021-01 The patient started taking niraparib 200mg qd. So far, the patient has no obvious adverse reactions, no dose reduction or discontinuation, and no obvious ecchymoses on the skin. During the maintenance treatment, routine blood tests (Figures 3-4) and serum tumor marker levels (Figure 5) fluctuated within the normal range; follow-up CT showed no obvious signs of recurrence.
Figure 3 Changes in hemoglobin levels during maintenance treatment
Figure 4 Changes in platelet levels during maintenance treatment
Figure 5 Changes in neutrophil levels during maintenance treatment
Figure 6 Changes in APTT levels during maintenance treatment
Figure 7 Maintenance treatment Changes in serum CA125 levels during the period
Case summary
2020-05 The patient came to our hospital for treatment due to abdominal pain for more than 4 months, which worsened for 1 month. After laparoscopic exploration, the pathological diagnosis was "ovarian poorly differentiated adenocarcinoma stage IVB with internal mammary lymph node metastasis" , underwent total abdominal hysterectomy, and used albumin-bound paclitaxel + carboplatin regimen for 6 courses of chemotherapy to achieve PR. Genetic test results: HRD negative. She started taking niraparib 200 mg qd as first-line maintenance treatment in January 2021. The data has been up to 1 year as of January 2022, and no recurrence has been seen. During the maintenance treatment, no obvious ecchymosis was found on the skin, and routine blood indicators and serum tumor marker levels fluctuated within the normal range. The safety profile is good, with no obvious adverse reactions.
03 Expert comments
Professor He Mian
Director of the Department of Obstetrics and Gynecology, the First Affiliated Hospital of Sun Yat-sen University
Director of the Teaching and Research Section of the Department of Obstetrics and Gynecology, the First Affiliated Hospital of Sun Yat-sen University; Postgraduate Tutor; Vice Chairman of the Gynecological Oncology Professional Committee of the Guangdong Provincial Medical Association; Guangdong Provincial Anti- Deputy Chairman of the Gynecological Oncology Professional Committee of the Cancer Association; Member of the Ovarian Cancer Quality Control Expert Committee of the National Cancer Center and National Cancer Quality Control Center; Member of the Gynecological Oncology Expert Committee of the Chinese Society of Clinical Oncology (COSO); Member of the Peritoneal Tumor Professional Committee of the Chinese Anti-Cancer Association; Guangdong Deputy leader of the Cervical Lesions and Colposcopy Group of the Obstetrics and Gynecology Branch of the Provincial Medical Association; Member of the Hereditary Tumor Professional Committee of the Guangdong Anti-Cancer Association; Vice Chairman of the Gynecological Professional Committee of the Guangdong Health Management Society; Gynecological Tumors of the Guangdong Health Management Society Deputy Chairman of the Special Committee for Discipline Collaboration; Member of the Clinical Department Director Management Branch of the Guangdong Provincial Hospital Association; Received honors such as March 8th Red Flag Bearer of Guangdong Province, Yangcheng Good Doctor, Lingnan Famous Doctor, and Southern Guangdong Women's Good Physician.
Expert comments
The prognosis of ovarian epithelial cancer is mainly related to the patient's age, stage, pathological grade, postoperative residual tumor size, sensitivity to chemotherapy drugs, and genetic mutations. Among them, the earlier the stage, the better the prognosis. The 5-year survival rate for stage III ovarian cancer is 30% to 40%; for stage IV ovarian cancer, it is only 10%. In terms of gene mutations, there has been evidence of the use of the PARP inhibitor in patients with BRCA mutations or HDR-positive patients. However, for HRD-negative patients, there is an urgent need for breakthrough maintenance treatment drugs in clinical practice. The patient's tumor was poorly differentiated, stage IVB, accompanied by internal mammary lymph node metastasis, HRD negative, and had many adverse prognostic factors, suggesting easy recurrence and poor prognosis. When platinum-containing chemotherapy is used to achieve PR after surgery, scientific selection of maintenance treatment drugs based on sufficient evidence-based medical evidence is crucial.Considering the patient's high possibility of recurrence and combined with the evidence-based data of different PARP inhibitors in patients with HRD-negative ovarian cancer, niraparib was chosen as first-line maintenance therapy.
The results of the PRIME study, which explored the therapeutic value of niraparib as first-line maintenance therapy in the entire Chinese population, showed [2] that regardless of the biomarker status, mPFS benefited in the niraparib group. In HRD-negative patients, the mPFS of the niraparib group compared with the placebo group was 14.0 months and 5.5 months respectively (HR=0.41; 95%CI: 0.25-0.65; P0.001). The PRIME study prospectively demonstrated that individualized starting doses of niraparib as first-line maintenance therapy for newly diagnosed advanced ovarian cancer resulted in a statistically significant PFS benefit compared with placebo regardless of HRD status. The safety profile is good, with only 6.7% of patients discontinuing treatment due to adverse events . Currently, many guidelines in my country recommend niraparib alone as maintenance treatment after first-line platinum-containing chemotherapy.[3].
As of January 2022, the data of this patient’s first-line maintenance treatment with niraparib has achieved a progression-free survival of 1 year, which has delayed the recurrence of the disease. The compliance and safety were good, and no dose reduction or discontinuation occurred. This case suggests that niraparib can also achieve excellent efficacy and is well tolerated through individualized administration in HRD-negative patients with advanced ovarian cancer and metastasis who have achieved PR through platinum-containing chemotherapy. It is expected that niraparib will bring more evidence-based medical evidence in the future to achieve maximum clinical benefit for patients.
References
[1]Gonzalez-Martin A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019; 381(25): 2391–2402.
[2 ]Li N, Zhu J, Yin R, et al. Efficacy and safety of niraparib as maintenance treatment in patients with newly diagnosed advanced ovarian cancer using an individualized starting dose (PRIME Study): a randomized, double-blind, placebo-controlled, phase 3 trial. Presented at: 2022 SGO Annual Meeting on Women's Cancer; March 18-21, 2022. Phoenix, Arizona.
[3] Chinese Anti-Cancer Association Gynecological Oncology Professional Committee. China Maintenance Treatment Guidelines for Epithelial Ovarian Cancer (2021) ［J］.Chinese Journal of Practical Gynecology and Obstetrics, 2021,37(6):640-649.
