Sunday, June 4, 2023

Extraordinary clinical response to ibrutinib in low-grade ovarian cancer guided by organoid drug testing – npj Precision Oncology

Case history

A 52-year-old Gulf War veteran with a history of prior hysterectomy for fibroids presented with constipation and intermittent diarrhea thought to be related to irritable bowel syndrome (IBS). She was treated for IBS for 9 months until she presented to the emergency department with increased abdominal pain, distension, and constipation. A CT scan showed an 11cm complex adnexal mass, peritoneal carcinomatosis, and pericapsular implants in the liver with a small volume ascites (Fig. 1a). Surgery was recommended and the patient underwent an exploratory laparotomy, lysis of adhesions, partial omentectomy, and partial resection of the abdominal wall. Debulking was unsuccessful due to extensive intra-abdominal disease with omentum and anterior abdominal wall involvement. At the time of this surgery, the patient’s CA-125 level was 199 U/mL (Fig. 2b).

Fig. 2: Clinical timeline of the patient and CA-125 levels.

a Interventions. Dx diagnosis. L, O, D exploratory laparotomy, partial omentectomy, debulking (unsuccessful), L, D exploratory laparotomy, debulking (unsuccessful), FO CDx Foundation One test, H hospitalization. b CA-125 levels during the disease and treatment course.

Tumor stage, pathology, and genomics

The histological diagnosis from the debulking surgery was LGSOC, stage IIIC. Immunohistochemistry studies on a sample of omentum tissue collected during this initial surgery revealed diffuse PAX8 positivity, consistent with EOC. Further companion diagnostic testing by Foundation One, which interrogated 324 cancer genes including TP53, BRCA1, and BRCA2, revealed a somatic pathogenic alteration in CHEK2 (T367fs*15). Several variants of unknown significance (VUS) were also reported, namely AKT1 D221E, IRS2 A701_V702insA, MLL2 P2210L, MSH3 L911W, MUTYH G162V, and NOTCH3 S663F (Fig. 1c).

Initial treatment

Following her diagnosis, the patient completed 6 cycles of paclitaxel (175 mg/m2) and carboplatin (AUC 6 IV) every 3 weeks in the adjuvant setting. Her CA-125 dropped to a nadir of 72 U/mL during treatment but rose to 94 U/mL during the sixth cycle (Fig. 2b). As her CA-125 level was steadily increasing, the patient underwent a second attempt at debulking surgery which was suboptimal due to significant bowel adhesive disease and with little evidence of response to chemotherapy.

Tumor organoid-based drug testing

Based on the poor response to the standard of care and deteriorating conditions of the patient, the oncologist ordered the PARIS® test to assess candidate drugs for their potential efficacy. On the day of the surgery, a sample of tumor tissue taken from the omentum was sent to SEngine’s CLIA laboratory. The sample had >70% tumor cell viability and was expanded as a 3D organoid culture for the drug screening assay. To confirm the tumor organoids represented the original tumor, genomic analysis of the organoid culture was performed using a CLIA-certified whole exome sequencing (WES) pipeline. Figure 1c shows confirmation of all seven mutations between the primary tumor and the organoid culture.

Drug screening was performed with a custom panel of 42 small molecule drugs selected based on standard-of-care chemotherapies, drugs targeting common cancer genes and pathways for LGSOC, and the genomic profile of the patient’s tumor, which included a CHEK2 mutation and several VUSs (Fig. 1c). The custom panel contained 34 targeted agents and 8 chemotherapies (fluorouracil, gemcitabine, methotrexate, oxaliplatin, paclitaxel, vinorelbine tartrate, SN-38, and doxorubicin HCl) (Supplementary Table 1). The drugs were ranked from the most effective to the least with a proprietary score report (SPM 100 to 1, with 100 to 70 considered active drugs). A report describing these results was sent to the treating oncologist 23 days after the sample was received (Fig. 1d). Of the eight chemotherapies tested, only gemcitabine had a low response (Supplementary Table 1) while the rest, including paclitaxel and oxaliplatin had no activity, consistent with her poor response to this class of agents. Carboplatin was not included as it was inactive in this drug library. In contrast to the resistance of the tumor organoids to chemotherapy drugs, multiple targeted agents showed good to exceptional activity, including the BTK inhibitor, ibrutinib (SPM score 97.3) and the EGFR inhibitor, afatinib (SPM score 95.9). Neratinib and erlotinib, both targeting the EGF receptor, were also active (SPM score 87.1 and 89.8, respectively) suggesting this patient’s tumor may be dependent on BTK and/or EGFR signaling. In addition, the experimental BET inhibitor CPI-0610 demonstrated an exceptional response (SPM score 97.3), and the WEE1 inhibitor adavosertib a moderate response (SPM score 84).

Post-PARIS® test treatments

Following the second surgery, the patient was treated with the aromatase inhibitor letrozole (2.5 mg p.o., daily) for 2 months, which is a standard second-line therapy for recurrent LGSOC. During this course of treatment, she was admitted to the hospital once for post-operative ileus and twice for malignant small bowel obstruction. A CT scan revealed omental caking indicative of chronic low-grade malignant bowel obstruction and a venting G-tube was placed.

Ibrutinib monotherapy results in biomarker reduction, symptom improvement, and prolonged tumor control

Following a review of the PARIS® test results and evaluation by an interdisciplinary molecular tumor board at the University of Washington, the treating oncologist elected to start treatment with ibrutinib (420 mg p.o., daily) as monotherapy. After four weeks of ibrutinib treatment, the patient’s CA-125 level decreased from 252 to 125 U/mL (Fig. 2b). She initially experienced anemia possibly linked to ibrutinib and was admitted several times for acute abdominal pain related to small bowel obstruction and carcinomatosis. As her pain was only able to be controlled with fentanyl patient-controlled-analgesia (PCA) and she was unable to eat, she elected to enter home hospice care. At this time, her disease was deemed end-stage with an expectation of weeks to months to live. She paused all treatment for one month and then restarted ibrutinib. Following the resumption of ibrutinib, her abdominal pain and bowel movements stabilized, and her CA-125 level decreased over the next 12 weeks from 149 to 23 U/mL. The patient showed continued improvement, with the ability to tolerate solid foods and bowel movements. After another 25 weeks, her CA-125 level had reduced further to 19.9 U/mL and a CT scan showed a slight improvement in carcinomatosis indicative of stable disease. During this time her performance status improved from ECOG 3 to ECOG 1 and her quality of life had improved so much that she was able to travel out of state and transition off PCA and opioid medication. The patient had a brief hold of ibrutinib for a several-week hospitalization due to line sepsis but restarted shortly thereafter.

After 65 weeks of stable disease on ibrutinib the patient’s CA-125 level began to rise, oscillating between 100 to ~150 U/mL (Fig. 2b). Afatinib, an FDA-approved EGFR inhibitor, was the third highest-scoring drug in the PARIS assay (Fig. 1d) and in consultation with the tumor board it was decided to put the patient on afatinib (150 mg p.o., daily) as monotherapy, since the second highest-scoring drug was experimental and not available for this patient. While on afatinib, her CA-125 levels remained stable in the low 100s for an additional 24 weeks and the patient had no hospitalizations. However, her hemoglobin levels frequently dropped below 8, requiring transfusions every 3–4 weeks from week 24 to 44. Because of the anemia and the rising levels of CA-125 to 1837 U/ml, afatinib was discontinued. The patient is currently taking erlotinib (150 mg p.o., daily), another EGFR inhibitor that was also among the top-scoring drugs in the PARIS assay (Fig. 1d). The patient’s Hb levels are currently at 9.1. In total, since starting ibrutinib and then continuing on afatinib, this patient has gone from hospice care with an inability to eat and an ECOG score of 3 and requiring opioids to control pain to an ECOG score of 1 with cessation of opioids and >20 months of stable disease.

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