“Lazarus Response” to Olaparib in a Virtually Chemonaive Breast Cancer Patient Carrying Gross BRCA2 Gene Deletion

Abstract

This report describes an estrogen receptor-positive breast cancer patient, who relapsed at two and a half years after the completion of adjuvant chemotherapy while being on the aromatase inhibition. Based on the clinical evidence for potential sensitivity of the tumor to hormone ablation, everolimus was added to continuing exemestane treatment. Oral chemotherapy was administered at further disease progression, however, it lasted only for 10 days due to rapidly deteriorating condition of the patient. BRCA test was performed just before the failure of endocrine therapy and revealed a gross deletion within BRCA2 gene. Since the patient already developed contraindications to the standard chemotherapy, olaparib (300 mg twice a day) was given as a last hope option. The patient demonstrated a “Lazarus response”: the performance status and the results of the biochemical tests went back to the norm within first two weeks of treatment. Positron emission tomography-computed tomography (PET-CT) was performed at one month after the start of olaparib therapy, and revealed complete metabolic response for all multiple metastatic lesions located in the liver, bones, small pelvis, lungs, mediastinum, retroperitoneum, etc. Cytotoxic therapy and poly ADP-ribose polymerase (PARP) inhibitors are known to have virtually identical mechanisms of tumor escape from the treatment, which are confined to the restoration of BRCA proficiency within cancer cells. The pronounced tumor response to the treatment in this patient can be attributed to the lack of recent exposure to standard cytotoxic treatment as well as to the inability of tumors with gross BRCA rearrangements to restore BRCA function via secondary mutation. This observation calls for comprehensive evaluation of PARP inhibitors in chemonaive patients with hereditary cancer.

Cytotoxic and targeted therapy for BRCA1/2-driven cancers

“…The analysis of tumors exposed to platinum therapy or PARPi revealed instances of the rescue of BRCA1/2 function, which is achieved by the second mutation in the affected gene, and, consequently, by the restoration of BRCA1/2 open reading frame [ 24 , 28 ]. These data are supported by clinical observations of extraordinarily good response in patients with deletion of large fragments of BRCA1/2 genes, i.e., in instances where BRCA1/2 function cannot be restored by the secondary mutation [ 51 , 77 ]. Studies on BRCA1 -mutated ovarian carcinomas demonstrated the persistence of a small fraction of BRCA1-proficient cells even in chemonaive tumors; these cells rapidly repopulate tumor mass during the first weeks of platinum-based therapy thus explaining the phenomenon of inevitable emergence of platinum-resistance [ 78 , 79 ].…”

Exceptional Response to Olaparib in a Patient With Recurrent Ovarian Cancer and an Entire BRCA1 Germline Gene Deletion

“…18,24,25 A single case report describes a patient with estrogen receptor-positive metastatic breast cancer and a large BRCA2 gene deletion who had a complete response to olaparib. 26 In patients with advanced OC and germline BRCA mutations who have received at least 2 lines of previous chemotherapy, olaparib maintenance has been shown to prolong PFS compared with placebo (median, 19.1 vs 5.5 months; hazard ratio [HR], 0.30; 95% CI, 0.22-0.41). 27 Another study of maintenance olaparib in a similar population showed a trend toward improved OS in women on olaparib versus placebo (HR, 0.73; 95% CI, 0.45-1.17) and a median OS of 34.9 months in women with germline BRCA mutations.…”

Mechanisms of acquired resistance of BRCA1/2-driven tumors to platinum compounds and PARP inhibitors

“…BRCA1/2 LGRs are not specifically considered in the studies on tumor drug sensitivity. However, there are case reports supporting exceptional responsiveness of BRCA1/2 LGR-associated tumors to PARPi[ 33 ].…”