Therapeutic Potential of Olaparib in Combination with Pembrolizumab in a Young Patient with a Maternally Inherited BRCA2 germline variant: A Research Report

INTRODUCTION

Lung cancer has traditionally been defined as a disease caused by acquired somatic mutational aberrations, but more recent advances in next-generation sequencing have identified several germline alterations that may correlate with lung cancer initiation and development. A family history of lung cancer is associated with a twofold increase in lung cancer risk, but the germline susceptibility varies greatly between men and women. Along with this, the incidence of lung cancer in recent years has shifted from older patients with history of classic somatic mutational exposures such as tobacco to younger patients, especially women, with none of these risk factors. BRCA1 and BRCA2 are known germline alterations and have been implicated in 1.8–2.7% of solid tumors, the most common being breast and ovarian cancers at 5–10% and 10–15% respectively¹. BRCA1 and BRCA2 genes are crucial in the repair of DNA and have been found to be required for several DNA damage-responses in the cell cycle. These responses allow for repair of DNA lesions, thereby preventing the damage from being passed on to the daughter cells^{2, 3}. Currently there is an increasing interest in germline alterations and their effect on a person’s susceptibility to developing lung cancer⁴. Here we present a case of a young woman with no history of smoking whom was diagnosed with stage IVB metastatic lung adenocarcinoma and an identified BRCA2 germline alteration.

CASE REPORT

Clinical presentation and family history

Our patient is a 26-year-old Caucasian female with no tobacco exposure or significant past medical history. She initially presented with dyspnea and her work up included a computed tomography (CT) angiography of the chest which demonstrated a right upper lobe mass with mediastinal involvement creating superior vena cava syndrome along with associated pulmonary embolisms and a large right sided pleural effusion secondary to complete right bronchial tree collapse (Figure 1). An ultrasound guided thoracentesis of the pleural effusion was performed with the cytology positive for CK7 and TTF-1 with CK20 and P40 being negative, consistent with lung primary. The thoracentesis high resolution CT of the chest noted significant mediastinal adenopathy, bilateral pleural effusions, and diffuse pulmonary nodules with the largest being in the posterior subsegment of the right upper lobe. (Figure 2A). The patient then underwent bronchoscopy, mediastinoscopy and right sided indwelling pleural catheter (IPC) placement with pathology consistent with poorly differentiated adenocarcinoma of the lung. Immunohistochemistry (IHC) staining was notable for: CK7 positive, TTF-1 positive, CK5/6 focally and weakly positive, P40 focally and weakly positive, CK20 negative, CDX-2 negative and BRST-2 negative. NeoGenomics genetic testing was negative for EGFR, ALK and ROS1 while PD-L1 (22C3) testing demonstrated high expression with a tumor proportion score of 90% and intensity of 3+. The patient went on to receive one cycle of Carboplatin and Pemetrexed prior to her discharge. She then presented to our clinic with increasing shortness of breath, swelling in her arms, back pain, fatigue, poor appetite, and continued SVC syndrome. Our team then discovered that the patient’s father had an extensive history of smoking, drug abuse, alcohol consumption, was diagnosed with lung cancer at the age of 48 and later, passed away due to the disease. Further workup for metastatic lung cancer included magnetic resonance imaging (MRI) of the brain and a positron emission tomography-CT (PET-CT). MRI imaging noted greater than 20 supratentorial and infratentorial lesions with the largest being 1.1 cm. Along with this, the PET-CT exams showed innumerable bilateral pulmonary micronodules, multiple osseous lesions including the right seventh rib, spine, sacrum, and left iliac wing (Figure 3). She was clinically staged as IVB (T3N2M1c) primary lung adenocarcinoma. Further mutational testing was performed using Ashion GEM ExTra with the DNA and RNA sequencing notable for BRCA2 S497*, tumor mutation burden (TMB) low at 4 mutations/Mb and microsatellite instability (MSI) defined as stable. Liquid biopsy utilizing Guardant360 detected BRCA2 S497* with 51.6% of cfDNA. Germline BRCA1/2 analysis with CustomNext-Cancer was positive for the pathogenic mutation BRCA2 S497*. Combining our work-up with her father’s history, a genetics specialist was consulted. This helped determine that the patient’s mother (aged 47) and maternal half-brother (aged 21) tested positive for the BRCA2 mutation, but the paternal half-sister (aged 32) and paternal half-brother (aged 27) were not carriers. The patient then underwent palliative radiation to her right lung and mediastinum with a total dose of 30 Gy delivered in 10 fractions along with whole brain radiotherapy (WBRT) reaching a total dose of 30 Gy over 10 fractions. Our patient’s SVC syndrome resolved, and she remains on maintenance Eliquis for her history of pulmonary thrombus. Systemic therapy was then initiated with a combination of Carboplatin (AUC 5), Pemetrexed (500 mg/m²), and Pembrolizumab (200 mg) every 3 weeks. Side effects of this therapy included nausea controlled with Zofran, Compazine, and Xanax, along with alopecia, constipation, and neuropathy of her hands and fingers. The patient’s IPC was able to be removed 3 months later due to her clinical improvement and associated lack of output. Laboratory findings showed thrombocytopenia and anemia related to chemotherapy and Carboplatin was discontinued after cycle 5 and Pemetrexed was discontinued after cycle 6. Upon identification of a BRCA2 alteration and after consultation with a cancer geneticist, a half-dose Olaparib (150 mg, BID) was added to her treatment along with continuation of maintenance Pembrolizumab. The patient experienced heart burn, severe right knee pain, and menometrorrhagia with this treatment regimen. The patient has thus far completed 17 cycles of Pembrolizumab (200 mg), now every 6 weeks, and continues Olaparib (150 mg, BID) with good tolerance. On this regimen she has both clinically as well as radiographically improved (Figure 2B).

Figure 1.

Computed tomography (CT) angiography of the chest demonstrates a right upper lobe mass with mediastinal involvement creating superior vena cava (SVC) syndrome along with associated pulmonary embolisms and a large right sided pleural effusion secondary to complete right bronchial tree collapse.

Figure 2.

High resolution CT of the chest notes significant mediastinal adenopathy, bilateral pleural effusions and diffuse pulmonary nodules with the largest being in the posterior subsegment of the right upper lobe before (A) and after (B) treatment with chemotherapy/immunotherapy and olaparib.

Figure 3.

PET-CT demonstrates innumerable bilateral pulmonary micronodules, multiple osseous lesions including the right seventh rib, spine, sacrum, and left iliac wing.

Genomic analyses

A stop-gain c.1490C>G alteration in BRCA2 (S497*) was identified on a circulating cell-free DNA (cfDNA) assay, Next Generation Sequencing (NGS) tumor/normal exome testing, and germline liquid biopsy panel. First, the detection of the BRCA S497* alteration in the patient’s blood sample discovered an allele fraction of 51.6% cfDNA, suspicious for germline origin. Confirmatory germline testing ordered and revealed the pathogenic germline mutation in the BRCA2 gene. Conclusively, the genomic DNA was extracted from the patient’s mediastinal mass (Supplemental Table 1).

Treatment outcomes

After initial genomic testing showed no actionable molecular targets, the patient received, on average, 640 mg (Target AUC=5) of Carboplatin, 800 mg of Pemetrexed and 200 mg of Pembrolizumab, intravenously. She tolerated the treatment regimen fairly well without any serious adverse events. She discontinued Carboplatin and Pemetrexed after receiving five and six cycles, respectively, and continues maintenance Pembrolizumab. Immune-related adverse events are monitored closely.

Her genetic testing results did not reveal a mutation in well-described lung cancer genes, such as TP53 or EGFR^{5, 6}. However, the diagnosis of germline alteration BRCA2 S497* prompted a consultation with the clinical cancer genomics group. The pathogenic alteration in the BRCA2 gene confers an increased risk of early onset breast cancer, an elevated risk of developing a second primary breast cancer and a significantly increased risk for ovarian cancer^7–9. Current guidelines for BRCA2 carriers include consideration of increased imaging and/or medications or surgery to reduce cancer risk. Given her young age, non-smoking history and positive BRCA2 mutation, the patient was initiated on Olaparib, a Poly (ADP-ribose) polymerase 1 (PARP1) inhibitor therapy, and she continues without serious side effects.

DISCUSSION

Our patient was 26 years old when diagnosed with widespread metastatic NSCLC disease driven by a BRCA2 mutation instead of the characteristic NSCLC oncogenic drivers in non-smokers such as EGFR, ALK, or BRAF. BRCA1 and BRCA2 germline mutations have been extensively described as oncogenic drivers of breast and ovarian cancer, although they have not been proven to be associated with lung cancer^{10, 11}. To study the potential link between BRCA2 and lung cancer, a retrospective study analyzed a total of 362 patients and identified a 4.97% incidence rate of BRCA2 somatic mutations in patient diagnosed with NSCLC¹². The study demonstrated a correlation between BRCA2 somatic mutations and patients with aggressive subtypes of NSCLC. In this case, the discovery of a stop-gain c.1490C>G alteration in BRCA2 (S497*) helped guide the treatment decision of adding Olaparib, a PARP inhibitor, to her Pembrolizumab treatment, with the patient demonstrating a great clinical response. Only three previous reports had shown efficacy of Olaparib in NSCLC BRCA1/2 mutated patients, and one reported exceptional prolonged stable disease on Olaparib maintenance following completion of Nivolumab therapy^13–15. While preclinical studies have shown that Olaparib does inhibit and induce apoptosis in BRCA1/2 mutated lung cancer, clinical evaluations are ongoing and there are currently eleven clinical trials evaluating Olaparib in NSCLC (NCT01562210, NCT04538378, NCT01513174, NCT02484404, NCT03334617, NCT02498613, NCT03976323, NCT02679963, NCT04380636, NCT03976362, NCT03775486)¹⁶.

The decision was made to continue treatment with Pembrolizumab and add Olaparib due to preclinical data reporting synergy between PARP inhibitors and immune checkpoint inhibitors. Olaparib and other PARP inhibitors have shown to upregulate PD-L1 expression in preclinical studies ¹⁷, which has the potential to sensitize the tumor to PD-1/PD-L1 therapy. Preliminary evidence for other metastatic solid tumors, including castration-resistant prostate, ovarian, breast, cervical, and uterine cancers, have shown therapeutic benefit and acceptable safety with PARP inhibitor and anti-PD-1/PD-L1 therapy ^{18, 19}. An ongoing phase III study of first-line Pembrolizumab plus Pemetrexed/Platinum followed by Pembrolizumab and maintenance Olaparib versus Pemetrexed in patients with metastatic NSCLC (KEYLYNK-006) is currently being evaluated ²⁰. While Olaparib has shown single-agent antitumor activity, preclinical results suggest it may have efficacy in combination ^{17, 21–23}. Several studies in multiple solid tumor cancer types are also ongoing to evaluate the efficacy of Olaparib in combination with anti-PD-1/PD-L1 therapy with preliminary evidence showing potential therapeutic benefit ^18–20.

Approximately 8% of lung cancer cases are considered familial due to genetic predisposition, although the incidence rate is higher when considering shared social lifestyles and environmental factors^{24, 25}. It has been reported that a diagnosis of lung cancer in a first-degree family member increases the risk of developing cancer, regardless of smoking history²⁶. In Xuanwei City in the Yunnan providence of China, both environmental and genetic factors have significantly increased the number of lung cancer diagnoses, especially in young women^{27, 28}. Our patient had a history of lung cancer in her family, which nevertheless increased her risk of developing it herself despite no smoking history. Furthermore, the prevalence of never smokers developing lung cancer has increased over time, with an estimated incidence of 15–20% in men and over 50% in women²⁹. A recent analysis of lung cancer diagnosis in young men versus women also described high rates of lung cancer frequency in young women but was not able to conclude that this was due to different smoking behaviors between genders³⁰. More studies are necessary to explain the genetic mechanisms resulting in a worldwide elevated incidence rate of BRCA1/2 mutated lung cancer in young women compared to young men.

CONCLUSION

We reported a rare case of a young woman with lung cancer and a germline BRCA2 mutation who was treated with immunotherapy and Olaparib. Germline mutations in lung cancer are rare but warrant further investigation and identification of appropriate personalized therapy.

Table 1.

The patient’s germline mutation in the BRCA2 gene.

Gene	Chrom osome	HGVS DNA reference	HGVS Protein Reference	Variant Type	Predicted Effect	dbSNP/ dbVar ID	Genotype (heterogous or homozygous	ClinVar ID
BRCA2	13	NM_000059.3 (BRCA2): c.1490C>G (p.Ser497Ter)	NP_000050.2: p.Ser497 Ter	Nonsense, stop-gain	Premature truncation	nsv4449760	Heterozygous	RCV000774812.3

Clinical Practice Points.

• Familial history of lung cancer is concerning in the clinical setting and often, germline testing is warranted.

• Individuals with germline alterations in BRCA1 and BRCA2 have increased susceptibility to hereditary cancers such as breast, ovarian, and prostate cancers.

• We present a clinical case of a young female patient with a notable germline mutation in BRCA2 gene (BRCA2 S497*), concomitantly diagnosed with widespread non-small cell lung cancer (NSCLC). The patient is currently treated with Pembrolizumab, an anti-PD-1 antibody, and Olaparib, a poly-ADP ribose polymerase (PARP) inhibitor, with positive treatment response.

• Olaparib has been shown to have potent antitumor activity in patients with BRCA-mutated breast cancer and in ovarian cancer. Although there is evidence of Olaparib’s effectiveness on lung cancer in the preclinical setting, ongoing investigation is underway to evaluate efficacy and safety of Olaparib alone or in combination with chemotherapy or immunotherapy as a promising therapeutic strategy in patients with NSCLC.