Response in BRCA1 mutation carrier with metastatic pancreatic adenocarcinoma treated with FOLFIRINOX

Abstract

A woman in her 50s previously treated for early-stage breast cancer, parotid mucoepidermoid carcinoma and Caroli’s disease was diagnosed with stage IV pancreatic ductal adenocarcinoma (PDAC) metastatic to the liver and was found to harbour a BRCA1 germline mutation. She had palliative chemotherapy, initially with 5-fluorouracil, leucovorin, irinotecan and oxaliplatin, and then FOLFIRI and capecitabine, achieving a sustained near-complete response for at least 86 months. Chemotherapy was eventually discontinued when she was diagnosed with a tongue squamous cell carcinoma. Despite withholding systemic therapy, she has maintained a durable response. This is the first report in the English literature showing a sustained duration of response in a patient with PDAC and BRCA1 germline mutation.

Background

Despite recent advances, the prognosis for metastatic pancreatic ductal adenocarcinoma (PDAC) remains poor with a 5-year survival rate <3%.¹ 5-Fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel are the mainstays of treatment for unresectable or metastatic PDAC² with median durations of response of 5.9 and 3.9 months, respectively. The median progression-free survival with these therapies is approximately 6 months.^{3 4}

Over the last decade, the genomic characteristics of PDAC have been well studied, and inherited syndromes associated with a predisposition for PDAC have been identified.⁵ Approximately 20% of patients with PDAC harbour a germline deleterious variant (mutation) in cancer predisposition genes⁶ with BRCA1 or BRCA2 being the most commonly mutated and present in 4%–7% of patients.⁷ The lifetime risk of developing PDAC is approximately 3.5 times higher among BRCA2 mutation carriers⁸ and 3 times higher among BRCA1 carriers as compared with the general population.⁹ BRCA1 and BRCA2 are tumour suppressor proteins involved in repairing double-strand DNA breaks via homologous recombination (HR), and their loss of function has an essential role in tumorigenesis.¹⁰

Although the optimal chemotherapy regimen for patients who develop PDAC in the setting of a germline BRCA mutation has not been established, several studies and case reports have demonstrated benefit from platinum-containing chemotherapy.¹¹ Complete responses (CRs) in PDAC are rare but have been reported in patients with BRCA2-associated PDAC.^12–14 Here we present a case of an exceptional duration of response lasting more than 86 months in a patient with BRCA1-associated stage IV PDAC.

Case presentation

A woman in her 50s initially presented with several months of mid-back pain. She had previously been diagnosed with oestrogen and progesterone receptor-negative stage II breast infiltrating ductal carcinoma in her 30s and was treated with lumpectomy followed by adjuvant chemotherapy with doxorubicin, cyclophosphamide and radiation. In her 40s, she was diagnosed with a low-grade mucoepidermoid carcinoma of the left parotid gland treated with surgical resection and radiation. Six years before, an MRI showed severe dilation of intrahepatic ducts of the lateral liver segment, findings consistent with left-sided Caroli’s disease. She was followed up annually with magnetic resonance cholangiopancreatography as screening for cholangiocarcinoma.

Her family medical history is notable for her father having died of hepatocellular carcinoma that developed in the setting of alcohol-associated cirrhosis in his 70s and her mother having died of tobacco-associated lung cancer in her 50s.

Investigations

At presentation, a screening MRI for cholangiocarcinoma identified a 3.9 cm×3.0 cm pancreatic tail mass and multiple liver lesions up to 2.5 cm. CA-19-9 was 43 652 U/mL. A liver biopsy confirmed adenocarcinoma of pancreaticobiliary origin (figures 1 and 2). Because of the personal history of multiple malignancies, she was referred for germline genetic testing, which identified a deletion (exons 1–23) in BRCA1.

Figure 1.

(A, B) CT abdomen demonstrated a 3.9 cm pancreatic tail mass (arrowhead, B) as well as multiple hepatic metastatic lesions measuring up to 2.5 cm (arrow, B) at the time of diagnosis.

Figure 2.

Hypodensity of 0.6 cm in the pancreatic tail, reflecting post-treatment change from the previously visualisedpancreatic tail mass.

Treatment

Approximately 5 weeks after diagnosis, the patient commenced palliative chemotherapy with FOLFIRINOX. Following four cycles, surveillance CT showed a marked response in both the pancreas and liver and her carbohydrate antigen 19-9 (CA 19-9) down-trended (figure 3). At the end of cycle 7 of FOLFIRINOX, the tumour measured 1 cm, showing a near-complete response (nCR). Oxaliplatin was discontinued due to the onset of grade 3 peripheral neuropathy, and she was continued on fluorouracil, leucovorin and irinotecan (FOLFIRI). She completed 20 cycles of FOLFIRI and was then maintained on oral capecitabine for almost 4 years. Surveillance imaging was performed every 3–6 months and showed no cancer progression. Given her increased risk for developing ovarian cancer, she underwent prophylactic bilateral salpingo-oophorectomy. Several years after, she was diagnosed with a squamous cell carcinoma of the tongue. Chemotherapy was discontinued while she pursued surgery for squamous cell carcinoma. She remains off chemotherapy and is in a stable nCR.

Figure 3.

Trend in carbohydrate antigen 19-9 biomarker, tumour measurements and clinical events.

The patient has been surveilled with history, physical examination, CA 19-9 every 3 months, and CT of the chest/abdomen/pelvis annually. Despite withholding chemotherapy for at least 33 months, her pancreatic and liver tumours have continued to regress per imaging figure 2. CA 19-9 has normalised, and the duration of response has persisted for longer than 86 months (about 7 years) per last CT scan.

Discussion

According to the Response Evaluation Criteria in Solid Tumours V.1.1, CR is defined as the disappearance of all target lesions, and partial response (PR) is defined as at least a 30% decrease in the sum of the diameters of the target lesions, compared with baseline sum diameters.¹³ Some retrospective studies have defined ‘nCRs’ as tumours less than 1 cm without nodal metastases.¹⁵ The National Cancer Institute defines exceptional responders by one or more of the following criteria: (1) they received treatment in which fewer than 10% of patients attain a CR or durable PR lasting 6 months or more; (2) they achieved either a CR or PR lasting at least 6 months; or (3) they achieved a sustained CR or PR (eg, >3 times longer than the median duration of response reported for specific treatment).¹⁴ In the ACCORD/PRODIGE-4 study that established FOLFIRINOX, 0.6% of subjects achieved a CR at 6 months, and the median duration of response was 5.9 months.⁴ Given that our patient had PR lasting more than 86 months, she meets all criteria for an exceptional responder.

Germline BRCA1 mutations confer a high lifetime risk of breast cancer (60%) and ovarian cancer (>40 %) and are associated with a 3% lifetime risk of pancreatic, prostate and other cancers.⁹ HR is an essential mechanism for the repair of DNA double-strand breaks, and the defining step is strand exchange directed by RAD51 monofilament formation. BRCA1 and BRCA2 have been identified as tumour suppressor genes in the same pathway but with different roles in HR.¹² BRCA1 protein protects broken DNA from nucleases and suppresses the formation of tandem duplication, sensing and initiating the process DNA repair.¹⁶ In contrast, BRCA2 promotes R-loop resolution allowing the formation of RAD51 monofilaments at the site of DNA breaks.¹⁷ PALB2 and RAD51 paralogs, proteins involved in HR, have also been identified as tumour suppressor genes.¹⁸ Some studies in human cells show that RAD51 foci formation induced by platinum drugs requires a functional BRCA1 protein.¹⁹ Genetic testing in our patient showed wild-type RAD51 and PALB2 genes.

The patient was first treated with FOLFIRINOX, an established cytotoxic chemotherapy regimen for advanced PDAC. Oxaliplatin is a cross-linking agent that exerts its cytotoxic effect through DNA damage during S-phase primarily by causing double-strand breaks. When combined with other chemotherapeutic agents such as fluorouracil, oxaliplatin can downregulate or inhibit dihydropyridine dehydrogenase, slowing 5FU catabolism.²⁰ Given the role of BRCA in DNA repair, it is hypothesised that BRCA1-mutant cells follow the paradigm of having spontaneous chromosome instability with resultant increased cancer incidence, as well as increased sensitivity to cross-lining agents.²¹ BRCA-associated ovarian cancer is associated with improved survival likely due to the high sensitivity to cisplatin.²² A case series of 12 patients with breast cancer who were carriers of BRCA1 mutation and treated with platinum chemotherapy as neoadjuvant treatment showed 83% CR rate,²³ although this finding has not yet been confirmed in a prospective randomised trial in the American population.²⁴ In recent years, growing evidence supports that BRCA mutation carriers with PDAC also respond better when treated with platinum-based chemotherapies.²⁵

Previously published retrospective studies and case reports have suggested a benefit in overall survival in patients with PDAC with BRCA germline mutations treated with platinum-based chemotherapy, but exceptional responses have not been explicitly described in BRCA1 carriers as they have been in BRCA2.^{25 26} In 2014, Golan et al conducted a retrospective study assessing overall survival and clinical characteristics of PDAC in BRCA carriers and found a higher median overall survival in those treated with platinum versus non-platinum chemotherapies.¹¹ More recently, the POLO (Pancreas Cancer Olaparib Ongoing)trial established the role of the poly ADP ribose polymerase (PARP) inhibition as maintenance therapy for patients with advanced PDAC and germline BRCA mutations who achieve disease control with platinum-containing chemotherapy. The POLO study is the largest and only prospective study evidencing the effect of platinum-based therapies in pancreatic cancer with BRCA germline mutations.²⁷ Still notably, only 8 out of 62 patients (9.6%) who received placebo after an initial period of platinum-based chemotherapy were progression-free after 2 years.²⁷

Historically, screening for BRCA mutations was limited to cases with a family history highly suggestive of familial pancreatic cancer, but given the recent implications of germline mutations in response to specific treatments, universal germline testing is now recommended.²⁸ According to the updated The American Socioety of Clinical Oncology (ASCO) guidelines for pancreatic cancer in 2019, germline genetic testing should be offered to patients with pancreatic cancer and unremarkable family history if an informative result could directly benefit the patient or family members.²⁹ The growing evidence of BRCA mutation impact on response and sensitivity to DNA damaging agents may guide the design of future treatments and clinical trials in PDAC.

Patient’s perspective.

I must admit when I was diagnosed with stage IV pancreatic cancer, I was unaware the mortality was so high. I had no experience with pancreatic cancer. I did not know anyone who had ever dealt with it. When my oncologist told me I would fight this disease for the rest of my life, what I was hearing was that I would receive treatment for the disease and when the treatment did its job I would continue to be followed through blood work and imaging. That is what happened with my previous cancers, so that was my expectation.

I chose to receive the most aggressive chemotherapy offered, FOLFIRINOX every 14 days. I was dreading chemo when I received it in the past, nausea and vomiting were the norms and I did take antinausea medication. I was pleasantly surprised that antinausea medication has come a long way since the 1990s. On the plus side, the hospital staff and volunteers were wonderful. They could not do enough for you. I still remember the warm blankets. I so looked forward to getting my CA-19–9 blood count each time I went for a treatment. It always went down and to me, it was a huge win, the treatment was working. Perhaps the best part was the support I received from my family and friends.

I do not know why I am so lucky, I am so thankful to be doing so well. What seems odd to me is that treatment for pancreatic cancer did not leave any lasting effects, while treatment for a less serious parathyroid tumor has left me with a mouth droop that affects my ability to smile. I cannot let it bother me as I do have a lot to smile about.

Learning points.

• Exceptional responders to chemotherapy in stage IV pancreatic ductal adenocarcinoma (PDAC) are rare.

• Patients with BRCA1 and BRCA2 germline mutations in pancreatic cancer represent a small subset but clinically significant group who benefit from therapies that interfere with homologous recombination.

• There is growing evidence that supports the early identification of BRCA germline mutations in treatment considerations of PDAC.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).