The Role of Precision Medicine in the Diagnosis and Treatment of Patients with Rare Cancers

Abstract

Rare cancers pose unique challenges for patients and their physicians arising from a lack of information regarding the best therapeutic options. Very often, a lack of clinical trial data leads physicians to choose treatments based on small case series or case reports. Precision medicine based on genomic analysis of tumors may allow for selection of better treatments with greater efficacy and less toxicity. Physicians are increasingly using genetics to identify patients at high risk for certain cancers to allow for early detection or prophylactic interventions. Genomics can be used to inform prognosis and more accurately establish a diagnosis. Genomic analysis may also expose therapeutic targets for which drugs are currently available and approved for use in other cancers. Notable successes in the treatment of previously refractory cancers have resulted. New more advanced sequencing technologies, tools for interpretation, and an increasing array of targeted drugs offer additional hope, but challenges remain.

Appendices

A Case Report from a Rare Cancer Precision Medicine Tumor Board

• Sourat Darabi 

1. Hoag Family Cancer Center, Newport Beach, CA 92603, USA

   Sourat Darabi

A 41-year-old woman with no family history of cancer was diagnosed with moderately differentiated serous adenocarcinoma of ovary. She underwent a radical hysterectomy with tumor debulking, followed by chemotherapy with carboplatin and paclitaxel (paclitaxel/carboplatin). The patient later developed recurrence of her cancer and was treated with carboplatin heated intraperitoneal chemotherapy.

A comprehensive somatic 592-gene sequencing panel tumor profiling (Caris Life Sciences, Phoenix AZ) was performed on the patient’s tumor. The results showed no microsatellite instability (MSI), proficient mismatch repair by immunohistochemistry, estrogen receptor positive immunostaining, and a pathogenic variant in BRCA1 gene, p.K1254fs (Table 3.4). The gene encodes BRCA1 protein that is involved in DNA damage repair. Pathogenic variants in this gene have been associated with increased risk of several types of cancer, including hereditary breast and ovarian cancer. Somatic BRCA1 mutations are illustrated in Fig. 3.1 with 63 truncating mutations from The Cancer Genome Atlas (TCGA) [120]. The specific loss of function BRCA1 mutation identified in this patient’s tumor could be a potential germline variant, so referral to a genetic counselor and germline testing is recommended. Individuals who harbor germline mutations in BRCA1 are at increased risk for cancers of the breast, ovary, prostate, pancreas, and possibly colon and other cancers.

Table 3.4 Highlights of patient’s tumor profiling results

Fig. 3.1

Spectrum of reported BRCA1 truncating mutations in cBIo portal [120]. The blue arrow indicates the approximate region where the p.K1254fs variant identified in this patient occurred. The horizontal axis displays the identified truncating mutations in 1754 samples (from three different TCGA datasets), and the boxes are BRCA1 domains. The vertical axis indicates the frequency of the identified variants

Ovarian cancer is estimated to be responsible for approximately 2.3% of all cancer deaths in the USA in 2018 [121]. Approximately half of tumors in patients with high-grade serous ovarian cancer have homologous recombination repair deficiencies, which are most often caused by pathogenic mutations in the BRCA1 or BRCA2 genes [122]. Germline mutations in BRCA1 and BRCA2 are also frequently seen in patients with high-grade serous ovarian cancer [123]. Homologous recombination repair deficiencies lead to insufficient double-stranded DNA breaks repair [124]. Poly (ADP-ribose) polymerase (PARP) enzymes repair single-stranded DNA breaks with a mechanism called base excision repair (BER). Inhibition of PARP in tumors with homologous recombination repair deficiencies causes inaccurate DNA repair leading to cell cycle arrest and apoptosis, as it is illustrated in Fig. 3.2 [124, 125].

Fig. 3.2

Molecular mechanism of PARP inhibition (PARPi). Single-strand break (SSB) DNA repair is carried by mismatch repair (MMR), nucleic acid excision repair (NER), and base excision repair (BER) mechanisms. PARPi impairs BER, so an SSB becomes a double-strand break (DSB). Non-homologous end joining (NHEJ) and homologous recombination (HR) mechanisms are involved in DSB repair. When PARP inhibition occurs in a patient who has a homologous recombination repair (HR) deficiency, due to a BRCA mutation, then a DSB cannot be repaired and cell death or apoptosis results [125, 131]

Olaparib is a PARP inhibitor and is approved to treat patients with ovarian cancer that harbor BRCA1 or BRCA2 mutations. Patients with platinum-sensitive high-grade serous ovarian cancer and somatic or germline BRCA1/2 mutations benefit similarly from olaparib treatment; progression-free survival (PFS) is illustrated in Fig. 3.3 [123]. A combination of olaparib with chemotherapy (carboplatin and paclitaxel) in patients with an advanced breast and ovarian cancer showed significant results [126–128]. There are other PARP inhibitors on the market such as niraparib and rucaparib. In a randomized, placebo control phase III clinical trial, niraparib increased PFS in patients with recurrent ovarian cancer [129]. The AREL3 study, a randomized, placebo control double-blinded phase III study, showed rucaparib in patients with platinum-sensitive ovarian cancer improved PFS [130].

Fig. 3.3

Progression-free survival of patients with BRCA1/2 somatic mutations compared with the ones with germline mutations treated with olaparib or placebo. The blue line is the group treated with olaparib, and the black line is for the placebo group (from Dougherty [123])

Thus, the results from tumor profiling, along with the outcomes from several clinical trials, provide valuable information to help clinicians offer a personalized precision care for this patient. If the BRCA1 mutation proves to be a germline mutation, then family members should be referred for genetic counseling as well.

Take Home Points

• (1) Referral to genetic counseling for germline testing is recommended based on the tumor profiling results;

• (2) Consider PARPi to treat the patient according to the data, showing the efficacy of PARPi in patients with BRCA mutations.