Precision Cancer Medicines for Ovarian Cancer
by C.H. Weaver M.D. updated 6/2020
Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack ovarian cancer cells with specific genetic abnormalities, leaving normal cells largely unharmed and can often be used instead of chemotherapy.
In order to identify which precision cancer medicines can be used molecular diagnostic testing, including DNA sequencing is necessary to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy that attacks a specific mutation or other cancer-related change in the DNA programming of the cancer cells can be selected for treatment.
Cancer cells may differ from one another based on what genes have mutations. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. This “genomic testing” is performed on a biopsy sample of the cancer and increasingly in the blood using a “liquid biopsy”
Precision cancer medicines can be used both instead of and in addition to chemotherapy to improve treatment outcomes.
All newly diagnosed individuals with ovarian cancer should make sure genomic-biomarker testing is performed on their cancer tissue. Once established these genomic markers can be followed in the blood using a "liquid biopsy" to evaluate response to treatment and the development of new mutations. (1-14)
PARP Inhibitors for Ovarian Cancer with BRCA Mutations
The poly ADP-ribose polymerase (PARP) enzyme plays a role in DNA repair, including the repair of DNA damage from chemotherapy. Precision cancer medicines that target and inhibit this enzyme may contribute to cancer cell death and increased sensitivity to chemotherapy and are called PARP inhibitors. By blocking this enzyme, DNA inside the cancerous cells is less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth. (1-7)
PARP inhibitors have the greatest effect in women with mutations of the BRCA genes but may benefit additional patients with different genetic profiles as well. BRCA genes are involved with repairing damaged DNA and normally work to prevent tumor development. However, mutations of these genes may lead to certain cancers, including ovarian cancers.
The BRCA genes are involved with repairing damaged DNA and normally work to suppress tumor growth. Women with mutations resulting in defective BRCA genes are more likely to get ovarian cancer.
Approximately 20% of ovarian cancers exhibit BRCA gene mutations and an additional 30% more have homologous recombination (HR) deficiencies. The BRCA gene plays a role in repairing DNA via homologous recombination (HR), and mutation of this gene leads to HR deficiency (HRD). This leads to disruptions in normal DNA damage repair. DNA breaks are normally repaired to protect the genome and unrepaired DNA damage can result in accumulated mutations, unregulated cell division, and cancer susceptibility. (1-3)
Using poly (ADP-ribose) polymerase (PARP) inhibitors in patients with HRD blocks two pathways of DNA repair, resulting in increased cancer cell death. Ovarian cancers with HRD behave similarly to those with BRCA mutations, and this behavior is termed “BRCAness”.
LynparzaTM (olaparib) constitutes the first PARP inhibitor approved for treating ovarian cancer. Lynparza was approved for patients with specific abnormalities in the BRCA gene. (5)
Zejula (niraparib) when used as maintenance therapy following platinum-based chemotherapy appears to improve the time to cancer progression among patients with recurrent ovarian cancer. Patients with BRCA 1 and BRCA 2 germline mutations appear to derive the greatest benefit from Zejula.
Rubraca™ (rucaparib): In patients with BRCA-positive ovarian cancer that had returned after previous treatment more than half of the patients treated with Rubraca responded to treatment for an overall response rate of 65%. Patients who had the longest time to cancer progression before the study had the highest response rates. (6)
Avastin is a precision cancer medicine that targets a protein known as VEGF. VEGF plays a key role in the development of new blood vessels necessary for cancer cell growth. By blocking VEGF, Avastin deprives the cancer of nutrients and oxygen and inhibits its growth. Clinical trials have shown an improvement in overall survival for women with platinum-sensitive recurrent ovarian cancer who were treated with Avastin plus chemotherapy compared to chemotherapy alone and when used in combination with a PARP inhibitor for maintenance therapy. (8,xx)
Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the lung cancer cells. Checkpoint inhibitors are being evaluated in combination with PARP inhibitors and other medications for the treatment of ovarian cancer.
Not all ovarian cancers respond to treatment with a PARP inhibitor. Clinical evidence suggests that most serous ovarian cancers respond to treatment with a PARP however mucinous, clear cell, and low grade serous cancers are much less likely to have HRD and respond to treatment. (4) Other cancer driving mutations however are being identified as potential treatment targets.
Targetable Cancer Driving Mutations in Ovarian Cancer
The RAS Genes: KRAS and NRAS are a family of proteins found in cells that when mutated promote cancer cell growth. (10,11)
BRAF: BRAF is also a gene that signals cells to divide. Some women will have a specific mutant BRAF gene called BRAFV600 although other BRAF mutations do exist. BRAFV600 cancers may benefit from treatment with specific precision cancer medicines that target BRAF. (12)
PIK3CA: While somewhat new, a growing number of clinicians are testing for mutant PIK3CA genes.
Microsatellite Instability High (MSI-H) MSI-H is a DNA abnormality found in a small number of ovarian cancers. It is most often found in tumors associated with genetic syndromes like Lynch syndrome but can also occur sporadically. MSI-H is what “happens” when the genes that regulate DNA function don’t work correctly. These DNA regulating genes, known as Mismatch Repair Genes (MMR), work like genetic “spell checkers.” When problems occur in these spell-checking MMR genes, it means that areas of DNA start to become unstable. A high frequency of instability is called MSI-H and these individuals often respond to checkpoint inhibitor immunotherapy and can avoid chemotherapy all together.
PD-1 and PD-L1 are proteins that inhibits certain types of immune responses, allowing cancer cells to evade an attack by certain immune cells. Drugs that block the PD-1 and PD-L1 pathway enhance the ability of the immune system to fight cancer and are referred to as checkpoint inhibitors for their ability to help the immune system recognize and attack cancer. A diagnostic test to measure the level of PD-L1 is available.(13,14)
- Keytruda (pembrolizumab) and Opdivo (nivolumab) are “checkpoint inhibitors” that have modest anti-cancer activity in advanced ovarian cancer patients. Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. The final analysis of the Keynote-100 clinical trial which evaluated Keytruda in women with advanced recurrent epithelial ovarian cancer was presented during the ASCO 2020 Virtual meeting. The overall response rate was a modest 8.1% in 285 women with 1-3 prior lines of therapy with a prior progression free interval of 3-12 months, and 9.9% in 91 women with 4-6 prior lines of therapy and a prior progression free interval of at least 3 months. When evaluating for response by PD-L1 expression, higher expression did correlate with increased response rates. Higher PD- L1 CPS scores greater than 10 was however associated with improved response rates to 13.8%. These results are also consistent with such as Opdivo, which demonstrated a response rate of 12.2% in the single arm of NRG GY003 clinical trial. (16) Checkpoint inhibitors also have anti-cancer activity in patients with microsatellite instability high (MSI-H) abnormalities (13.14)
HER 2 is a protein involved in normal cell growth and well know as a target for treatment in breast cancer. Some ovarian cancers over-express (make too much of) the HER2 protein, and this over-expression contributes to cancer cell growth and survival. HER2 targeted therapies is HER2 + cancer can dramatically improved outcomes.
TRK: TRK fusions are chromosomal abnormalities that occur when one of the NTRK genes (NTRK1, NTRK2, NTRK3) becomes abnormally connected to another, unrelated gene (e.g. ETV6, LMNA, TPM3). This abnormality results in uncontrolled TRK signaling that can lead to cancer. TRK fusions occur rarely but can occur in ovarain cancer. TRK fusions can be identified through various diagnostic tests, including targeted next-generation sequencing (NGS), immunohistochemistry (IHC), polymerase chain reaction (PCR), and fluorescent in situ hybridization (FISH).(15)
- Li X, Heyer WD. Homologous recombination in DNA repair and DNA damage tolerance. Cell Res. 2008;18((1)):99–113. doi: 10.1038/cr.2008.1.
- Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature. 2001;411((6835)):366–74. doi: 10.1038/35077232.
- Petrucelli N, Daly MB, Feldman GL. Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2. Genet Med. 2010;12((5)):245–59. doi: 10.1097/GIM.0b013e3181d38f2f.
- Elvin JA, He Y, Sun J, Odunsi K, Szender JB, Moore KN, et al. Comprehensive Genomic Profiling (CGP) with Loss of Heterozygosity (LOH) Identifies Therapeutically Relevant Subsets of Ovarian Cancer (OC) J Clin Oncol. 2017;34(15 Suppl):5512. doi: 10.1200/JCO.2017.35.15_suppl.5512. abstr.
- Shapira-Frommer R, Oza AM, Domchek SM, et al. A phase II open-label, multicenter study of single-agent rucaparib in the treatment of patients with relapsed ovarian cancer and a deleterious BRCA mutation. Journal of Clinical Oncology. 33, 2015 (supplement; abstract 5513).
- Tesaro Inc., press release. Tesaro’s niraparib significantly improved progression-free survival for patients with ovarian cancer in both cohorts of the phase 3 NOVA trial. Available at: . Accessed July 6, 2016.
- Coleman RL, et al. Lancet Oncol 2017;18:779-91.
- Aghajanian C, et al. J Clin Oncol 2012;30:2039-45
- Karapetis CS, Khambata-Ford S, Jonker DJ et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. New England Journal of Medicine. 2008;359:1757-65.
- Amado RG, Wolf M, Peeters M et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. Journal of Clinical Oncology. 2008;26:1626-1634.
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