BRCA1 and BRCA2 mutations and PARP inhibitors

BRCA1 and BRCA2 mutations and PARP inhibitors
PARP inhibitors are a group of cancer drugs that inhibit the enzyme Poly ADP Ribose Polymerase and are typically designed to be used with inheritable mutations such as BRCA1 and BRCA2 in Breast cancer and Ovarian cancer; the group includes oliparib, talazoparib, nilaparib, veliparib and rucaparib.  
 
PARP - Poly(ADP-ribose) polymerase - is actually a group of enzymes usually activated by DNA damage. Used by healthy cells to repair themselves, cancer cells also use PARP to repair DNA damage, thus extending their life. PARP inhibitors first received FDA approval in 2016. 
 
PARP and breast and ovarian cancer
 
Breast cancer is the most frequently occurring cancer in women, worldwide, with ovarian the most frequent gynaecological cancer – over 40,000 women die from breast cancer and 14,000 from ovarian per year (1). While the overall 5-year survival rate for breast cancer is 80%, for ovarian it is 36% and has not improved in 50 years (2). In part this is due to the late diagnosis of the latter disease.
 
More than 70% of ovarian cancers are now thought to originate not in the ovaries but in the Fallopian Tubes. Pathogens in the Fallopian tubes have been linked to the cancer.
 
BRCA1 gene mutations account for about 1-2% of all breast cancers, but virtually all of familial breast and ovary tumours (3). BRCA1 gene mutations are more often associated with Triple Negative Breast Cancer (TNBC). BRCA1 and BRCA2 tumour suppressor proteins form a complex with a third protein Rad51, and this plays an important role in DNA repair. BRCA1 is involved with the tumour suppressor protein p53. This is a signaling protein that confirms DNA damage, and works to repair or kill off the cell. BRCA1 related cancers are more likely to be Oestrogen negative (ER-ve).
 
List of PARP inhibitors
 
PARP inhibitors such as oliparib, talazoparib, nilaparib, veliparib and rucaparib, have been approved by the U.S. FDA for the treatment of women with breast cancer, or ovarian cancer who have recurrent disease or received prior therapies. They do have side-effects – some differing greatly depending upon the brand used – and so side-effects can determine choice of brand. In all cases to date, the cancer does withstand them after a while.
 
Rucaparib and pancreatic cancer

But, given that BRCA1 and BRCA2 mutations are found in about 7% of the overall Western population – female and male – it is of little surprise that rucaparib has now been shown relevant to pancreatic patients with BRCA mutations in a phase II clinical trial (4).

"These results not only point us in a new treatment direction to further investigate for patients with pancreatic cancers, but it also reinforces the clinical significance of the BRCA genes beyond ovarian and breast cancer and the utility of PARP inhibitors in other cancers," said Dr. Susan M. Domchek, executive director of the Basser Center for BRCA at the Abramson Cancer Center of the University of Pennsylvania.

Importantly, Domchek said, none of the patients who benefited from rucaparib had tumours that had progressed on a prior platinum-based chemotherapy, suggesting a potential role for rucaparib as an earlier treatment for patients whose tumours are not resistant to such treatments.
 
Rucaparib is a PARP inhibitor shown to be an effective therapy in ovarian cancers with BRCA 1 and 2 mutations. In 2016, the drug was approved by the FDA for women with BRCA-associated ovarian cancer who received two or more prior chemotherapies. And in April 2018, the approval was extended to women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are having a complete or partial response to platinum-based chemotherapies.
 
Overall, a clinical benefit was observed in 32 percent of pancreatic patients (6/19) treated with rucaparib, and 45 percent in patients (4/9) who had received only one prior chemotherapy for locally advanced or metastatic disease. Nine patients had progressive disease, and three were not evaluable for response. The objective confirmed response rate, the primary endpoint for the study, was 16 percent (3/19).

The trial included 11 men and eight women, with a median age of 57. Twenty-one percent of the patients had BRCA1 mutation-associated pancreatic cancer, while 79 percent were associated with BRCA2 mutations.

Go to: Gene Mutations like BRCA 1 and BRCA 2 and your increased risk of cancer

Go to: Having a gene mutation makes no difference to survival once you have cancer

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References  
 
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29. 
 
2.  Howlader N, Noone AM, Krapcho M, et al., editors. SEER cancer statistics review, 1975–2011, National Cancer Institute [Internet Bethesda: National Cancer Institute; 2014.
 
3. Karami F, Mehdipour P. A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer. Biomed Res Int. 2013;2013:928562. 4. .  Rucaparib Monotherapy in Patients With Pancreatic Cancer and a Known Deleterious BRCA Mutation. Shroff, RT et al. JCO Precision Oncology (May 16, 2018): 
2018 Research
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