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. Author manuscript; available in PMC: 2019 Jun 15.
Published in final edited form as: Cancer. 2018 Apr 16;124(12):2498–2506. doi: 10.1002/cncr.31307

PARP Inhibition in BRCA-Mutant Breast Cancer

Anita Turk 1, Kari B Wisinski 2
PMCID: PMC5990439  NIHMSID: NIHMS940810  PMID: 29660759

Abstract

Individuals with BRCA1 or BRCA2 germline mutations have a significantly increased lifetime risk for breast and ovarian cancers. BRCA-mutant cancer cells have abnormal Homologous Recombination (HR) repair of DNA. In these tumors, the Base Excision Repair (BER) pathway is important for cell survival. The Poly(ADP-ribose) polymerase (PARP) enzymes play a key role in BER and PARP inhibitors (PARPi) are effective in causing cell death in BRCA-mutant cells while sparing normal cells-a concept called synthetic lethality. PARPi are the first cancer therapy designed to exploit synthetic lethality. Recent clinical trials in BRCA-mutant metastatic breast cancer have demonstrated improved outcomes with single agent PARPi’s (olaparib and talazoparib) over chemotherapy. However, resistance to PARPi remains a challenge and due to myelosupression, the combination of PARPi with chemotherapy has been difficult. Novel combinations with chemotherapy, immunotherapy and other targeted therapies are being pursued. In this article, we discuss current knowledge of PARPi in BRCA-mutant breast cancer and potential future directions for these agents.

Keywords: PARP, BRCA-mutant, Breast Cancer, Hereditary, DNA Repair

BRCA1/2 mutations in Breast Cancer

The majority of breast cancers are sporadic, with 5–10% classified as hereditary breasts cancers. Germline mutations in the BRCA1 or BRCA2 genes result in hereditary breast and ovarian cancer syndrome (HBOC). The BRCA1 gene, located on chromosome 17, was first identified and cloned in 1994.1 Subsequently, BRCA2 was identified on chromosome 13.2 These tumor suppressor proteins function in the homologous recombination (HR) repair of double stranded DNA breaks. HR repair mechanism protects the integrity of the genome in proliferating cells during the S and G2 phases of the cell cycle. BRCA1 has multiple functions in DNA repair including recognition of DNA damage, checkpoint activation and recruitment of DNA repair proteins. BRCA2 mediates the recruitment of RAD51 to double stranded DNA breaks to allow for HR repair.3

Alterations in BRCA1 and BRCA2 lead to a highly penetrant, autosomal dominant predisposition to breast cancer with lifetime estimates as high as 84%.4 BRCA1 and BRCA2 mutations do result in different clinical phenotypes. Breast cancer risk begins to rise at younger ages for BRCA1 mutation carriers compared to BRCA2.5 BRCA1-mutated breast cancers are more often high grade, triple negative (TNBC) and have a basal epithelial phenotype, whereas BRCA2-mutant breast cancers more often exhibit a luminal B phenotype with expression of hormone receptors with higher Oncotype Dx recurrence score compared to sporadic tumors.6–8 The National Comprehensive Cancer Network guidelines recommend genetic testing for all patients with TNBC age 60 or lower as 15–33% will have an abnormal gene mutation.9,10

Mechanism of Poly (ADP-ribose) polymerase (PARP)

PARP is a family of enzymes, with the PARP1 and PARP2 isoforms having a key role in Base Excision Repair (BER) in response to single stranded DNA breaks.11,12 In response to DNA damage, the zinc-finger DNA binding domains localize PARP-1 and PARP-2 to the site of DNA damage. PARP enzymes then cause post-translational modification with the addition of ADP-ribose to target nuclear proteins.13–15 There is also evidence to suggest the role of PARP in restarting stalled DNA-fork replication and BRCA1/2-mediated homologous recombination.16

When PARP is inhibited, single strand breaks persist and result in stalled replication forks and double strand breaks. PARP function is impeded by PARP inhibitors (PARPi), which result in catalytic inhibition and can also trap PARP on DNA. These PARP-DNA complexes interfere with DNA replication and recent studies have indicated that PARP trapping is important for the cytotoxicity of PARPi.17 BRCA-mutant tumors develop HR deficiency secondary to germline mutation in one allele and loss of heterozygosity inactivating the other copy. Treatment of these tumors with a PARP inhibitor (PARPi) leads to accumulation of DNA damage resulting in cell cycle arrest and apoptosis.18–20 This effect of PARPi’s in cells with defects in the HR pathway is an example of synthetic lethality (Figure 1). Increased PARP activity is also one of the mechanisms by which tumor cells avoid apoptosis caused by DNA-damaging chemotherapy agents, which would normally be repaired through the BER system. Therefore, inhibition of PARP sensitizes tumor cells to cytotoxic agents such as alkylators and topoisomerase I inhibitors.21,22

Figure 1.

Figure 1

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Synthetic Lethality: Single-strand DNA breaks (SSB) lead to PARP recruitment and activation. PARP inhibition and trapping on DNA results in persistent single-strand breaks and stalling of replication forks. This leads to double-strand DNA breaks (DSB) which require homologous recombination (HR) for repair. In BRCA-mutant cancer cells, loss of heterozygosity leads to non-functional BRCA and HR repair cannot occur. This ultimately results in cell death. Normal cells retain a functional BR

Clinical Development in Breast Cancer

Several PARPi’s are being studied in BRCA-mutant breast cancer. PARPi clinical application has progressed under two strategies: PARPi monotherapy in malignancies with impaired DNA-damage repair pathways or PARPi in combination with DNA-damaging chemotherapy. Currently, there are five PARPi’s being investigated in clinical trials. These include olaparib, rucaparib, niraparib, talazoparib, and veliparib (Table 1). Initially, another agent, iniparib, was developed as a PARPi. However, after the negative results from a phase 3 trial of iniparib in combination with platinum and gemcitabine chemotherapy in metastatic TNBC,23 studies demonstrated that iniparib does not inhibit PARP in vitro.24

Table 1.

PARPi Developed in BRCA+ Breast Cancer In Order of Potency

Drug Name Mechanism
Inhibition Trapping PARP-DNA Complex
Veliparib PARP 1/2 No
Olaparib PARP 1/2/3 Yes
Rucaparib* PARP1/2/3 Yes
Niraparib PARP 1/2 Yes
Talazoparib PARP 1/2 Yes
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*

There is data demonstrating higher efficacy of PARP inhibition with rucaparib over niraparib83

PARPi’s differ in their potency for catalytic inhibition and ability to trap PARP. PARP trapping does not correlate with potency of PARP enzyme inhibition. Of the available PARPi’s, talazoparib is the most potent catalytic inhibitor, approximately 100 times more potent than niraparib.17 Talazoparib is the most potent in PARP trapping, but rucaparib, olaparib, and niraparib also achieve PARP trapping.17,25 Although PARP trapping with veliparib has been reported, it appears the weakest at this mechanism.25,26 These differences in potency and trapping ability may be a predictor of PARPi cytotoxicity in BRCA-mutant malignancies, with talazoparib having the most profound effect, but data is needed to determine if this leads to improved clinical outcomes.27 Increased cytotoxicity from PARP trapping may also increase toxicities, including cytopenias, and thereby, limit the single agent maximum tolerated dose and combinations with chemotherapy.26

Single Agent PARPi in Metastatic Breast Cancer

The initial phase 1 trial of olaparib enriched with carriers of BRCA mutations demonstrated promising early results: 47% of patients with any BRCA-mutant malignancy achieved a partial response.28 One of the three BRCA-mutant breast cancer patients had a complete response lasting more than 60 weeks on olaparib 200 mg BID. Of note, no response was seen in patients without a BRCA mutation. Several early phase studies with the other PARPi’s showed similar signals of efficacy in BRCA-mutant breast cancer (Table 2).29–32

Table 2.

PARPi in Metastatic BRCA+ Breast Cancer

PARPi Combination Agent(s) Ref Phase Tumor type PARPi Dose No of patients (BRCA breast cancer) MTD Results
Olaparib
N/A 26 1 Solid tumors 10-600mg BID 60 (3) 400 mg BID ORR 33% in BRCA breast cancer cohort
N/A 32 2 BRCA+ Breast Cancer 400mg BID or 100mg BID 54 (54) _ 400 mg BID ORR 41%; 100mg BID ORR 22%
N/A 31 2 BRCA+ breast cancer and ovarian cancer, TNBC, HGSOC 400 mg BID 90 (10) _ ORR 0% in breast cancer cohort
N/A 33 2 BRCA+ solid tumors 400 mg BID 317 (62) _ ORR 12.9% in BRCA+ breast cancer cohort
N/A 38 3 BRCA+ Breast Cancer 300 mg BID 302 (302) _ ORR 59.9% in the olaparib group vs 28.8%. PFS 7.0 m in the olaparib group vs 4.2 m
Cisplatin 40 1 Breast, Ovarian, Pancreatic, Peritoneal cancers 50 - 200 mg BID (continuous and intermittent dosing schedules) 53 (17) Not reached (cisplatin 60 mg/m2 with intermittent olaparib 50 mg bid deemed tolerable) ORR 71% in BRCA+breast cancer cohort
Carboplatin 41 1/1b BRCA+ Breast and Ovarian Cancer 100 - 400 mg BID (continous and intermittent dosing schedules) 45 (8) Not reached (carboplatin AUC 5 with intermittent olaparib 400 mg BID highest tested dose) ORR 87.5% in the BRCA+ breast cancer cohort
Niraparib N/A 29 1 Solid tumors 30-400mg 100 (4) 300mg ORR 50% in BRCA+ breast cancer cohort
Talazoparib N/A 28 1 Solid tumors 0.025–1.10 mg 110 (14) 1.0 mg ORR 50% in BRCA+ breast cancer cohort
N/A 34 2 BRCA+Breast Cancer 1mg qD 84 (84) _ ORR 26% in the TNBC cohort; ORR 29% in HR+ Her2 +/− cohort
Rucaparib N/A 27 1/2 Solid tumors 40–500 mg qD and 240–840 mg BID 56 (27) 600 mg BID ORR 15% in BRCA+ breast cancer cohort
Veliparib N/A 30 1 BRCA+ Breast and Ovarian Cancer, TNBC, HGSOC 50–500mg BID 98 (13) 400 mg BID ORR 24% in BRCA+ breast cancer cohort
Doxorubicin/Cyclophosphamide 43 1 Solid tumors 50 - 150 mg BID 18 (5) 100 mg BID ORR 60% in BRCA+ breast cancer cohort
Carboplatin/Gemcitabine 44 1 Solid tumors 30 - 310 mg BID 62 (4) 250 mg BID ORR 34%; ORR 0% in BRCA+ breast cancer cohort
Cisplatin/Vinorelbine 45 1 BRCA+ breast cancer and TNBC 20 - 300 mg BID 50 (14) Not reached (cisplatin 75 mg/m2 and vinorelbine 25 mg/m2 with veliparib 300 mg highest tested dose) ORR 57% in BRCA+ breast cancer cohort
Carboplatin 46 1/2 BRCA+ Breast Cancer 50 - 200 mg BID 72 (72) 150 mg BID ORR 14% in the BRCA1 cohort; ORR 36% in the BRCA2 cohort
Carboplatin/Paclitaxel 47 1 Solid tumors/TNBC 50 - 200 mg BID 30 (5) 150 mg BID ORR 60% in BRCA+ TNBC cohort; ORR 52% in TNBC cohort
Carboplatin/Paclitaxel 48 2 BRCA+ Breast Cancer 40 mg BID 196 (196) _ ORR 77.8% vs 61.3%; PFS 14.2m vs 12.3m; OS 28.5m vs 25.0m
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Multiple phase 2 studies further demonstrated activity of olaparib in metastatic breast cancer with germline BRCA mutations.33–35 A phase 2 study by Tutt et al. studied olaparib monotherapy in 54 patients with centrally confirmed germline BRCA-mutant breast cancer. Patients were treated with olaparib 400 mg BID or 100 mg BID.34 The primary endpoint of ORR was 22% in the 100 mg BID cohort and 41% at the 400 mg BID dose.

Similarly, phase 2 studies of talazoparib have demonstrated activity in patients with germline BRCA-mutant breast cancer. The phase 2 ABRAZO trial studied the use of talazoparib (1mg/day) in 2 cohorts: 1) Patients with BRCA-mutant metastatic breast cancer who responded to platinum-chemotherapy with disease progression >8 weeks following the last dose of platinum therapy and 2) patients who have progressed on at least 3 systemic regimens but no history of platinum-chemotherapy exposure.36 The ORR was 26% in patients with TNBC and 29% in patients with hormone receptor positive, HER2 +/− disease. Interestingly, increased time from last platinum dose in cohort 1 correlated with improved ORR and progression-free survival (PFS). There are several other ongoing phase 2/3 trials studying PARPi monotherapy in advanced disease.37–39

Olaparib’s activity was ultimately confirmed in the phase 3 OlympiAD trial, comparing olaparib vs single-agent chemotherapy in metastatic breast cancer.40 Patients with HER2 negative, germline BRCA-mutant breast cancer and no more than two prior chemotherapy treatments for metastatic cancer were randomized, in a 2:1 ratio, to olaparib tablets (300mg twice a day) or physician’s choice chemotherapy (capecitabine, eribulin or vinorelbine). The primary endpoint of median PFS was significantly longer in the olaparib group than in the chemotherapy group (7.0 months vs. 4.2 month; HR 0.58; 95% CI 0.43–0.80; p<0.001). The response rate was nearly 60% in the olaparib group versus 28.8% in the control arm. There was no difference in overall survival (OS) between the olaparib and control arms (19.3 months vs. 19.6 months respectively), likely due to high degree of cross over. In the subgroup analysis, patients with TNBC were more likely to benefit from olaparib (HR 0.43 [0.29–0.63]). Conversely, patients with hormone-receptor positive breast cancers did not statistically benefit from olaparib (HR 0.82 [0.55–1.26]). Although a small cohort in this study, patients who previously received platinum chemotherapy were less likely to benefit from olaparib therapy (HR 0.67 [0.48–1.14]), suggesting overlap in mechanisms of resistance. The rate of grade 3 or higher adverse events was lower in the olaparib group than in the standard-therapy group (36.6% and 50.5%, respectively). Toxicities of olaparib are similar to other PARPi’s, with most common being anemia, nausea/vomiting, diarrhea, and fatigue. Overall, patient-reported quality of life metrics (QLQ-C30) were improved in the olaparib arm with a mean difference improvement of 7.5 points (2.5–12.4, p=0.004) compared to the control arm. Olaparib is now FDA-approved for treatment of patients with germline or somatic BRCA1/2-mutant breast cancer.

Recently, talazoparib’s activity in BRCA-mutant breast cancer has been demonstrated in the phase 3 EMBRACA trial.41 Initial results demonstrate a median PFS of 8.6 months compared to 5.6 months for those treated with chemotherapy (p<0.0001). In addition, the ORR in the talazoparib group was more than twice that of the control arm (62.6% vs. 27.2% for chemotherapy, p<0.0001]). This benefit was seen benefit with talazoparib was consistent across subgroups, including hormone receptor status, BRCA mutation, prior chemotherapy, and history of central nervous system (CNS) metastases.

PARPi in Combination with Chemotherapy in Metastatic Breast Cancer

PARP inhibition has been shown to sensitize tumor cells to DNA-damaging therapies including platinums, temzolomide, and radiation.27, 28 Given this pre-clinical data, several clinical trials are studying combination therapy with the goal of potentiating the effect of cytotoxic chemotherapy (Table 2).42–49 In particular, veliparib has been explored as part of combination therapy. In a dose-escalation study of veliparib plus carboplatin and paclitaxel in patients with advanced solid tumors, promising activity was observed with a ORR of 57% in the breast cancer cohort. Additional phase 1 data in patients with breast cancer established the recommended phase 2 dose of veliparib as 150 mg BID (days-2–5) with carboplatin (AUC 6, day 1) and paclitaxel (80mg/m2, days 1, 8, 15).49 This dose is lower than the single agent maximum tolerated dose due to myelosuppression. The subsequent randomized phase 2 BROCADE trial studied the combination of veliparib and temzolomide or carboplatin/paclitaxel in platinum-naïve BRCA-mutant metastatic breast cancer.50 Nearly 78% of patients who were treated with a combination of veliparib and carboplatin/paclitaxel responded to treatment versus an ORR of 61% with this chemotherapy regimen alone. However, PFS and OS did not meet the threshold for statistically significant improvement. Grade 3/4 adverse events occurred in 34.4% and 27.1% of the veliparib and placebo arms, respectively with the most common toxicities being hematologic. The veliparib/temozolomide arm has not been presented. The international phase 3 BROCADE trial studying the carboplatin/paclitaxel with or without veliparib combination is ongoing.

Clinical Development in Early Stage Disease

Given the successful development of PARPi in metastatic BRCA-mutant breast cancer, trials are underway to study their role in early stage disease in both the neoadjuvant and adjuvant settings. The I-SPY 2 trial is a multicenter, randomized phase 2 platform with multiple experimental arms adding novel agents or combinations to standard neoadjuvant chemotherapy with a primary endpoint of pathological complete response (pCR).51 Patients with TNBC were randomized to veliparib (50 mg BID, days 1–21) with carboplatin and paclitaxel versus paclitaxel alone for 4 cycles. All patients then received 4 cycles of doxorubicin and cyclophosphamide (AC) followed by primary breast surgery. An estimated 52% (95% CI 36–66%) pCR rate was observed in the investigational veliparib/carboplatin arm versus 26% (95% CI 9–43%) in the standard treatment arm of paclitaxel followed by AC. Pathologic complete response is the primary endpoint which has been associated with an improved event free survival in breast cancer.52 It is notable that results based on germline BRCA mutation status has not been reported for this cohort. This promising activity is the basis for the phase 3 Brightness Study which completed randomization of stage II-III TNBC patients to carboplatin plus veliparib, carboplatin alone, or placebo to standard neoadjuvant paclitaxel chemotherapy followed by AC.53

Neoadjuvant talazoparib monotherapy has shown promising activity in a pilot phase 2 study. Thirteen BRCA-mutant breast cancer patients were treated with two months of talazoparib monotherapy with 88% (range 30–98%) median tumor shrinkage by ultrasound.54 The study was halted early to allow for expansion of neoadjuvant talazoparib as the only treatment prior to surgery to assess for the pCR rate.55

The phase 3 OlympiA study will assess the safety and efficacy of up to 12 months of adjuvant olaparib (300 mg BID) versus placebo in patients with BRCA-mutant TNBC or hormone receptor positive/HER2 negative breast cancer.56 Patients must have completed definitive local treatment and neoadjuvant/adjuvant chemotherapy. Randomization will be stratified by hormone receptor status, prior neoadjuvant versus adjuvant chemotherapy, and prior use of platinum chemotherapy. The post-neoadjuvant treatment group will include patients who did not achieve pCR. The primary endpoint is invasive disease-free survival with secondary endpoints of overall survival, distant disease-free survival, and the development of new primary malignancies as well as safety and tolerability. Olaparib is also being studied in the neoadjuvant setting in combination with platinum based chemotherapy for basal TNBC and BRCA-mutant breast cancer.57

Lastly, rucaparib is being tested in a phase 2 trial as adjuvant treatment with cisplatin in TNBC and BRCA-mutant breast cancer with residual disease following anthracycline and/or taxane neoadjuvant therapy.58 Patients were randomized to cisplatin with or without rucaparib for 24 weeks. Preliminary data demonstrated significant improvement in 2-year disease free survival with rucaparib and cisplatin (69.9% vs. 55.9%, p=0.04) in patients who received an anthracycline-containing regimen. Of note, BRCA mutation status did not impact disease-free survival.

Resistance to PARPi

As with other targeted therapies, malignancies can acquire resistance to PARPi therapy. One proposed mechanism is restoration of the HR repair pathway. There is evidence that the increased genomic instability promoted by PARP inhibition can lead to reversion mutations leading to restoration of BRCA1/2 function and PARP resistance.59 Other mechanisms of HR repair restoration include loss of DNA-repair proteins p53 binding protein 1 (53BP1) and REV7.60,61 A second mechanism of resistance is increased drug efflux leading to reduction of PARPi intracellular concentration via up-regulation of P-glycoprotein expression.28 Finally, changes in PARP1 expression levels in cancer cells also lead to resistance to PARPi. Elevation of PARP1 mediates resistance to PARPi and is related to worse outcomes in patients with breast cancer.62,63 Some of these resistance mechanisms are shared between PARPi and platinum chemotherapy, though the degree of overlap is not clear.64 These resistance mechanisms in platinum-resistant disease may limit the clinical utility of PARPi; additional strategies to overcome acquired resistance will be needed. Notably, most ongoing studies of PARPi exclude patients with platinum-resistant disease.

Expanding Clinical Application for PARPi

The anti-tumor activity seen with PARPi’s in BRCA-mutant breast and ovarian cancers has demonstrated synthetic lethality as a therapeutic strategy. There is emerging data of the efficacy of PARPi in other BRCA-mutant malignancies including prostate and pancreatic cancers. It remains to be seen if this can be expanded into other tumor types with deficiencies in DNA-repair mechanisms without BRCA1/2 germline mutations. Investigation has expanded in malignancies with the “BRCAness” phenotype. The term “BRCAness” refers to malignancies that have not arisen from germline BRCA1 or BRCA2 mutations, but nonetheless share the phenotypic and molecular features of HR repair deficiency due to a different genetic signature.65 This includes somatic mutation in either BRCA1 or BRCA2, promoter hypermethylation of BRCA1, or mutations in other genes involved in double stranded break DNA repair [ATM, RAD51, PALB2, FANC, PTEN].65 These malignancies share the same therapeutic vulnerabilities with BRCA-associated tumors including sensitivity to platinum chemotherapy.66,67

There is no standardized biomarker of “BRCAness” currently available. Significant effort has been made to develop classifiers of “BRCAness” to help predict susceptibility to PARP inhibition.67–70 Recently, Severson, et al. has developed a 77 gene signature to help define “BRCAness” and to investigate its ability to predict response to veliparib and carboplatin neoadjuvant therapy within the I-SPY2 clinical trial.71 Though limited by small sample size, they demonstrated an association between the “BRCAness” classification and patient response seen in the verliparib/carboplatin arm. Studies are also evaluating a HR deficiency score to help identify “BRCAness” by summing three different measures of genomic instability (loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions).72 A positive score, defined as >42 was able to identify patients who are more responsive to platinum chemotherapy. There are ongoing studies expanding on this hypothesis with other PARPi’s including rucaparib and talazoparib.37,73

Other strategies to extend the role of PARP inhibition in BRCA-mutant breast cancer include phosphoinositide 3-kinase (PI3K) inhibition. In addition to its role in pro-proliferative and anti-apoptotic functions, the PI3K/MAPK pathway contributes to repair of double-stranded DNA breaks in tumor cells.74 In pre-clinical breast cancer models, the combination of a PI3K inhibitor and olaparib delayed tumor growth in mouse models, suggesting that combined PI3K- and PARP-inhibition might be effective treatment for BRCA-mutant malignancies.74 Preliminary clinical efficacy has been demonstrated by Matulonis et al, studying the combination of olaparib with the PI3K inhibitor BKM120 in patients with ovarian or TNBC with an ORR of 24% (10 of 42 patients).75

Finally, combinations of PARPi with immunotherapies including antibodies to CTLA-4 and PD1/PD-L1 are being clinically investigated. Tumors with HR deficiency have higher genomic instability which may be associated with an elevated neo-antigen load which has been associated with a stronger anti-tumor immune response.76,77 This combination rationale is also supported by preclinical evidence that immune therapy may be enhanced with PARPi.78 Additionally, there is evidence that tumors with DNA-repair deficiency may induce a STING-dependent innate immune response in a cell-cycle specific manner.79 An early phase 1 study by Lee et al. studied the combination of darvalumab with olaparib or an anti-angiogenesis agent cediranib in advanced female solid malignancies.80 Among 12 evaluable patients receiving durvalumab and olaparib, 2 had a partial response and 8 had stable disease greater than 4 months, yielding a disease control rate of 83%. Based on this emerging evidence, there are ongoing trials studying the combination of PARPi with PD-L1 inhibitors.81,82

Conclusions

PARP inhibition is an emerging strategy for treatment of BRCA-mutant breast cancer. With the recent OlympiAD data, PARPi are another agent for consideration in patients with metastatic disease. PARPi should be considered in particular for BRCA-mutant TNBC, based on the improved outcomes and lack of other targeted therapy options. Future directions will include optimizing combination therapy with chemotherapy, other targeted therapies and immunotherapies, understanding and overcoming resistance mechanisms, and expanding the application of PARPi’s beyond BRCA-mutant breast cancer, particularly in malignancies with “BRCAness.”

Condensed abstract.

Individuals with BRCA1 or BRCA2 mutations are at elevated risk for breast cancer. Recent clinical trials in BRCA-mutant metastatic breast cancer have demonstrated activity of single agent PARP inhibitors.

Acknowledgments

Funding: This work was supported by the NCI Cancer Center Support Grant P30 CA014520.

Footnotes

These are not applicable: formal analysis, funding acquisition, investigation, methodology, software supervision, validation procedures

COI/Disclosures: None

Both authors participated in the conceptualization, data curation, project administration, resources, visualization, writing - original draft, and writing - review and editing.

Contributor Information

Anita Turk, University of Wisconsin Carbone Cancer Center, 600 Highland Avenue, #5666, Madison, WI 53792, Phone: 608-265-7816.

Kari B. Wisinski, University of Wisconsin Carbone Cancer Center, 1111 Highland Avenue, WIMR 6033, Madison, WI 53705-2275.

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