Review ArticleReviewsR

‘BRCAness’ and Its Implications for Platinum Action in Gynecologic Cancer

FRANCO MUGGIA and TAMAR SAFRA
Anticancer Research February 2014, 34 (2) 551-556;

Abstract

Gynecological carcinomas are major therapeutic targets of platinum-containing regimens. They may be particularly susceptible to these agents if their origins are related to hereditary breast cancer (BRCA) mutations; this implicates defective DNA repair secondary to inherited alterations in BRCA function. The concept of ‘BRCAness’ was introduced by Ashworth and colleagues in order to identify phenotypic changes in sporadic cancer that would lead to analogous treatment susceptibility. In fact, recent analyses of genetic alterations in ovarian cancer have led to further extending this concept to all women with high-grade serous cancer, the predominant form of ovarian cancer arising in association with hereditary mutations in BRCA genes. Presumably, most serous types of cancer of gynecological origin share BRCA dysfunction to some extent. This renders these types of cancer susceptible to platinum and to other DNA-damaging agents, justifying the general inclusion of this histology in trials of new drugs and therapeutic strategies that have shown activity against hereditary cancer. More recently, however, differences in outcome between BRCA mutation carriers vis-à-vis those with no mutations or those with epigenetic or acquired forms of BRCA genes (somatic mutations) in their respective tumors have been identified. These findings raise additional questions on modifiers of ‘BRCAness’ and other pathways that appear to contribute to the effects of platinum and other DNA-damaging agents in ovarian cancer. The Cancer Genome Atlas analyses delineate the complexity of genomic alterations in ovarian cancer and other malignancies of Mullerian epithelial origin promising further refinements of the ‘BRCAness’ concept.

Platinum drugs play an essential role in gynecological cancer treatment. Cisplatin or carboplatin (1-3) are coupled to surgery as part of the initial treatment in more than 90% of patients with epithelial ovarian cancer. Upon recurrence, all patients except those whose disease is labeled as platinum-resistant usually receive multiple courses of carboplatin (4). Platinum-based chemotherapy has also emerged in the last decade as the prevailing strategy (over radiation) for adjuvant treatment of endometrial cancer following identification of some high-risk features at hysterectomy, and forms part of the systemic treatment of patients with metastatic disease beyond rare cases of well-differentiated tumors that metastasize (5-13). Finally, in cancer of the uterine cervix, the use of either cisplatin or carboplatin in combination with other drugs or use of cisplatin as a radiosensitizer have yielded improvements in outcome for patients with locally advanced or metastatic presentations (14-18).

The Cancer Genome Atlas (TCGA) provides some insight into the efficacy of platinum compounds whether alone or in combination with other drugs in the treatment of ovarian and endometrial cancer (19). Specifically, TCGA has shown some common abnormalities among high-grade ovarian cancer with poorly-differentiated endometrioid, high-grade serous cancer of the endometrium, and basal-like carcinomas of breast origin (also updated on line at cancergenome.nih.gov). All of these are characterized by high genomic instability and BRCA mutation/silencing through epigenetic changes. Such genomic changes have not readily provided identifiable driver mutations that may be targeted; however, they have re-inforced the concept of ‘BRCAness’ introduced by Ashworth and colleagues to identify phenotypic changes in sporadic cancer that would imply similar treatment susceptibility to DNA-damaging agents (20). We elaborate on the evolving clinical implications behind this concept in the main portion of this article.

BRCA Function and DNA Repair

The past decade has witnessed impressive advances in our understanding over various cellular components required for maintenance of the genome under the on-slaught of DNA damage. Among these, the sensors of DNA damage, ataxia telangiectasia and Rad3-related protein (ATR) and ataxia telangiectasia mutated (ATM) are central to turning on DNA repair machinery (21-30). In recent years, major roles have also been assigned to BRCA1 and BRCA2 functions in leading high-fidelity repair by homologous recombination (HR) (31-41). Cellular systems have served to probe and identify defects in such repair functions by verifying the formation of foci when BRCA-mediated repair is intact. Lack of foci formation implies defects in the HR pathway, among others. BRCA2 and a number of other Fanconi-related genes also have additional key functions in non-HR repair (20, 42-56). Selective forms of DNA damage, such as nucleotide excision repair (NER) or base excision repair (BER), rely on other repair pathways, in which polyadenosyldiphosphate ribose polymerase (PARP) plays a major role, particularly in the absence of HR.

Interest in tumor repair pathways has led to the recognition of their importance in determining cellular sensitivity to chemotherapeutic agents. Attention was naturally drawn to epithelial ovarian cancer and its known sensitivity to the classical DNA-damaging drugs, alkylating agents (from 1950-1980), and subsequently the more effective platinum agents. In particular, the clinical and analog development of cisplatin was greatly stimulated by its remarkable activity in the common advanced presentations of ovarian cancer.

Clinical trials by the Gynecologic Oncology Group (GOG) and others eventually identified a consistent pattern of greater sensitivity of high-grade serous carcinomas to cisplatin, and relative resistance of other epithelial types such as mucinous, clear cell, and low-grade serous carcinomas to this agent (57-68). Additional studies in patients after platinum-based treatment suggested the loss of mismatch repair function and increasing tolerance of platinum–DNA adducts as a mechanism of resistance. The incidental finding of invasive and in situ high-grade serous carcinomas in Fallopian tube fimbriae of BRCA mutation carriers subjected to risk-reducing surgeries spurred focus on BRCA function as a determinant of the known platinum sensitivity of this histological type. In addition, as more reports accumulated (69), it became evident that ovarian adenocarcinomas, arising in BRCA1 and BRCA2 mutation carriers, had better overall outcomes and greater response rates to platinum compounds, as well as to other drugs in common use for ovarian cancer recurrence (e.g. pegylated liposomal doxorubicin, gemcitabine, topotecan) (70). Such results have strengthened the association between lack of BRCA function and platinum sensitivity, as well as a similar association with sensitivity to other DNA-damaging agents that were known to be active in ovarian cancer.

PARP Inhibitors and Synthetic Lethality

Research groups in Newcastle and the Institute for Cancer Research (led by Curtin and Ashworth, respectively) independently reported the remarkable in vitro findings in 2005 of ‘synthetic lethality’ in BRCA−/− cells, i.e. enhanced lethality of DNA-damaging agents (including radiation) and PARP, respectively in knock-out versus wild-type cells, that is, when HR- and PARP-related repair were either defective or blocked. These finding have rekindled the clinical development of PARP inhibitors that had begun at Newcastle under the leadership of A. Hilary Calvert and culminated in a trial of AGO14699 (now known as rucaparib) in a trial mostly consisting of patients with melanoma conducted by Ruth Plummer (summarized in references 71-74).

The subsequent clinical development of PARP inhibitors has not been without challenges. Although these agents are well-tolerated by themselves, when administered in combination with other drugs, their doses generally had to be reduced. Although iniparib was an exception to this, this agent was subsequently proven as unlikely to function as a PARP1 inhibitor. Disappointingly, the initial lead identified in phase I showing single-agent efficacy of olaparib against ovarian cancer in mutation carriers was also not pursued as vigorously as many gynecological oncologists would have wished for their patients. Nevertheless, veliparib (GOG270, unpublished data) and niratinib (J. DeBono, June 1st, poster presentation at ASCO 2013) have also shown single-agent activity in BRCA mutation carriers with ovarian cancer. Furthermore, retrospective analyses have also suggested that these patients do particularly well when maintained with oliparib after platinum-induced complete responses, a finding that is less obvious when epigenetic BRCA function is silenced, or if an unidentifiable mutation is present (3, 34, 36, 71-78) (and further documented in the oral presentation by J Ledermann, ASCO June 2nd, 2013).

Prospective studies of PARP inhibitors have utilized the concept of ‘BRCAness’ to enrich the population under study beyond those with known hereditary cancer that were shown to benefit during the phase I study of olaparib as documented through imaging as far back as April 2006 by Fong et al. (76). Several studies have shown that olaparib also presented certain clinical benefit in patients with ovarian cancer who are not BRCA mutation carriers, and thus this PARP inhibitor may be used to treat a larger subset of patients with epithelial ovarian cancer but not patients with low-grade tumors, mucinous, or clear-cell adenocarcinomas. Some patients with high-grade endometrioid adenocarcinomas do share sensitivity to platinum and point to the risk of over-relying on a histological diagnosis alone to identify those tumors that may be extremely sensitive to platinum and PARP inhibitors (79-80).

Refining the Definition of ‘BRCAness’

As noted above, when ‘BRCAness’ was introduced in 2004, it was hoped that the hallmarks of susceptibility to breast and ovarian cancer through the known inherited BRCA1 and BRCA2 mutations would be identified in otherwise sporadic cancer. Specifically, the postulate was that “the existence of a significant proportion of sporadic breast, ovarian, and other cancers with BRCA-like functional abnormalities raises the possibility of a wider application of treatment regimens designed for familial BRCA tumors” (20). Moreover, the authors pointed out the need to seek phenotypic changes that would allow such assignment of ‘BRCAness’. Subsequent articles (now 30 in number under PubMed) have been published separately in the breast and ovarian cancer literature–not unreasonable, since the phenotypic expression of BRCA1 mutations in breast cancer relates primarily to triple-negative breast cancer with basal cell features, whereas BRCA2 mutations have more variable phenotypic features. Some of the literature on breast cancer has sought correlations beyond the anticipated enhanced benefit from DNA-damaging drugs, including lack of responsiveness to taxanes (81, 82).

The terminology itself, although widely used, is potentially open to ambiguous interpretation. For example, it has been pointed out that ‘BRCAness’ actually refers to ‘BRCAlessness’ because it is the deficiency of BRCA function that defines this phenotype (83). Tan et al. (84) upon comparing chemoresponsiveness in BRCA mutation carriers to that of patients with ‘non-hereditary’ cancer characterized the ‘BRCAness’ syndrome in ovarian cancer by the following: i) high response rates to first-line platinum-based treatment; ii) high response rates to subsequent therapies including platinum agents; iii) long treatment-free intervals beyond relapse, iv) improved overall survival; and v) tumors that are usually, but not exclusively, of serous histology. Thus, this study refers to hereditary BRCA mutation carriers, albeit in the less studied non-Ashkenazi Jewish population, under the term ‘BRCAness’. Notwithstanding potential ambiguities, the term has caught on, and although “there is no standardized method to detect ‘BRCAness’” (83), the original intent of Turner et al. (20) to provide more robust indications of extending the therapeutic implications beyond BRCA mutations remains valid and awaits further development.

Konstantinopoulos et al. developed a “gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer” (85). Their “optimal classifier” was a 60-gene diagonal linear discriminant predictor and was then applied to 35 clinical samples that were sequenced to ensure that BRCA1 and BRCA2 were wild-type for classification as BRCA-like to non-BRCA-like, and this ‘optimal classifier’ was similarly applied to another 35 clinical samples that were non-sequenced. This ‘BRCAness’ profile was shown to correlate with responsiveness to platinum and to PARP inhibitors and had an independent prognostic value on multivariate analysis. The 70 patients had stage III (80%), grade 3 (86%) disease with mostly serous histology (93%). This study supports the notion that genes other than BRCA1 or BRCA2 are responsible for ‘BRCAness’ in sporadic disease; one cannot exclude, however, that sporadic mutations or epigenetic alterations in the BRCA genes themselves account for their BRCA-like classifier. An editorial by Bast and Mills stressed platinum sensitivity as a reliable predictor of ‘BRCAness’ (86): the gene expression profile signature of ‘BRCAness’ correctly identified 8 out of 10 BRCA mutation carriers as responders to platinum agents; the two exceptions had BRCA2 mutations, suggesting that the signature is better at detecting BRCA1 than BRCA2 dysfunction. The authors go on to emphasize that “identifying genomic signatures associated with BRCA dysfunction may directly impact the extent of platinum sensitivity and could have substantial impact on clinical outcomes”. In fact, Lesnock and Krivak's group and our retrospective experience within phase II studies of intra-peritoneal platinum agents (87) suggest that BRCA status (by immunohistochemistry in the GOG172 study or by known BRCA mutation carrier state) predicts an especially favorable outcome after intra-peritoneal therapy. Bast and Mills further suggest that reverse-phase protein arrays have the potential to add a new dimension to predictive assays of sensitivity to treatment beyond BRCA status (86).

‘BRCAness’ in Ovarian Cancer: Implications for Platinum Agents and Other Drugs

As noted in the preceding section, a decade after its introduction, refining our definition of ‘BRCAness’ has become a central theme in the treatment of epithelial ovarian cancer. The most dramatic demonstration of its impact may be in the benefit conferred by cisplatin when given by the intraperitoneal route. Whether this impressive gain in sensitivity carries over to outcomes from PARP inhibitors and other drugs is not known. However, our studies suggest that BRCA mutation carrier status also confers greater sensitivity to pegylated liposomal doxorubicin (69), and to drugs such as gemcitabine; not enough experience is available for topotecan (70). Since TGCA did not identify driver mutations, and the predominant theme remains sensitivity to platinum agents, future studies into ‘BRCAness’ and correlations with outcome remain a high priority for study. Additionally, manipulations to enhance platinum sensitivity such as by increasing uptake, for example through the use of bortezomib and carboplatin given by intraperitoneal administration, have high interest. Another area that needs further research is identification of genes that affect BRCA function, such as EMSY amplification and overexpression capable of inhibiting BRCA2 transcriptional activity (20, 88, 89). Factors resulting in re-gaining (e.g. reversing) activity of BRCA even in the presence of deleterious mutations need to be identified, including the suggestion that prior exposure to anticancer agents for breast cancer enhances the likelihood of such reversing activity. Table I lists ‘BRCAness’-related genetic and epigenetic alterations.

View this table:
Table I.

Genetic and other characteristics associated with ‘BRCAness’ in ovarian cancer*.

In conclusion, the concept of ‘ BRCAness’, as originally introduced, has proven useful in emphasizing the central role of the BRCA genes both in breast and in ovarian cancer biology and treatment. Therapeutic implications emanating from this concept appear to differ in ovarian cancer compared with breast cancer, further reinforcing the importance of the context in which BRCA and related genes function in these malignancies. The remarkable effects of the platinum compounds may hopefully be extended further by studying to what extent the population with ‘BRCAness’ attains similar outcomes to those with germline BRCA mutations.

Acknowledgements

Supported in part by NYU grants P30 CA16087 and CTSI (NIH), and the Chemotherapy Foundation.

Footnotes

  • ↵† Currently on sabbatical at American Cancer Hospital, Shanghai, China.

  • ↵* Combining individual presentations made on gynecologic cancers at ISPCC2012.

  • Received December 16, 2013.
  • Revision received January 17, 2014.
  • Accepted January 20, 2014.

References

  1. ↵
    1. Ledermann JA
    : Primary chemotherapy: the future for the management of advanced ovarian cancer? Int J Gynecol Cancer 20: S17-19, 2010.
    OpenUrlCrossRefPubMed
    1. Ledermann JA,
    2. Kristeleit RS
    : Optimal treatment for relapsing ovarian cancer. Ann Oncol 21(Suppl 7): vii218-222, 2010.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Liu J,
    2. Matulonis UA
    : New advances in ovarian cancer. Oncology (Williston Park) 24: 721-728, 2010.
    OpenUrlPubMed
  4. ↵
    1. Markman M,
    2. Hoskins W
    : Responses to salvage chemo-therapy in ovarian cancer: a critical need for precise definitions of the treated population. J Clin Oncol 10: 513-514, 1992.
    OpenUrlFREE Full Text
  5. ↵
    1. Tazi Y,
    2. Pautier P,
    3. Lhomme C
    : Systemic therapy for advanced endometrial cancer. Bull Cancer 99: 93-97, 2012.
    OpenUrlPubMed
    1. Johnson N,
    2. Bryant A,
    3. Miles T,
    4. Hogberg T,
    5. Cornes P
    : Adjuvant chemotherapy for endometrial cancer after hysterectomy. Cochrane Database Syst Rev: CD003175, 2011.
    1. Hogberg T
    : What is the role of chemotherapy in endometrial cancer? Curr Oncol Rep 13: 433-441, 2011.
    OpenUrlCrossRefPubMed
    1. Olawaiye AB,
    2. Boruta DM 2nd.
    : Management of women with clear cell endometrial cancer: a Society of Gynecologic Oncology (SGO) review. Gynecol Oncol 113: 277-283, 2009.
    OpenUrlPubMed
    1. Kodama J,
    2. Seki N,
    3. Hiramatsu Y
    : Chemotherapy for high-risk early-stage endometrial cancer. Curr Opin Obstet Gynecol 19: 42-47, 2007.
    OpenUrlPubMed
    1. Humber CE,
    2. Tierney JF,
    3. Symonds RP,
    4. Collingwood M,
    5. Kirwan J,
    6. Williams C,
    7. Green JA
    : Chemotherapy for advanced, recurrent or metastatic endometrial cancer: a systematic review of Cochrane collaboration. Ann Oncol 18: 409-420, 2007.
    OpenUrlCrossRefPubMed
    1. Obel JC,
    2. Friberg G,
    3. Fleming GF
    : Chemotherapy in endometrial cancer. Clin Adv Hematol Oncol 4: 459-468, 2006.
    OpenUrlPubMed
    1. Markman M
    : Unresolved issues in the chemotherapeutic management of gynecologic malignancies. Semin Oncol 33: S33-38, 2006.
    OpenUrlPubMed
  13. ↵
    1. Muggia FM
    : Recent updates in the clinical use of platinum compounds for the treatment of gynecologic cancers. Semin Oncol 31: 17-24, 2004.
    OpenUrlPubMed
  14. ↵
    1. Scatchard K,
    2. Forrest JL,
    3. Flubacher M,
    4. Cornes P,
    5. Williams C
    : Chemotherapy for metastatic and recurrent cervical cancer. Cochrane Database Syst Rev 10: CD006469, 2012.
    1. Rosa DD,
    2. Medeiros LR,
    3. Edelweiss MI,
    4. Pohlmann PR,
    5. Stein AT
    : Adjuvant platinum-based chemotherapy for early stage cervical cancer. Cochrane Database Syst Rev 6: CD005342, 2012.
    1. Klopp AH,
    2. Eifel PJ
    : Chemoradiotherapy for cervical cancer in 2010. Curr Oncol Rep 13: 77-85, 2011.
    OpenUrlPubMed
    1. Al-Mansour Z,
    2. Verschraegen C
    : Locally advanced cervical cancer: what is the standard of care? Curr Opin Oncol 22: 503-512, 2010.
    OpenUrlPubMed
  18. ↵
    Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: individual patient data meta-analysis. Cochrane Database Syst Rev: CD008285, 2010.
  19. ↵
    1. Kandoth C,
    2. Schultz N,
    3. Cherniack AD,
    4. Akbani R,
    5. Liu Y,
    6. Shen H,
    7. Robertson AG,
    8. Pashtan I,
    9. Shen R,
    10. Benz CC,
    11. Yau C,
    12. Laird PW,
    13. Ding L,
    14. Zhang W,
    15. Mills GB,
    16. Kucherlapati R,
    17. Mardis ER,
    18. Levine DA
    : Integrated genomic characterization of endometrial carcinoma. Nature 497: 67-73, 2013.
    OpenUrlCrossRefPubMed
  20. ↵
    1. Turner N,
    2. Tutt A,
    3. Ashworth A
    : Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer 4: 814-819, 2004.
    OpenUrlCrossRefPubMed
  21. ↵
    1. Furgason JM,
    2. Bahassi el M
    : Targeting DNA repair mechanisms in cancer. Pharmacol Ther 137: 298-308, 2013.
    OpenUrlCrossRefPubMed
    1. Sperka T,
    2. Wang J,
    3. Rudolph KL
    : DNA damage checkpoints in stem cells, ageing and cancer. Nat Rev Mol Cell Biol 13: 579-590, 2012.
    OpenUrlCrossRefPubMed
    1. Thompson LH
    : Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: the molecular choreography. Mutat Res 751: 158-246, 2012.
    OpenUrlCrossRefPubMed
    1. Roos WP,
    2. Kaina B
    : DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett 332: 237-248, 2013.
    OpenUrlCrossRefPubMed
    1. Chen BP,
    2. Li M,
    3. Asaithamby A
    : New insights into the roles of ATM and DNA-PKcs in the cellular response to oxidative stress. Cancer Lett 327: 103-110, 2012.
    OpenUrlCrossRefPubMed
    1. Langerak P,
    2. Russell P
    : Regulatory networks integrating cell cycle control with DNA damage checkpoints and double-strand break repair. Philos Trans R Soc Lond B Biol Sci 366: 3562-3571, 2011.
    OpenUrlCrossRefPubMed
    1. Flynn RL,
    2. Zou L
    : ATR: a master conductor of cellular responses to DNA replication stress. Trends Biochem Sci 36: 133-140, 2011.
    OpenUrlCrossRefPubMed
    1. Lopez-Contreras AJ,
    2. Fernandez-Capetillo O
    : The ATR barrier to replication-born DNA damage. DNA Repair (Amst) 9: 1249-1255, 2010.
    OpenUrlCrossRefPubMed
    1. Poehlmann A,
    2. Roessner A
    : Importance of DNA damage checkpoints in the pathogenesis of human cancers. Pathol Res Pract 206: 591-601, 2010.
    OpenUrlCrossRefPubMed
  30. ↵
    1. Smith J,
    2. Tho LM,
    3. Xu N,
    4. Gillespie DA
    : The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res 108: 73-112, 2010.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Pennington KP,
    2. Swisher EM
    : Hereditary ovarian cancer: beyond the usual suspects. Gynecol Oncol 124: 347-353, 2012.
    OpenUrlCrossRefPubMed
    1. Foulkes WD,
    2. Shuen AY
    : In brief: BRCA1 and BRCA2. J Pathol 230: 347-349, 2013.
    OpenUrlCrossRefPubMed
    1. Rigakos G,
    2. Razis E
    : BRCAness: finding the Achilles heel in ovarian cancer. Oncologist 17: 956-962, 2012.
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Tinker AV,
    2. Gelmon K
    : The role of PARP inhibitors in the treatment of ovarian carcinomas. Curr Pharm Des 18: 3770-3774, 2012.
    OpenUrlPubMed
    1. Bast RC Jr..
    : Molecular approaches to personalizing management of ovarian cancer. Ann Oncol 22(Suppl 8): viii5-viii15, 2011.
    OpenUrlCrossRefPubMed
  36. ↵
    1. Banerjee S,
    2. Kaye S
    : PARP inhibitors in BRCA gene-mutated ovarian cancer and beyond. Curr Oncol Rep 13: 442-449, 2011.
    OpenUrlCrossRefPubMed
    1. Kalamanathan S,
    2. Bates V,
    3. Lord R,
    4. Green JA
    : The mutational profile of sporadic epithelial ovarian carcinoma. Anticancer Res 31: 2661-2668, 2011.
    OpenUrlAbstract/FREE Full Text
    1. Long KC,
    2. Kauff ND
    : Hereditary ovarian cancer: recent molecular insights and their impact on screening strategies. Curr Opin Oncol 23: 526-530, 2011.
    OpenUrlCrossRefPubMed
    1. Trainer AH,
    2. Lewis CR,
    3. Tucker K,
    4. Meiser B,
    5. Friedlander M,
    6. Ward RL
    : The role of BRCA mutation testing in determining breast cancer therapy. Nat Rev Clin Oncol 7: 708-717, 2010.
    OpenUrlCrossRefPubMed
    1. Martin SA,
    2. Hewish M,
    3. Lord CJ,
    4. Ashworth A
    : Genomic instability and the selection of treatments for cancer. J Pathol 220: 281-289, 2010.
    OpenUrlPubMed
  41. ↵
    1. Safra T
    : Hereditary ovarian cancer: biology, response to chemotherapy and prognosis. Womens Health (Lond Engl) 5: 543-553, 2009.
    OpenUrlPubMed
  42. ↵
    1. Garcia MJ,
    2. Benitez J
    : The Fanconi anaemia/BRCA pathway and cancer susceptibility. Searching for new therapeutic targets. Clin Transl Oncol 10: 78-84, 2008.
    OpenUrlCrossRefPubMed
    1. Bogliolo M,
    2. Cabre O,
    3. Callen E,
    4. Castillo V,
    5. Creus A,
    6. Marcos R,
    7. Surralles J
    : The Fanconi anaemia genome stability and tumour suppressor network. Mutagenesis 17: 529-538, 2002.
    OpenUrlCrossRefPubMed
    1. Duker NJ
    : Chromosome breakage syndromes and cancer. Am J Med Genet 115: 125-129, 2002.
    OpenUrlCrossRefPubMed
    1. Thompson LH,
    2. Schild D
    : Recombinational DNA repair and human disease. Mutat Res 509: 49-78, 2002.
    OpenUrlCrossRefPubMed
    1. Yao CJ,
    2. Du W,
    3. Zhang Q,
    4. Zhang F,
    5. Zeng F,
    6. Chen FP
    : Fanconi anemia pathway – the way of DNA interstrand cross-link repair. Pharmazie 68: 5-11, 2013.
    OpenUrlPubMed
    1. Kim H,
    2. D'Andrea AD
    : Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway. Genes Dev 26: 1393-1408, 2012.
    OpenUrlAbstract/FREE Full Text
    1. Stecklein SR,
    2. Jensen RA
    : Identifying and exploiting defects in the Fanconi anemia/BRCA pathway in oncology. Transl Res 160: 178-197, 2012.
    OpenUrlPubMed
    1. Knoch J,
    2. Kamenisch Y,
    3. Kubisch C,
    4. Berneburg M
    : Rare hereditary diseases with defects in DNA-repair. Eur J Dermatol 22: 443-455, 2012.
    OpenUrlCrossRefPubMed
    1. Crossan GP,
    2. Patel KJ
    : The Fanconi anaemia pathway orchestrates incisions at sites of crosslinked DNA. J Pathol 226: 326-337, 2012.
    OpenUrlCrossRefPubMed
    1. Su X,
    2. Huang J
    : The Fanconi anemia pathway and DNA interstrand cross-link repair. Protein Cell 2: 704-711, 2011.
    OpenUrlPubMed
    1. Symington LS,
    2. Gautier J
    : Double-strand break end resection and repair pathway choice. Annu Rev Genet 45: 247-271, 2011.
    OpenUrlCrossRefPubMed
    1. Deans AJ,
    2. West SC
    : DNA interstrand crosslink repair and cancer. Nat Rev Cancer 11: 467-480, 2011.
    OpenUrlCrossRefPubMed
    1. Deakyne JS,
    2. Mazin AV
    : Fanconi anemia: at the crossroads of DNA repair. Biochemistry (Mosc) 76: 36-48, 2011.
    OpenUrlPubMed
    1. Hucl T,
    2. Gallmeier E
    : DNA repair: exploiting the Fanconi anemia pathway as a potential therapeutic target. Physiol Res 60: 453-465, 2011.
    OpenUrlPubMed
  56. ↵
    1. Cantor SB,
    2. Guillemette S
    : Hereditary breast cancer and the BRCA1-associated FANCJ/BACH1/BRIP1. Future Oncol 7: 253-261, 2011.
    OpenUrlCrossRefPubMed
  57. ↵
    1. Vargas-Hernandez VM
    : Endometriosis as a risk factor for ovarian cancer. Cir Cir 81: 163-168, 2013.
    OpenUrlPubMed
    1. Gurung A,
    2. Hung T,
    3. Morin J,
    4. Gilks CB
    : Molecular abnormalities in ovarian carcinoma: clinical, morphological and therapeutic correlates. Histopathology 62: 59-70, 2013.
    OpenUrlPubMed
    1. Ahmed N,
    2. Abubaker K,
    3. Findlay J,
    4. Quinn M
    : Cancerous ovarian stem cells: obscure targets for therapy but relevant to chemoresistance. J Cell Biochem 114: 21-34, 2013.
    OpenUrlCrossRefPubMed
    1. Lalwani N,
    2. Prasad SR,
    3. Vikram R,
    4. Shanbhogue AK,
    5. Huettner PC,
    6. Fasih N
    : Histologic, molecular, and cytogenetic features of ovarian cancers: implications for diagnosis and treatment. Radiographics 31: 625-646, 2011.
    OpenUrlCrossRefPubMed
    1. McCluggage WG
    : Morphological subtypes of ovarian carcinoma: a review with emphasis on new developments and pathogenesis. Pathology 43: 420-432, 2011.
    OpenUrlCrossRefPubMed
    1. Prat J
    : Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features. Virchows Arch 460: 237-249, 2012.
    OpenUrlCrossRefPubMed
    1. Romero I,
    2. Bast RC Jr..
    : Minireview: human ovarian cancer: biology, current management, and paths to personalizing therapy. Endocrinology 153: 1593-1602, 2012.
    OpenUrlCrossRefPubMed
    1. Muggia F,
    2. Safra T,
    3. Dubeau L
    : BRCA genes: lessons learned from experimental and clinical cancer. Ann Oncol 22(Suppl 1): i7-10, 2011.
    OpenUrlCrossRefPubMed
    1. Cho KR
    : Ovarian cancer update: lessons from morphology, molecules, and mice. Arch Pathol Lab Med 133: 1775-1781, 2009.
    OpenUrlPubMed
    1. Muggia F
    : Platinum compounds 30 years after the introduction of cisplatin: implications for the treatment of ovarian cancer. Gynecol Oncol 112: 275-281, 2009.
    OpenUrlCrossRefPubMed
    1. Gilks CB
    : Subclassification of ovarian surface epithelial tumors based on correlation of histologic and molecular pathologic data. Int J Gynecol Pathol 23: 200-205, 2004.
    OpenUrlCrossRefPubMed
  68. ↵
    1. Kurman RJ,
    2. Shih Ie M
    : Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications. Int J Gynecol Pathol 27: 151-160, 2008.
    OpenUrlCrossRefPubMed
  69. ↵
    1. Safra T,
    2. Borgato L,
    3. Nicoletto MO,
    4. Rolnitzky L,
    5. Pelles-Avraham S,
    6. Geva R,
    7. Donach ME,
    8. Curtin J,
    9. Novetsky A,
    10. Grenader T,
    11. Lai WC,
    12. Gabizon A,
    13. Boyd L,
    14. Muggia F
    : BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin. Mol Cancer Ther 10: 2000-2007, 2011.
    OpenUrlAbstract/FREE Full Text
  70. ↵
    1. Safra T,
    2. Rogowski O,
    3. Muggia FM
    : Effect of germ-line BRCA mutations on response to chemotherapy and outcome of recurrent ovarian cancer. Submitted 2013.
  71. ↵
    1. Farmer H,
    2. McCabe N,
    3. Lord CJ,
    4. Tutt AN,
    5. Johnson DA,
    6. Richardson TB,
    7. Santarosa M,
    8. Dillon KJ,
    9. Hickson I,
    10. Knights C,
    11. Martin NM,
    12. Jackson SP,
    13. Smith GC,
    14. Ashworth A
    : Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434: 917-921, 2005.
    OpenUrlCrossRefPubMed
    1. Bryant HE,
    2. Schultz N,
    3. Thomas HD,
    4. Parker KM,
    5. Flower D,
    6. Lopez E,
    7. Kyle S,
    8. Meuth M,
    9. Curtin NJ,
    10. Helleday T
    : Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434: 913-917, 2005.
    OpenUrlCrossRefPubMed
    1. Plummer R,
    2. Jones C,
    3. Middleton M,
    4. Wilson R,
    5. Evans J,
    6. Olsen A,
    7. Curtin N,
    8. Boddy A,
    9. McHugh P,
    10. Newell D,
    11. Harris A,
    12. Johnson P,
    13. Steinfeldt H,
    14. Dewji R,
    15. Wang D,
    16. Robson L,
    17. Calvert H
    : Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res 14: 7917-7923, 2008.
    OpenUrlAbstract/FREE Full Text
  74. ↵
    1. Calvert H,
    2. Azzariti A
    : The clinical development of inhibitors of poly(ADP-ribose) polymerase. Ann Oncol 22(Suppl 1): i53-59, 2011.
    OpenUrlCrossRefPubMed
    1. Banerjee S,
    2. Kaye S
    : The role of targeted therapy in ovarian cancer. Eur J Cancer 47(Suppl 3): S116-130, 2011.
    OpenUrlPubMed
  76. ↵
    1. Fong PC,
    2. Boss DS,
    3. Yap TA,
    4. Tutt A,
    5. Wu P,
    6. Mergui-Roelvink M,
    7. Mortimer P,
    8. Swaisland H,
    9. Lau A,
    10. O'Connor MJ,
    11. Ashworth A,
    12. Carmichael J,
    13. Kaye SB,
    14. Schellens JH,
    15. de Bono JS
    : Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. The New England journal of medicine 361: 123-134, 2009.
    OpenUrlCrossRefPubMed
    1. Liang H,
    2. Tan AR
    : Iniparib, a PARP1 inhibitor for the potential treatment of cancer, including triple-negative breast cancer. IDrugs 13: 646-656, 2010.
    OpenUrlPubMed
  78. ↵
    1. Westin SN,
    2. Herzog TJ,
    3. Coleman RL
    : Investigational agents in development for the treatment of ovarian cancer. Invest New Drugs 31: 213-229, 2013.
    OpenUrlPubMed
  79. ↵
    1. Kaye SB,
    2. Lubinski J,
    3. Matulonis U,
    4. Ang JE,
    5. Gourley C,
    6. Karlan BY,
    7. Amnon A,
    8. Bell-McGuinn KM,
    9. Chen LM,
    10. Friedlander M,
    11. Safra T,
    12. Vergote I,
    13. Wickens M,
    14. Lowe ES,
    15. Carmichael J,
    16. Kaufman B
    : Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 30: 372-379, 2012.
    OpenUrlAbstract/FREE Full Text
  80. ↵
    1. Ledermann J,
    2. Harter P,
    3. Gourley C,
    4. Friedlander M,
    5. Vergote I,
    6. Rustin G,
    7. Scott C,
    8. Meier W,
    9. Shapira-Frommer R,
    10. Safra T,
    11. Matei D,
    12. Macpherson E,
    13. Watkins C,
    14. Carmichael J,
    15. Matulonis U
    : Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. The New England journal of medicine 366: 1382-1392, 2012.
    OpenUrlCrossRefPubMed
  81. ↵
    1. Quinn JE,
    2. Carser JE,
    3. James CR,
    4. Kennedy RD,
    5. Harkin DP
    : BRCA1 and implications for response to chemotherapy in ovarian cancer. Gynecol Oncol 113: 134-142, 2009.
    OpenUrlCrossRefPubMed
  82. ↵
    1. Quinn JE,
    2. James CR,
    3. Stewart GE,
    4. Mulligan JM,
    5. White P,
    6. Chang GK,
    7. Mullan PB,
    8. Johnston PG,
    9. Wilson RH,
    10. Harkin DP
    : BRCA1 mRNA expression levels predict for overall survival in ovarian cancer after chemotherapy. Clin Cancer Res 13: 7413-7420, 2007.
    OpenUrlAbstract/FREE Full Text
  83. ↵
    1. Chalasani P,
    2. Livingston R
    : Differential Chemotherapeutic Sensitivity for Breast Tumors With “BRCAness”: A Review. Oncologist 18: 909-916, 2013.
    OpenUrlAbstract/FREE Full Text
  84. ↵
    1. Tan DS,
    2. Rothermundt C,
    3. Thomas K,
    4. Bancroft E,
    5. Eeles R,
    6. Shanley S,
    7. Ardern-Jones A,
    8. Norman A,
    9. Kaye SB,
    10. Gore ME
    : “BRCAness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol 26: 5530-5536, 2008.
    OpenUrlAbstract/FREE Full Text
  85. ↵
    1. Konstantinopoulos PA,
    2. Spentzos D,
    3. Karlan BY,
    4. Taniguchi T,
    5. Fountzilas E,
    6. Francoeur N,
    7. Levine DA,
    8. Cannistra SA
    : Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncol 28: 3555-3561, 2010.
    OpenUrlAbstract/FREE Full Text
  86. ↵
    1. Bast RC Jr..,
    2. Mills GB
    : Personalizing therapy for ovarian cancer: BRCAness and beyond. J Clin Oncol 28: 3545-3548, 2010.
    OpenUrlFREE Full Text
  87. ↵
    1. Lesnock JL,
    2. Darcy KM,
    3. Tian C,
    4. Deloia JA,
    5. Thrall MM,
    6. Zahn C,
    7. Armstrong DK,
    8. Birrer MJ,
    9. Krivak TC
    : BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study. Br J Cancer 108: 1231-1237, 2013.
    OpenUrlCrossRefPubMed
  88. ↵
    1. Hughes-Davies L,
    2. Huntsman D,
    3. Ruas M,
    4. Fuks F,
    5. Bye J,
    6. Chin SF,
    7. Milner J,
    8. Brown LA,
    9. Hsu F,
    10. Gilks B,
    11. Nielsen T,
    12. Schulzer M,
    13. Chia S,
    14. Ragaz J,
    15. Cahn A,
    16. Linger L,
    17. Ozdag H,
    18. Cattaneo E,
    19. Jordanova ES,
    20. Schuuring E,
    21. Yu DS,
    22. Venkitaraman A,
    23. Ponder B,
    24. Doherty A,
    25. Aparicio S,
    26. Bentley D,
    27. Theillet C,
    28. Ponting CP,
    29. Caldas C,
    30. Kouzarides T
    : EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 115: 523-535, 2003.
    OpenUrlCrossRefPubMed
  89. ↵
    1. Kwa M,
    2. Edwards S,
    3. Downey A,
    4. Reich E,
    5. Wallach R,
    6. Curtin J,
    7. Muggia F
    : Ovarian Cancer in BRCA Mutation Carriers: Improved Outcome After Intraperitoneal (IP) Cisplatin. Ann Surg Oncol 2013.
    1. Zhang S,
    2. Royer R,
    3. Li S,
    4. McLaughlin JR,
    5. Rosen B,
    6. Risch HA,
    7. Fan I,
    8. Bradley L,
    9. Shaw PA,
    10. Narod SA
    : Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol 121: 353-357, 2011.
    OpenUrlCrossRefPubMed
    1. Hilton JL,
    2. Geisler JP,
    3. Rathe JA,
    4. Hattermann-Zogg MA,
    5. DeYoung B,
    6. Buller RE
    : Inactivation of BRCA1 and BRCA2 in ovarian cancer. J Natl Cancer Inst 94: 1396-1406, 2002.
    OpenUrlCrossRefPubMed
    1. Wang X,
    2. Wang RH,
    3. Li W,
    4. Xu X,
    5. Hollander MC,
    6. Fornace AJ Jr..,
    7. Deng CX
    : Genetic interactions between Brca1 and Gadd45a in centrosome duplication, genetic stability, and neural tube closure. J Biol Chem 279: 29606-29614, 2004.
    OpenUrlAbstract/FREE Full Text
    1. Brown LA,
    2. Irving J,
    3. Parker R,
    4. Kim H,
    5. Press JZ,
    6. Longacre TA,
    7. Chia S,
    8. Magliocco A,
    9. Makretsov N,
    10. Gilks B,
    11. Pollack J,
    12. Huntsman D
    : Amplification of EMSY, a novel oncogene on 11q13, in high grade ovarian surface epithelial carcinomas. Gynecol Oncol 100: 264-270, 2006.
    OpenUrlCrossRefPubMed
    1. Shen WH,
    2. Balajee AS,
    3. Wang J,
    4. Wu H,
    5. Eng C,
    6. Pandolfi PP,
    7. Yin Y
    : Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128: 157-170, 2007.
    OpenUrlCrossRefPubMed
    1. Sigurdsson S,
    2. Trujillo K,
    3. Song B,
    4. Stratton S,
    5. Sung P
    : Basis for avid homologous DNA strand exchange by human Rad51 and RPA. J Biol Chem 276: 8798-8806, 2001.
    OpenUrlAbstract/FREE Full Text
  96. Integrated genomic analyses of ovarian carcinoma. Nature 474: 609-615, 2011.
    OpenUrlCrossRefPubMed
    1. Soslow RA,
    2. Han G,
    3. Park KJ,
    4. Garg K,
    5. Olvera N,
    6. Spriggs DR,
    7. Kauff ND,
    8. Levine DA
    : Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma. Mod Pathol 25: 625-636, 2012.
    OpenUrlCrossRefPubMed
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‘BRCAness’ and Its Implications for Platinum Action in Gynecologic Cancer
FRANCO MUGGIA, TAMAR SAFRA
Anticancer Research Feb 2014, 34 (2) 551-556;
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