Editorial For reprint orders, please contact: [email protected]
Pharmacogenomics
Elucidating the genomic landscape of breast cancer: how will this affect treatment? “The pattern that has emerged from whole exome DNA sequencing
of primary breast cancers is that somatic mutations in only three genes are observed with a greater than 10% incidence across primary breast cancers (TP53, PIK3CA and GATA3), with a ‘long tail’ of somatic mutations that are found infrequently.” Keywords: breast cancer • CDK • ERBB2 • ESR1 • FGFR • homologous recombination deficiency • PI3K pathway
Background Breast cancer is the most frequently diagnosed cancer in women worldwide and the secondleading cause of cancer-associated mortality [1] . Current treatment for breast cancer is based upon the identification of patients whose tumors express the estrogen receptor (ER positive) and/or demonstrate gene amplification or protein overexpression of HER2/ERBB2 (HER2 positive). Advances in sequencing technology have enabled large-scale studies to elucidate the genomic landscape of breast cancer and other malignancies through The Cancer Genome Atlas [2] project. The pattern that has emerged from whole exome DNA sequencing of primary breast cancers is that somatic mutations in only three genes are observed with a greater than 10% incidence across primary breast cancers (TP53, PIK3CA and GATA3), with a ‘long tail’ of somatic mutations that are found infrequently. This poses a challenge to identify driver mutations in an individual patient’s breast cancer that can be targeted with treatment. Below we review recurrent genomic alterations in breast cancer and selected targeted agents in clinical development that are relevant to a genotype-matched treatment approach. PI3K/AKT/mTOR pathway The PI3K, AKT and mTOR pathway regulates the cell cycle, survival, metabolism,
10.2217/PGS.15.27 © 2015 Future Medicine Ltd
motility and angiogenesis. In breast cancers, the PI3K pathway may mediate resistance to endocrine therapy [3] and HER2-targeted treatments [4] . The most frequent alterations of the PI3K/AKT/mTOR pathway are: activating mutations of PIK3CA, present in 40% of ER-positive tumors; PTEN dysregulation, found in 40% of HER2 positive and 30% of basal like tumors and aberrant activation of AKT, in 24% of all breast cancer subtypes [5] . The mTOR inhibitor everolimus showed clinical benefit in combination with aromatase inhibitor exemestane in postmenopausal endocrine-resistant ER-positive breast cancer patients (BOLERO-2) [6] that lead to regulatory approval, but only modest antitumor activity was seen when combined with trastuzumab and vinorelbine in HER2-positive patients resistant to prior HER2-targeted treatment (BOLERO-3) [7] . Recently, the addition of everolimus to trastuzumab and paclitaxel failed to improve progression-free survival (PFS), although a benefit was observed in the ER-negative negative subgroup (BOLERO-1) [8] . The PI3K-α isoform specific PI3K inhibitor BYL719 [9] and the b-isoform-sparing inhibitor GDC-0032 [10] reported single agent activity in heavily pretreated advanced PIK3CA mutant breast cancers in Phase I
Pharmacogenomics (2015) 16(6), 569–572
Neda Stjepanovic Bras Drug Development Program, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, 5–125, 610 University Avenue, Toronto, ON M5G 2M9, Canada and Department of Medicine, University of Toronto, Toronto, ON, Canada
Philippe L Bedard *Author for correspondence: Bras Drug Development Program, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, 5–125, 610 University Avenue, Toronto, ON M5G 2M9, Canada and Department of Medicine, University of Toronto, Toronto, ON, Canada Tel.: +1 416 946 4534 Fax: +1 416 946 4563 philippe.bedard@ uhn.ca
part of
ISSN 1462-2416
569
Editorial Stjepanovic & Bedard clinical trials. A Phase III clinical trial (SANDPIPER) designed to demonstrate the efficacy of the combination of GDC-0032 and fulvestrant (NCT02340221) recently began recruitment. The pan-PI3K inhibitor GDC-0941 in combination with fulvestrant has recently shown activity in ER-positive breast cancer patients in a Phase II clinical trial (FERGI), although the PFS improvement was not statistically significant [11] . Retrospective analysis of the BOLERO-2 [12] and FERGI clinical trials [11] failed to show PI3K pathway alteration as drivers of response to mTOR or panPI3K inhibitors. However, the preliminary results of the b-isoform-sparing inhibitor GDC-0032 suggested increased efficacy in PIK3CA mutant ER-positive breast cancer compared with PIK3CA wild-type [13] . FGF/FGFR pathway The FGFs and their receptors (FGFR1–4) regulate proliferation, differentiation, migration and survival. Amplification of the 8p11–12 chromosomal region, which includes FGFR1, is observed in 10% of breast cancers, predominantly luminal-B subtype and has been associated with resistance to endocrine treatment and poor prognosis [14] . Amplification of the 11q12–14 chromosomal region, which includes the FGF3 and CCND1 among other genes, occurs in 15–30% of breast cancers and has been associated with increased recurrence risk [15] . The FGF/FGFR pathway can effectively be inhibited with FGFR tyrosine kinase unit inhibitors (TKIs). The first-generation of FGFR TKIs (dovitinib and lucitanib) are broadly potent against other signaling kinases as VEGFR1–3, PDGFRα-β, cKit and others. Tumor responses and prolonged disease stabilizations in FGFR1 or FGFR3 amplified ER-positive breast cancer patients were seen in a Phase II trial of dovitinib [16] and a Phase I trial of lucitanib [17] which has further led to two Phase II trials of lucitanib in ER-positive advanced breast cancer (NCT02202746, NCT02053636). The second-generation FGFR TKIs (BGJ398 and AZD4547) are potent, highly selective inhibitors of FGFR1–3, whose antitumor activity has been reported in advanced solid tumors with FGFR1 amplification or translocations. Prolonged stable disease was observed in breast cancer patients treated in the Phase I trial with AZD4547 [18] , leading to a Phase II trial of AZD4547 with fulvestrant that recently completed enrollment (NCT01202591). ERBB2 (HER2/neu) Amplification or overexpression of ERBB2 is observed in 15–20% of breast cancers, and is validated thera-
570
Pharmacogenomics (2015) 16(6)
peutic target with several approved HER2-directed treatments, including trastuzumab, lapatinib, pertuzumab and trastuzumab-emtansine. Somatic mutation of ERBB2 is an alternative mechanism of HER2pathway activation that may be targeted with existing HER2-directed therapies [19,20] . These mutations are observed in 1–2% of breast cancers, although they may be enriched in lobular carcinomas (up to 9% frequency), particularly in cancers harboring comutation of CDH1 [2] . Several ERBB2 variants have been shown to be resistant to reversible ERBB2 TKIs, although they may be sensitive to irreversible TKIs, such as neratinib [19] providing the rationale for an ongoing Phase II study (NCT01670877). Homologous recombination DNA repair Germline BRCA1/2 mutations are found in up to 7% of all breast cancers unselected for family history, age of onset or molecular subtype [21] . Tumors lacking functional BRCA1 or BRCA2 proteins, either through germline or somatic mutation or other mechanisms of silencing, have a homologous recombination deficiency (HRD) that provides a therapeutic opportunity for therapies against DNA repair systems, such as the PARP inhibitors.
“
HER2 amplification is the only genomic alteration that is routinely tested for in clinical practice… Ongoing clinical trials will establish if other driver mutations can be effectively targeted to usher in a new paradigm of genotype-directed therapy in breast cancer.
”
In breast cancer patients with germline BRCA1/ BRCA2 mutations, the reported response rate with PARP-inhibitors (olaparib, veliparib, niraparib and BMN-673) ranges from 13–55%, with greater clinical benefit in the triple negative subgroup [22–27] . Based on these promising results, Phase III clinical trials in advanced breast cancers in patients with germline BRCA1/2 mutations have started with the four PARP-inhibitors: olaparib (OLYMPIA trial, NCT02000622), veliparib (NCT02163694), niraparib (BRAVO trial, NCT01905592) and BMN 673 (EMBRACA trial, NCT01945775). Responses to PARP-inhibitors have also been reported in patients with sporadic high grade serous ovarian carcinoma [27] and triple negative breast cancer [24] . Tumor responses to PARP-inhibitors in the BRCA1 and BRCA2 wild-type population may be related to other types of HRD. Great efforts are being made to develop a HRD signature that can identify patients, beyond germline BRCA1/2 mutations, who may benefit from PARP-inhibitors.
future science group
Elucidating the genomic landscape of breast cancer
Cell cycle regulation CDKs The interaction between cyclin D1 and the cyclindependent kinases (CDKs) regulates the progression of the cell cycle from G1 to S Phase. In breast cancers, amplification of the CCND1 gene and CDK genes occur frequently in ER-positive breast cancers [2] . Inhibitors of CDK4/6 induce G1 arrest during cell division and show synergistic antiproliferative effects in combination with endocrine therapy in ER-positive breast cancer preclinical models [28] . A Phase II clinical trial (PALOMA-1) demonstrated a doubling of PFS with palbociclib (PD-0332991) in combination with letrozole as a first line of treatment for metastatic ERpositive breast cancer patients compared with letrozole monotherapy [29] . This led to a Phase III clinical trial with a similar design (PALOMA-2; NCT01740427) and a Phase III trial palbociclib in combination with fulvestrant in endocrine-resistant ER-positive advanced breast cancers (NCT01942135). Both studies have recently completed enrollment with results anticipated in the near future.
Editorial
degrader fulvestrant, currently used in clinical practice, could inhibit breast cancers with ESR1 ligand-binding mutations [30] . The novel potent oral selective estrogen receptor degrader ARN-810 demonstrated antitumor activity in ESR1 mutant preclinical models. A Phase I trial with ARN-810 reported a clinical benefit rate of 41% in patients with endocrine resistant advanced ER-positive breast cancer [34] . A Phase II trial that will enroll patients previously treated with aromatase inhibitors and fulvestrant, including those with ESR1 mutations, has been announced. Conclusion Our understanding of the genomic landscape of breast cancer has rapidly expanded in recent years. In spite of these advances, HER2 amplification is the only genomic alteration that is routinely tested for in clinical practice, as it linked to the activity of approved HER2targeted therapies. Ongoing clinical trials will establish if other driver mutations can be effectively targeted to usher in a new paradigm of genotype-directed therapy in breast cancer.
ESR1
Somatic mutations in ESR1 occur in less than 2% of primary ER-positive breast cancers [2,30] . However, ESR1 mutations are enriched in metastatic ER-positive breast cancer occurring in 11–55% [30–33] . These activating mutations are found in the ligand-binding domain in ESR1 and occur as an adaptive mechanism of resistance to long-term estrogen deprivation induced by aromatase inhibitor treatment. The recent discovery of these acquired ESR1 mutations raises the compelling hypothesis that more potent direct ER-antagonists than tamoxifen or the selective estrogen receptor
Financial & competing interests disclosure
References
6
Baselga J, Campone M, Piccart M et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366(6), 520–529 (2012).
7
André F, O’Regan R, Ozguroglu M et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled Phase 3 trial. Lancet Oncol. 15(6), 580–591 (2014).
8
Hurvitz SA, Andre F, Jiang Z et al. Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and paclitaxel as firstline therapy in women with HER2+ advanced breast cancer: BOLERO-1. (Abstract S6–01). Presented at: 37th San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 9–13 December 2014.
9
Juric D, Burris H, Schuler M et al. Phase I study of the PI3Kα inhibitor BYL719, as a single agent in patients with advanced solid tumors (aST) (Abstract 451PD). Ann. Oncol. 25, iv146–iv64 (2014).
1
Ferlay J, Soerjomataram I, Dikshit R et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136(5), E359–86 (2015).
2
The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490(7418), 61–70 (2012).
3
Miller TW, Hennessy BT, Gonzalez-Angulo AM et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptorpositive human breast cancer. J. Clin. Invest. 120(7), 2406–2413 (2010).
4
Berns K, Horlings HM, Hennessy BT et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12(4), 395–402 (2007).
5
Hernandez-Aya LF, Gonzalez-Angulo AM. Targeting the phosphatidylinositol 3-kinase signaling pathway in breast cancer. Oncologist 16(4), 404–414 (2011).
future science group
L Bedard has provided consulting services to Pfizer, Genentech/ Roche and Sanofi, and clinical trials support to Bristol-Myers Squibb, Sanofi, AstraZeneca, Servier, GlaxoSmithKline, Oncothyreon, Novartis, SignalChem and PTC Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
www.futuremedicine.com
571
Editorial Stjepanovic & Bedard 10
Juric D, Krop I, Ramanathan RK et al. GDC-0032, a beta isoform-sparing PI3K inhibitor: results of a first-in-human Phase Ia dose escalation study (Abstract LB-64). Presented at: 104th American Association for Cancer Research Annual Meeting. Washington, DC, USA, 6–10 April 2013.
11
Krop I, Johnston S, Mayer IA et al. The FERGI Phase II study of the PI3K inhibitor pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER+, aromatase inhibitor (AI)-resistant advanced or metastatic breast cancer – Part I results (Abstract S2-02). Presented at: 37th San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 9–13 December 2014.
12
13
572
Hortobagyi GN, Piccart-Gebhart MJ, Rugo HS et al. Correlation of molecular alterations with efficacy of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer: results from BOLERO-2. J. Clin. Oncol. 31(Suppl. 15), Abstract LBA509 (2013). Saura C, Sachdev J, Patel MR et al. Ph1b study of the PI3K inhibitor taselisib (GDC-0032) in combination with letrozole in patients with hormone receptor-positive advanced breast cancer (Abstract PD5-2). Presented at: 37th San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 9–13 December 2014.
14
Turner N, Pearson A, Sharpe R et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 70(5), 2085–2094 (2010).
15
Dienstmann R, Rodon J, Prat A et al. Genomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors. Ann. Oncol. 25(3), 552–563 (2014).
16
Andre F, Bachelot T, Campone M et al. Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer. Clin. Cancer Res. 19(13), 3693–3702 (2013).
17
Dienstmann R, Andrè F, Soria JC et al. Significant antitumor activity of E-3810, a novel FGFR and VEGFR inhibitor, in patients with FGFR1 amplified breast cancer (Abstract 3190). Ann. Oncol. 23(Suppl. 9), ix116–ix43 (2012).
18
Andre F, Ranson M, Dean E et al. Results of a Phase I study of AZD4547, an inhibitor of fibroblast growth factor receptor (FGFR), in patients with advanced solid tumors (Abstract LB-145). Presented at: 104th American Association for Cancer Research Annual Meeting. Washington, DC, USA, 6–10 April 2013.
19
Bose R, Kavuri SM, Searleman AC et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 3(2), 224–237 (2013).
20
Palmer GA, Ross JS, Wang K et al. Activating mutations in ERBB2/HER2 as found by FoundationOneTM represent potential therapeutic targets in breast cancer (Abstract P4-15-03). Presented at: 37th San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 9–13 December 2014.
21
Antoniou A, Pharoah PDP, Narod S et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am. J. Hum. Genet. 72(5), 1117–1130 (2003).
Pharmacogenomics (2015) 16(6)
22
Kaufman B, Shapira-Frommer R, Schmutzler RK et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J. Clin. Oncol. 33(3), 244–250 (2015).
23
Tutt A, Robson M, Garber JE et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-ofconcept trial. Lancet 376(9737), 235–244 (2010).
24
Pahuja S, Beumer JH, Appleman LJ et al. Outcome of BRCA 1/2-mutated (BRCA+) and triple-negative, BRCA wild type (BRCA-wt) breast cancer patients in a Phase I study of singleagent veliparib (V). J. Clin. Oncol. 32(Suppl. 26), Abstract 135 (2014).
25
Ramanathan R, Wainberg Z, Mina L et al. PARP inhibition with BMN 673 in ovarian and breast cancer patients with deleterious mutations of BRCA1 and BRCA2. Eur. J. Cancer 49(Suppl. 3), Abstract LBA29 (2013).
26
Sandhu SK, Schelman WR, Wilding G et al. The poly(ADPribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a Phase 1 dose-escalation trial. Lancet Oncol. 14(9), 882–892 (2013).
27
Gelmon KA, Tischkowitz M, Mackay H et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a Phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 12(9), 852–861 (2011).
28
Finn RS, Dering J, Conklin D et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 11(5), R77 (2009).
29
Finn RS, Crown JP, Lang I et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptorpositive, HER2-negative, advanced breast cancer (PALOMA-1/ TRIO-18): a randomised Phase 2 study. Lancet Oncol. 16(1), 25–35 (2015).
30
Toy W, Shen Y, Won H et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat. Genet. 45(12), 1439–1445 (2013).
31
Robinson DR, Wu YM, Vats P et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat. Genet. 45(12), 1446–1451 (2013).
32
Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A et al. D538G mutation in estrogen receptor-alpha: a novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res. 73(23), 6856–6864 (2013).
33
Jeselsohn R, Yelensky R, Buchwalter G et al. Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin. Cancer Res. 20(7), 1757–1767 (2014).
34
Bardia A, Dickler MN, Mayer IA et al. Phase I study of ARN-810, a novel and potent oral selective estrogen receptor degrader, in postmenopausal women with metastatic estrogen receptor positive (ER+), HER2- breast cancer (Abstract P1-1301). Presented at: 37th San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 9–13 December 2014.
future science group
Pharmacogenomics
Elucidating the genomic landscape of breast cancer: how will this affect treatment? “The pattern that has emerged from whole exome DNA sequencing
of primary breast cancers is that somatic mutations in only three genes are observed with a greater than 10% incidence across primary breast cancers (TP53, PIK3CA and GATA3), with a ‘long tail’ of somatic mutations that are found infrequently.” Keywords: breast cancer • CDK • ERBB2 • ESR1 • FGFR • homologous recombination deficiency • PI3K pathway
Background Breast cancer is the most frequently diagnosed cancer in women worldwide and the secondleading cause of cancer-associated mortality [1] . Current treatment for breast cancer is based upon the identification of patients whose tumors express the estrogen receptor (ER positive) and/or demonstrate gene amplification or protein overexpression of HER2/ERBB2 (HER2 positive). Advances in sequencing technology have enabled large-scale studies to elucidate the genomic landscape of breast cancer and other malignancies through The Cancer Genome Atlas [2] project. The pattern that has emerged from whole exome DNA sequencing of primary breast cancers is that somatic mutations in only three genes are observed with a greater than 10% incidence across primary breast cancers (TP53, PIK3CA and GATA3), with a ‘long tail’ of somatic mutations that are found infrequently. This poses a challenge to identify driver mutations in an individual patient’s breast cancer that can be targeted with treatment. Below we review recurrent genomic alterations in breast cancer and selected targeted agents in clinical development that are relevant to a genotype-matched treatment approach. PI3K/AKT/mTOR pathway The PI3K, AKT and mTOR pathway regulates the cell cycle, survival, metabolism,
10.2217/PGS.15.27 © 2015 Future Medicine Ltd
motility and angiogenesis. In breast cancers, the PI3K pathway may mediate resistance to endocrine therapy [3] and HER2-targeted treatments [4] . The most frequent alterations of the PI3K/AKT/mTOR pathway are: activating mutations of PIK3CA, present in 40% of ER-positive tumors; PTEN dysregulation, found in 40% of HER2 positive and 30% of basal like tumors and aberrant activation of AKT, in 24% of all breast cancer subtypes [5] . The mTOR inhibitor everolimus showed clinical benefit in combination with aromatase inhibitor exemestane in postmenopausal endocrine-resistant ER-positive breast cancer patients (BOLERO-2) [6] that lead to regulatory approval, but only modest antitumor activity was seen when combined with trastuzumab and vinorelbine in HER2-positive patients resistant to prior HER2-targeted treatment (BOLERO-3) [7] . Recently, the addition of everolimus to trastuzumab and paclitaxel failed to improve progression-free survival (PFS), although a benefit was observed in the ER-negative negative subgroup (BOLERO-1) [8] . The PI3K-α isoform specific PI3K inhibitor BYL719 [9] and the b-isoform-sparing inhibitor GDC-0032 [10] reported single agent activity in heavily pretreated advanced PIK3CA mutant breast cancers in Phase I
Pharmacogenomics (2015) 16(6), 569–572
Neda Stjepanovic Bras Drug Development Program, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, 5–125, 610 University Avenue, Toronto, ON M5G 2M9, Canada and Department of Medicine, University of Toronto, Toronto, ON, Canada
Philippe L Bedard *Author for correspondence: Bras Drug Development Program, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, 5–125, 610 University Avenue, Toronto, ON M5G 2M9, Canada and Department of Medicine, University of Toronto, Toronto, ON, Canada Tel.: +1 416 946 4534 Fax: +1 416 946 4563 philippe.bedard@ uhn.ca
part of
ISSN 1462-2416
569
Editorial Stjepanovic & Bedard clinical trials. A Phase III clinical trial (SANDPIPER) designed to demonstrate the efficacy of the combination of GDC-0032 and fulvestrant (NCT02340221) recently began recruitment. The pan-PI3K inhibitor GDC-0941 in combination with fulvestrant has recently shown activity in ER-positive breast cancer patients in a Phase II clinical trial (FERGI), although the PFS improvement was not statistically significant [11] . Retrospective analysis of the BOLERO-2 [12] and FERGI clinical trials [11] failed to show PI3K pathway alteration as drivers of response to mTOR or panPI3K inhibitors. However, the preliminary results of the b-isoform-sparing inhibitor GDC-0032 suggested increased efficacy in PIK3CA mutant ER-positive breast cancer compared with PIK3CA wild-type [13] . FGF/FGFR pathway The FGFs and their receptors (FGFR1–4) regulate proliferation, differentiation, migration and survival. Amplification of the 8p11–12 chromosomal region, which includes FGFR1, is observed in 10% of breast cancers, predominantly luminal-B subtype and has been associated with resistance to endocrine treatment and poor prognosis [14] . Amplification of the 11q12–14 chromosomal region, which includes the FGF3 and CCND1 among other genes, occurs in 15–30% of breast cancers and has been associated with increased recurrence risk [15] . The FGF/FGFR pathway can effectively be inhibited with FGFR tyrosine kinase unit inhibitors (TKIs). The first-generation of FGFR TKIs (dovitinib and lucitanib) are broadly potent against other signaling kinases as VEGFR1–3, PDGFRα-β, cKit and others. Tumor responses and prolonged disease stabilizations in FGFR1 or FGFR3 amplified ER-positive breast cancer patients were seen in a Phase II trial of dovitinib [16] and a Phase I trial of lucitanib [17] which has further led to two Phase II trials of lucitanib in ER-positive advanced breast cancer (NCT02202746, NCT02053636). The second-generation FGFR TKIs (BGJ398 and AZD4547) are potent, highly selective inhibitors of FGFR1–3, whose antitumor activity has been reported in advanced solid tumors with FGFR1 amplification or translocations. Prolonged stable disease was observed in breast cancer patients treated in the Phase I trial with AZD4547 [18] , leading to a Phase II trial of AZD4547 with fulvestrant that recently completed enrollment (NCT01202591). ERBB2 (HER2/neu) Amplification or overexpression of ERBB2 is observed in 15–20% of breast cancers, and is validated thera-
570
Pharmacogenomics (2015) 16(6)
peutic target with several approved HER2-directed treatments, including trastuzumab, lapatinib, pertuzumab and trastuzumab-emtansine. Somatic mutation of ERBB2 is an alternative mechanism of HER2pathway activation that may be targeted with existing HER2-directed therapies [19,20] . These mutations are observed in 1–2% of breast cancers, although they may be enriched in lobular carcinomas (up to 9% frequency), particularly in cancers harboring comutation of CDH1 [2] . Several ERBB2 variants have been shown to be resistant to reversible ERBB2 TKIs, although they may be sensitive to irreversible TKIs, such as neratinib [19] providing the rationale for an ongoing Phase II study (NCT01670877). Homologous recombination DNA repair Germline BRCA1/2 mutations are found in up to 7% of all breast cancers unselected for family history, age of onset or molecular subtype [21] . Tumors lacking functional BRCA1 or BRCA2 proteins, either through germline or somatic mutation or other mechanisms of silencing, have a homologous recombination deficiency (HRD) that provides a therapeutic opportunity for therapies against DNA repair systems, such as the PARP inhibitors.
“
HER2 amplification is the only genomic alteration that is routinely tested for in clinical practice… Ongoing clinical trials will establish if other driver mutations can be effectively targeted to usher in a new paradigm of genotype-directed therapy in breast cancer.
”
In breast cancer patients with germline BRCA1/ BRCA2 mutations, the reported response rate with PARP-inhibitors (olaparib, veliparib, niraparib and BMN-673) ranges from 13–55%, with greater clinical benefit in the triple negative subgroup [22–27] . Based on these promising results, Phase III clinical trials in advanced breast cancers in patients with germline BRCA1/2 mutations have started with the four PARP-inhibitors: olaparib (OLYMPIA trial, NCT02000622), veliparib (NCT02163694), niraparib (BRAVO trial, NCT01905592) and BMN 673 (EMBRACA trial, NCT01945775). Responses to PARP-inhibitors have also been reported in patients with sporadic high grade serous ovarian carcinoma [27] and triple negative breast cancer [24] . Tumor responses to PARP-inhibitors in the BRCA1 and BRCA2 wild-type population may be related to other types of HRD. Great efforts are being made to develop a HRD signature that can identify patients, beyond germline BRCA1/2 mutations, who may benefit from PARP-inhibitors.
future science group
Elucidating the genomic landscape of breast cancer
Cell cycle regulation CDKs The interaction between cyclin D1 and the cyclindependent kinases (CDKs) regulates the progression of the cell cycle from G1 to S Phase. In breast cancers, amplification of the CCND1 gene and CDK genes occur frequently in ER-positive breast cancers [2] . Inhibitors of CDK4/6 induce G1 arrest during cell division and show synergistic antiproliferative effects in combination with endocrine therapy in ER-positive breast cancer preclinical models [28] . A Phase II clinical trial (PALOMA-1) demonstrated a doubling of PFS with palbociclib (PD-0332991) in combination with letrozole as a first line of treatment for metastatic ERpositive breast cancer patients compared with letrozole monotherapy [29] . This led to a Phase III clinical trial with a similar design (PALOMA-2; NCT01740427) and a Phase III trial palbociclib in combination with fulvestrant in endocrine-resistant ER-positive advanced breast cancers (NCT01942135). Both studies have recently completed enrollment with results anticipated in the near future.
Editorial
degrader fulvestrant, currently used in clinical practice, could inhibit breast cancers with ESR1 ligand-binding mutations [30] . The novel potent oral selective estrogen receptor degrader ARN-810 demonstrated antitumor activity in ESR1 mutant preclinical models. A Phase I trial with ARN-810 reported a clinical benefit rate of 41% in patients with endocrine resistant advanced ER-positive breast cancer [34] . A Phase II trial that will enroll patients previously treated with aromatase inhibitors and fulvestrant, including those with ESR1 mutations, has been announced. Conclusion Our understanding of the genomic landscape of breast cancer has rapidly expanded in recent years. In spite of these advances, HER2 amplification is the only genomic alteration that is routinely tested for in clinical practice, as it linked to the activity of approved HER2targeted therapies. Ongoing clinical trials will establish if other driver mutations can be effectively targeted to usher in a new paradigm of genotype-directed therapy in breast cancer.
ESR1
Somatic mutations in ESR1 occur in less than 2% of primary ER-positive breast cancers [2,30] . However, ESR1 mutations are enriched in metastatic ER-positive breast cancer occurring in 11–55% [30–33] . These activating mutations are found in the ligand-binding domain in ESR1 and occur as an adaptive mechanism of resistance to long-term estrogen deprivation induced by aromatase inhibitor treatment. The recent discovery of these acquired ESR1 mutations raises the compelling hypothesis that more potent direct ER-antagonists than tamoxifen or the selective estrogen receptor
Financial & competing interests disclosure
References
6
Baselga J, Campone M, Piccart M et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366(6), 520–529 (2012).
7
André F, O’Regan R, Ozguroglu M et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled Phase 3 trial. Lancet Oncol. 15(6), 580–591 (2014).
8
Hurvitz SA, Andre F, Jiang Z et al. Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and paclitaxel as firstline therapy in women with HER2+ advanced breast cancer: BOLERO-1. (Abstract S6–01). Presented at: 37th San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 9–13 December 2014.
9
Juric D, Burris H, Schuler M et al. Phase I study of the PI3Kα inhibitor BYL719, as a single agent in patients with advanced solid tumors (aST) (Abstract 451PD). Ann. Oncol. 25, iv146–iv64 (2014).
1
Ferlay J, Soerjomataram I, Dikshit R et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136(5), E359–86 (2015).
2
The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490(7418), 61–70 (2012).
3
Miller TW, Hennessy BT, Gonzalez-Angulo AM et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptorpositive human breast cancer. J. Clin. Invest. 120(7), 2406–2413 (2010).
4
Berns K, Horlings HM, Hennessy BT et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12(4), 395–402 (2007).
5
Hernandez-Aya LF, Gonzalez-Angulo AM. Targeting the phosphatidylinositol 3-kinase signaling pathway in breast cancer. Oncologist 16(4), 404–414 (2011).
future science group
L Bedard has provided consulting services to Pfizer, Genentech/ Roche and Sanofi, and clinical trials support to Bristol-Myers Squibb, Sanofi, AstraZeneca, Servier, GlaxoSmithKline, Oncothyreon, Novartis, SignalChem and PTC Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
www.futuremedicine.com
571
Editorial Stjepanovic & Bedard 10
Juric D, Krop I, Ramanathan RK et al. GDC-0032, a beta isoform-sparing PI3K inhibitor: results of a first-in-human Phase Ia dose escalation study (Abstract LB-64). Presented at: 104th American Association for Cancer Research Annual Meeting. Washington, DC, USA, 6–10 April 2013.
11
Krop I, Johnston S, Mayer IA et al. The FERGI Phase II study of the PI3K inhibitor pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER+, aromatase inhibitor (AI)-resistant advanced or metastatic breast cancer – Part I results (Abstract S2-02). Presented at: 37th San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 9–13 December 2014.
12
13
572
Hortobagyi GN, Piccart-Gebhart MJ, Rugo HS et al. Correlation of molecular alterations with efficacy of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer: results from BOLERO-2. J. Clin. Oncol. 31(Suppl. 15), Abstract LBA509 (2013). Saura C, Sachdev J, Patel MR et al. Ph1b study of the PI3K inhibitor taselisib (GDC-0032) in combination with letrozole in patients with hormone receptor-positive advanced breast cancer (Abstract PD5-2). Presented at: 37th San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 9–13 December 2014.
14
Turner N, Pearson A, Sharpe R et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 70(5), 2085–2094 (2010).
15
Dienstmann R, Rodon J, Prat A et al. Genomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors. Ann. Oncol. 25(3), 552–563 (2014).
16
Andre F, Bachelot T, Campone M et al. Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer. Clin. Cancer Res. 19(13), 3693–3702 (2013).
17
Dienstmann R, Andrè F, Soria JC et al. Significant antitumor activity of E-3810, a novel FGFR and VEGFR inhibitor, in patients with FGFR1 amplified breast cancer (Abstract 3190). Ann. Oncol. 23(Suppl. 9), ix116–ix43 (2012).
18
Andre F, Ranson M, Dean E et al. Results of a Phase I study of AZD4547, an inhibitor of fibroblast growth factor receptor (FGFR), in patients with advanced solid tumors (Abstract LB-145). Presented at: 104th American Association for Cancer Research Annual Meeting. Washington, DC, USA, 6–10 April 2013.
19
Bose R, Kavuri SM, Searleman AC et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 3(2), 224–237 (2013).
20
Palmer GA, Ross JS, Wang K et al. Activating mutations in ERBB2/HER2 as found by FoundationOneTM represent potential therapeutic targets in breast cancer (Abstract P4-15-03). Presented at: 37th San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 9–13 December 2014.
21
Antoniou A, Pharoah PDP, Narod S et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am. J. Hum. Genet. 72(5), 1117–1130 (2003).
Pharmacogenomics (2015) 16(6)
22
Kaufman B, Shapira-Frommer R, Schmutzler RK et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J. Clin. Oncol. 33(3), 244–250 (2015).
23
Tutt A, Robson M, Garber JE et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-ofconcept trial. Lancet 376(9737), 235–244 (2010).
24
Pahuja S, Beumer JH, Appleman LJ et al. Outcome of BRCA 1/2-mutated (BRCA+) and triple-negative, BRCA wild type (BRCA-wt) breast cancer patients in a Phase I study of singleagent veliparib (V). J. Clin. Oncol. 32(Suppl. 26), Abstract 135 (2014).
25
Ramanathan R, Wainberg Z, Mina L et al. PARP inhibition with BMN 673 in ovarian and breast cancer patients with deleterious mutations of BRCA1 and BRCA2. Eur. J. Cancer 49(Suppl. 3), Abstract LBA29 (2013).
26
Sandhu SK, Schelman WR, Wilding G et al. The poly(ADPribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a Phase 1 dose-escalation trial. Lancet Oncol. 14(9), 882–892 (2013).
27
Gelmon KA, Tischkowitz M, Mackay H et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a Phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 12(9), 852–861 (2011).
28
Finn RS, Dering J, Conklin D et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 11(5), R77 (2009).
29
Finn RS, Crown JP, Lang I et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptorpositive, HER2-negative, advanced breast cancer (PALOMA-1/ TRIO-18): a randomised Phase 2 study. Lancet Oncol. 16(1), 25–35 (2015).
30
Toy W, Shen Y, Won H et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat. Genet. 45(12), 1439–1445 (2013).
31
Robinson DR, Wu YM, Vats P et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat. Genet. 45(12), 1446–1451 (2013).
32
Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A et al. D538G mutation in estrogen receptor-alpha: a novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res. 73(23), 6856–6864 (2013).
33
Jeselsohn R, Yelensky R, Buchwalter G et al. Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin. Cancer Res. 20(7), 1757–1767 (2014).
34
Bardia A, Dickler MN, Mayer IA et al. Phase I study of ARN-810, a novel and potent oral selective estrogen receptor degrader, in postmenopausal women with metastatic estrogen receptor positive (ER+), HER2- breast cancer (Abstract P1-1301). Presented at: 37th San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 9–13 December 2014.
future science group
