Pharmacogenetics and breast cancer management: current status and perspectives.

Review

Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by McMaster University on 02/27/15 For personal use only.

Pharmacogenetics and breast cancer management: current status and perspectives 1.

Introduction

2.

Somatic profiling

3.

Germ-line profiling

4.

Conclusion

5.

Expert opinion

Joseph Ciccolini, Raphaelle Fanciullino, Cindy Serdjebi & Gerard Milano† †

Centre Antoine Lacassagne, Laboratoire d’ Oncopharmacologie, Nice, France

Introduction: Breast cancer has benefited from a number of innovative therapeutics over the last decade. Cytotoxics, hormone therapy, targeted therapies and biologics can now be given to ensure optimal management of patients. As life expectancy of breast cancer patients has been significantly stretched and that several lines of treatment are now made available, determining the best drug or drug combinations to be primarily given and the best dosing and scheduling for each patient is critical for ensuring an optimal toxicity/ efficacy balance. Areas covered: Defining patient’s characteristics at the tumor level (pharmacogenomics) and the constitutional level (pharmacogenetics) is a rising trend in oncology. This review covers the latest strategies based upon the search of relevant biomarkers for efficacy, resistance and toxicity to be undertaken at the bedside to shift towards precision medicine in breast cancer patients. Expert opinion: In the expanding era of bioguided medicine, identifying relevant and clinically validated biomarkers from the plethora of published material remains an uneasy task. Sorting the variety of genetic and molecular markers that have been investigated over the last decade on their level of evidence and addressing the issue of drug exposure should help to improve the management of breast cancer therapy. Keywords: breast cancer, pharmacogenetics, pharmacogenomics, pharmacokinetics Expert Opin. Drug Metab. Toxicol. [Early Online]

1.

Introduction

Over the last two decades, in addition to striking progress in the field of surgery and radiotherapy, breast cancer has benefited from major advances with the constant development of innovative drugs addressing newly discovered targets [1]. Cytotoxics, hormone therapy, targeted therapies and biologics including the latest antibody-drug conjugates are now widely used to better manage breast cancer patients, with either localized or metastatic disease. This increase in drugs made available has significantly stretched the therapeutic options at the bedside. Shifting towards a more personalized care of patients is now considered as the next major advance to be achieved in clinical oncology. Among the various strategies to be possibly undertaken, a better understanding of molecular and genetic characteristics of each tumor (a.k.a. pharmacogenomics) is critical so as to help defining the best choice of drugs to be given, depending on the expression or the mutational status of the targets at the tumor level. Implementing pharmacogenomic testing in routine practice has largely benefited from the progress in the field molecular biology techniques and from screening single SNP (Single Nucleotide Polymorphism: genotyping) to large throughput sequencing using the latest NGS (Next-Generation Sequencing) approaches [2]. The rise of targeted therapies in oncology in the early 2000’s has been progressively associated with the use of companion testing required to check at the bedside that the tumor would indeed express correctly the target to be hit, 10.1517/17425255.2015.1008447 © 2015 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted

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J. Ciccolini et al.

Article highlights. . .

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Breast cancer therapy has benefited from major improvements over the last decade. Precision medicine is a rising trend in medical oncology, aiming at sorting patients on their genetic and molecular characteristics prior to drug administration. Although somatic deregulations are extensively studied as part of pharmacogenomic strategies, germinal polymorphisms impacting on pharmacokinetics remain to be fully explored and used at the bedside. A growing level of evidence indicates that the efficacy/ toxicity balance of most anticancer agents widely prescribed in breast cancer patients could be improved by addressing the issue of genetic-driven pharmacokinetics variability.

This box summarizes key points contained in the article.

a strategy widely publicized now as bioguided therapy. In breast cancer patients and as extensively described in this review, preliminary checking for HER2 expression prior to prescribing anti-HER2 trastuzumab is paradigmatic of this major trend in clinical oncology. Besides breast cancer, treatments of CML, lung cancer, melanoma or colorectal cancer are now similarly largely based upon preliminary testing for various relevant markers such as C-Kit, BRaf or KRas status to name but a few, thus highlighting how biomarker-based medicine is now an irreversible trend in clinical oncology [3]. In addition to screening tumors, and although less widely used at the bedside, a comprehensive understanding of each patient’s constitutive characteristics and germinal polymorphisms is as critical as searching for tumoral mutations, because predicting possible changes in drug disposition and pharmacokinetics profiles should help to ensure an optimal toxicity/efficacy balance [4]. Indeed, dedicated adaptive dosing strategies should enable custom drug dosing so as to maintain drug levels within their respective therapeutic windows, provided that metabolic status has been assessed in patients. Changes in drug clearance, mostly related to reduced ability of some patients to metabolize drugs in the liver, are associated indeed with drug overexposure possibly leading to severe and possibly lethal toxicities with major cytotoxics given to breast cancer patients such as pyrimidine derivatives (5-fluorouracil [5-FU], capecitabine) or other nucleosidic analogs (gemcitabine) [5]. Conversely, ultrametabolizer patients on enzymes implicated in drug disposition are likely to be underexposed when treated with standard dosing, thus reducing their chance to fully benefit from the treatment [3,6]. In addition to cytotoxics, erratic pharmacokinetics of targeted therapies is currently recognized as a major cause for treatment failure (3) and recent clinical reports suggest that this could be an issue with monoclonal antibodies as well, although no data have been made available in breast cancer thus far [7]. Owing to the number of drugs made available now, understanding key issues related to both pharmacogenetics (constitutional changes in DMPK (Drug Metabolism & Pharmacokinetics) pattern) and pharmacogenomics (somatic 2

deregulations affecting drug response) is thus critical in breast cancer patients. This review covers the current knowledge about the various genetic polymorphisms likely to affect clinical outcome in breast cancer patients. 2.

Somatic profiling

HER2 polymorphisms HER2 may be considered as a paradigmatic target, in particular in breast cancer, where its inhibition has been shown to achieve significant clinical benefit, both in metastatic and in adjuvant setting. HER2 is known to carry a germinal polymorphism in codon 655 (Ile655Val, rs1136201). This position corresponds to the transmembrane domain of the receptor [8]. We do not dispose of clearcut experimental data illustrating a functional impact of this polymorphism in breast cancer patients, despite several studies investigating on its importance [9,10]. However, by analogy, chemical mutagenesis in mice leads to an elevation of HER2 mutation in position 664 (Val/Glu) [11]. This mutation, which is affecting the transmembrane domain of HER2, leads to a superactivation of HER2 tyrosine kinase activity (factor of 100), which could be responsible for the carcinogenesis process. A reasonable hypothesis could be thus advocated that there is a functional link between the HER2 655 Val/Ile in man and the functionality of the protein. This hypothesis is strongly supported by the clinical data reported by Xie et al. [12], who put into evidence an association between the relative presence of Val allele and a significant risk of breast cancer (odds ratio [OR] = 14.1, CI 95% 1.8 -- 113.4 for Val/Val subjects). Other studies have evidenced the relationship between HER2 status and both treatment response and breast cancer invasiveness [9,10]. Our group has previously conducted a prospective pharmacological--clinical study in a group of 61 patients receiving a trastuzumab-based treatment [13]. Of note, HER2 genotyping was performed on DNA extracted from blood mononuclear cells. Allele distribution was as follows: Ile/Ile 59, Ile/Val 34 and Val/Val 7%. It was not put into evidence a link between HER2 genotypes and objective response rate, disease-free survival and overall survival. In contrast, an association was found between the occurrence of a HER2-related cardiac toxicity and HER2 genotype. This specific toxicity was found in five patients (two grade I, two grade II and one grade III). This toxicity was put into evidence between 1 and 19 months following the initiation of treatment by trastuzumab. None of the affected patients had a previous story of cardiovascular abnormality. Of note, all episodes of cardiac toxicity were encountered in Val carrying patients: no cardiotoxicity in 36 Ile/Ile vs 5 cardiotoxicity in 21 Ile/Val vs no cardiotoxicity in 4 Val/Val (p = 0.0059). Interestingly, these original initial data were recently confirmed by other investigators in a larger set of 132 patients treated by trastuzumab: OR associated with cardiotoxicity in patients carrying at least one Val allele was 3.83 (CI 95% 1.11 -- 13.2, p = 0.025) when compared to patients with the Ile/Ile genotype [14]. 2.1

Expert Opin. Drug Metab. Toxicol. (2015) 11(4)

Pharmacogenetics and breast cancer management: current status and perspectives

Taking into account that treatment by trastuzumab is now becoming largely applied in breast cancer management not only in the metastatic situation but also in the adjuvant setting, it seems potentially interesting to take into consideration the HER2 655 polymorphism as a potentially interesting factor, easily accessible, for identifying patients at risk for HER2-related cardiotoxicity [15]. VEGF-related germinal polymorphisms Angiogenesis is a key component of cancer growth, invasion and metastasis. Therefore, inhibition of angiogenesis is an attractive option now largely adapted in the treatment of cancer. As concerns breast cancer, a recent review by Ku¨mler and co-workers has critically examined the impact of the antiVEGF monoclonal antibody bevacizumab in Phase II and Phase III clinical trials [3,16]. All studies found increased response rates although no clear benefits were demonstrated in terms of overall survival. Above all, the use of bevacizumab remains justified in breast cancer treatment in Europe with an urgent need to identify predictive biomarkers in order to get a better discrimination of potentially responsive patients. VEGF-A gene (Figure 1) is highly polymorphic and carries numerous SNPs in the promoter region and in the 3¢-region [17]. Among these germinal polymorphisms five have a potential functional impact (-2578C>A (rs699947); -1498T>C, -1154G>A (rs1570360); -634G>C (rs2010963) and 936C>T (rs3025039)). These polymorphisms have been reported as having a potential impact on VEGF-A plasma levels [18,19] and on cancer risk [20-22]. Our group has recently conducted a pharmacological--clinical study aiming at examining the impact of these five VEGF-A polymorphisms on the pharmacodynamics of bevacizumab in advanced breast cancer [23]. There were 137 patients in total, prospectively explored and with bevacizumab given at a dose of 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks in association or not with a taxane-based chemotherapy. In this group of patients the objective response rate was 61%. Median time for progression was 11 months. None of these considered polymorphisms was linked to response rate. Concerning survival, patients being homozygous 936 CC have shown a strong tendency for a shorter event-free survival (median 9.7 months) when compared to the 936 TT or TC (median at 11.5 months, p = 0.022). Of note, the 936T allele is known to be linked to a lower expression of VEGF-A. Thus, this pharmacological--genetic--clinical relationship could be explained by a lower expression for the bevacizumab’s target in 936 T allele carriers. To be underlined, as concerns a link between VEGF-A explored germinal polymorphisms and toxicity, the percentage of patients having encountered a toxicity score higher than 1 (sum of maximal grades considering arterial hypertension, hemorrhages, venous and arterial thromboembolisms) was, respectively, of 39, 49 and 81% in patients -634 GG, GC and CC (p = 0.01). Given the complexity of angiogenesis it is rather unlike that a single germline SNP might be a faithful predictor of pharmacodynamics


2.2

(response/toxicity) of bevacizumab. Other fields of investigation touching VEGF A receptor gene polymorphisms could be of additional value in this respect as recently shown in colorectal cancer treated by bevacizumab [24]. However, it has to be stressed out that search for predictive biomarkers with bevacizumab has generated inconsistent, when not highly conflictual, results to date, including when investigating on the role VEGF polymorphisms and expression could play in the clinical outcome of breast cancer patients [25-27]. Other genes closely related to angiogenic process (i.e., VEGFR-2, HIF-1a, TIMP-3, eNOS, PLGF, TSP-1 or pericyte germline polymorphisms) have all been proposed as putative biomarkers with bevacizumab, with similarly inconsistent or negative results [28-30]. More recently, combined Ang1 and Tie2 levels have been proposed as a new predictive marker for efficacy in patients with ovarian cancer [31], although further studies will have to be performed to fully confirm this role, including breast cancer patients. 3.

Germ-line profiling

CYP2D6 gene polymorphisms Tamoxifen, an anti-estrogen targeting estrogen receptor (ER), remains at the core of treatment of ER + breast cancer patients. This molecule may be in fact considered as a prodrug, which necessitates a hepatic metabolic activation into active metabolites (endoxifen mainly). This biotransformation occurs through the intermediary of the isoenzyme 2D6 of P450 cytochrome (CYP2D6). This isoenzyme presents numerous gene polymorphisms with > 80 described alleles [32]. Four groups of patients are conventionally classified according to their phenotype: ultrarapid metabolizers (UM, ~ 2% of Caucasians), normal or extensive (EM, 70% of Caucasians), intermediary (IM, 20% of Caucasians) and those with almost null activity (or poor metabolizers, PM, ~ 7% of Caucasians). This phenotypic classification can be covered by the analysis of nine variants, variants *9, *10 and *41 being associated with an intermediary activity and variants *3, *4, *5 and *6 with a null activity. In Caucasians, the distribution can be reduced to *1 variant (null activity) and *3, *4, *6, *10 and *41 variants. Theoretically, PM patients should not draw a significant benefit from a treatment by tamoxifen. The pivotal study by Goetz [33] has shown in a group of 190 menopausal patients that subjects being PM (*4/*4) and/or receiving a co-treatment potentially impairing CYP2D6 activity were exhibiting an overall survival significantly shorter when compared to WT/WT or WT/*4 patients (RR 1.6, p = 0.027). Among more recent studies, all conducted on smaller groups of patients, the data of Goetz were either confirmed [34-36] or not [37-39]. Among the negative studies, two pivotal ones [38,39] were retracted because of major methodological failures (analyses of tumoral DNA and not germinal DNA potentially impacting on Hardy--Weinberg equilibrium). A recent meta-analysis by the International Tamoxifen Pharmacogenomics Consortium [40], based on 3.1


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Promoter

Coding region

5’UTR

3’UTR

Initiation of translation ATG (1)


1

-2578 C>A (rs699947)

-1498 C>T (rs833061)

-1154 G>A (rs1570360)

2

3

Codon STOP

4

5

-634 G>C (rs2010963)

6

7

8

936 C>T (rs3025039)

Figure 1. VEGF-A gene structure and main polymorphisms. Reproduced from [23] with permission from the authors, British Journal of Clinical Pharmacology. Copyright 2011, The British Pharmacological Society. UTR: Untranslated region.

almost 5000 patients, concluded that PM patients have a lower event-free survival with an however modest HR at 1.25 (CI 95% 1.06 -- 1.47, p = 0.009) and this being true only in patients ER +, menopausal receiving 20 mg/day during 5 years. Well-conducted prospective studies with large groups of patients, including pre-menopausal subjects, remain necessary in order to get a firm opinion on the practical interest to screen for CYP2D6 genotype in breast cancer patients to be treated by tamoxifen. In addition to CYP2D6 polymorphism, other genetic alterations affecting ESR1 PvuII, CYP2C19*2, UGT2B15*2 have all been potentially pointed as possibly impacting on the clinical outcome with tamoxifen, although little data are made available thus far [41-43].

expression remains to be elucidated [45]. However, several clinical studies have evidenced the link between DPD deficiency, a condition caused by a partial or complete lack of DPD activity in patients, and the incidence of severe/lethal toxicities with 5-FU [47-49]. Besides 5-FU, and of the highest clinical importance, DPD deficiency is associated with potentially lethal toxicities in patients undergoing capecitabine intake, a standard treatment in breast cancer as well [50-52]. Despite a critical lack of consensus about the best strategy to be undertaken at the bedside to evaluate properly DPD status in patients, the data collected thus far advocate for a systematic prescreening for DPD in breast cancer patients scheduled for any 5-FU or capecitabine-containing regimen [53].

DPYD gene polymorphisms Nearly 60 years after its first introduction as an antimetabolite, fluoropyrimidine drugs (i.e., 5-FU and oral 5-FU capecitabine) remain the backbone of a variety of regimens for treating breast cancer, either as a localized disease or in metastatic setting. As most cytotoxics, 5-FU therapeutic window is narrow and erratic systemic exposure may impact on clinical outcome. Standard 5-FU administration usually leads to 10 -- 20% of severe hematological and digestive toxicities, and 0.5 -- 2% of toxic deaths, depending on the regimen [44]. 5-FU pharmacokinetics and resulting exposure levels are primarily driven by dihydropyrimidine dehydrogenase (DPD), a liver enzyme that converts 5-FU into inactive metabolite FUH2. It is acknowledged that > 80% of the 5-FU dose is usually metabolized in the liver, thus highlighting the critical role this enzyme plays in drug disposition. DPD is coded by a gene (DPYD), which is affected by genetic polymorphism and several dozens of SNPs have been identified so far, with however inconsistent impact on enzymatic activity [45]. Today, it is considered that three allelic variants (i.e., *2A, *13 and 2846A>T (rs67376798)) could be possibly associated with loss of DPD activity [45,46]. The exact role of additional epigenetic dysregulations and changes in transcription factors

Cytidine deaminase genetic polymorphism Cytidine deaminase (CDA) genetic polymorphism has been first extensively studied because CDA detoxifies gemcitabine, a drug potentially given to breast cancer patients. Many studies have investigated how CDA deficiency could be associated with severe or lethal toxicities with nucleosidic analogs because this liver enzyme detoxifies most drugs into inactive metabolites [54-57]. Although the role of particular polymorphisms affecting CDA gene (i.e., 79A>C (rs2072671), 208G>A (rs60369023)) with possible reduction in enzymatic activity remains to be fully elucidated [58,59], several independent clinical reports have demonstrated that CDA deficiency identified on a functional basis is predictive of severe and sometimes lethal toxicities with standard gemcitabine doses and thus should be screened prior to starting the treatment, although no specific data have been made available thus far in breast cancer patients [55,60]. Besides gemcitabine, CDA is implicated as well in the metabolic pattern of a variety of nucleosidic analogs such as capecitabine. As an oral form, capecitabine is usually recognized as a safe and convenient alternative to infusional 5-FU. Triple pro-drug capecitabine is serially converted in the liver into several inactive metabolites by carboxyl esterase (CE) and CDA, then finally cleaved

3.2

4

3.3




by thymidine phosphorylase in tumors to generate 5-FU that will be next activated towards its own metabolites. Both CE and CDA are coded by genes known to be affected by several genetic polymorphisms [58]. Whereas little available data indicate clearly that erratic CE activity could play a role in capecitabine efficacy or toxicity [61], there are mounting evidences that changes in CDA activity could impact on the clinical outcome of patients given capecitabine. Of note, CDA genetic polymorphism can lead to either loss or increase in CDA activity. With regard to capecitabine metabolic pattern, CDA ultrametabolizer status, a condition characterized by a marked increase in enzymatic activity, is likely to boost capecitabine activation into 5-FU, thus triggering severe toxicities eventually. Recent clinical reports presenting patients with life-threatening toxicities upon capecitabine intake have demonstrated that CDA UM status (i.e., CDA activities > 150% higher than standard values recorded in patients with no deficiency) was at the origin of the lethal cases [62,63]. CDA UM status has been associated with the -31delC deletion in the promoter region of the gene, and screening for this deletion could be predictive of severe toxicities with capecitabine [63,64], although as for gemcitabine, data collected thus far did not include yet breast cancer patients.

Other germinal polymorphisms of potential interest in breast cancer therapy

3.4

A variety of polymorphisms or mutations affecting genes coding for transporters or drug-metabolizing enzymes, all relevant with agents potentially used to treat breast cancer (i.e., cyclophosphamide, taxanes, anthracyclines, etc.), have been described over the last decade. However, most of these studies have been only performed in a single institute and independent replications remain required to confirm the importance of related polymorphisms, or several independent groups have investigated on the same polymorphisms but have generated inconsistent or contradictory results thus far [65]. Therefore, and despite intriguing results, too little rationale is provided to date for proposing their routine screening at the bedside. Cyclophosphamide has been the backbone of several regimens such as the canonical FEC combination with epirubicin and FU. Several studies have searched for predictive biomarkers for cyclophosphamide, with seemingly inconsistent results to date. CYP2B6*6 allelic variant has been associated with increased drug clearance and reduced plasma half-life when compared to wild-type or CYP2B6*1 patients [66]. In particular, four polymorphisms (i.e., g-2320T>C, g-750T>C, g.18492T>C and g.15582C>T) affecting CYP2B6, the liver enzyme responsible for the conversion of cyclophosphamide to hydroxyl cyclophosphamide, have been linked to changes in the drug disposition and exposure in women. Three out of these four SNPs (i.e., g-2320T>C, g-750T>C and g.18492T>C) were further associated with severe leucopenia in breast cancer patients [66]. However, other pharmacogenetic

studies of CYP2B6 failed to confirm the implication of these genetic polymorphisms in the clinical outcome of breast cancer patients treated with cyclophosphamide [67-69]. Other investigations have been performed on the possible role genetic polymorphisms affecting CYP3A4/A5 have played. Similarly, the exact role of CYP3A4/A5 in the pharmacokinetics and efficacy/toxicity balance of cyclophosphamide remains controversial. Petros et al. [67] first found that CYP3A4*1B and CYP3A5*1 allelic variants were associated with increase in parent drug exposure, and that CYP3A4*1B was predictive of poor survival when compared with wild-type status. However, as for CYP2B6, further studies failed in confirming the implication of genetic polymorphism in breast cancer patients treated with cyclophosphamide [65,68]. Of note, multianalytical approaches have recently identified CYP3A5*3, CYP2C19*2 and CYP2B6*5 as relevant alleles associated with treatment efficacy, whereas CYP2C8*3 and CYP2C9*2 were predictive of overall toxicity [70]. Besides CYP Phase I enzymes, GST is a Phase II liver enzyme implicated in the detoxification pattern of several drugs, including cyclophosphamide. Inconsistent data have been generated so far about a possible role genetic polymorphisms affecting GST could play in the efficacy of cyclophosphamide. For instance, Miyake et al. have shown that overexpression of GSTp1 was associated with weaker response in breast cancer patients [71], whereas it had been only found to be predictive of better tolerance in another study [72]. Finally, genetic changes in ABCC4 expression could trigger cyclophosphamide-induced toxicity [73], although further confirmatory studies are awaiten to confirm this. Taxanes (i.e., docetaxel, paclitaxel) have been introduced in the 1990’s and remain drugs widely used to treat breast cancer. Several liver enzymes and transporters are involved in taxoids disposition, with possible impact on the efficacy/toxicity balance eventually. Among the various polymorphisms affecting CYP2C8, CYP1B1 and ABCB1 efflux protein, Jabir et al. showed that the CYP1B1*3 allele was associated with reduced hypersensitivity reaction in breast cancer patients [74,75]. However, as for cyclophosphamide, determining the exact clinical relevance of the pharmacogenetics of taxoids remains an uneasy task today, and further independent studies are required to confirm the impact of polymorphisms on transporters and drug-metabolizing enzymes [74]. For instance, Hertz et al. have reported that the CYP2C8*3 allelic variant was predictive both of treatment efficacy and toxicities in patients undergoing paclitaxel-based therapy [76], whereas in a previous study Marsh et al. failed to evidence such relationship but found instead a relevant association between clinical outcome and the CYP1B1*3 allele, as Jabir et al. and Rizzo et al. did [77]. Similarly, whereas significant relationships were evidenced between polymorphisms of SLCO1B3 and docetaxel [78], further studies failed to confirm this association [79]. Anthracycline drugs (i.e., doxorubicin or liposomal doxorubicin) have been widely used to treat breast cancer, both in adjuvant and neoadjuvant setting. In a recent study,


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Table 1. Pharmacogenetics/genomics polymorphisms possibly affecting clinical outcome in breast cancer patients. Drug

Protein

Genotype--phenotype

Clinical impact

Ref.

Trastuzumab

HER2

Bevacizumab

VEGF-A

rs1136201 Expression -634G>C, 936C>T, 2578C>A, -1498T>C, -1154G>A Expression *4 *2, *13, 2846A>T Expression Poor metabolizer Ultrametabolizer -31delC Poor metabolizer Ultrarapid metabolizer Expression Expression g.2320T>C, g.750T>C, g.18492T>C *1B Overexpression *3 *3 Expression Expression Expression Expression

Cardiotoxicity Longer survival Highly variable

[12] [8] [21]

Efficacy Reduced survival Severe toxicity Reduced efficacy

[29] [24-27] [36,37,43] [82] [43,45,46,55-57]

Severe toxicity Poor response Poor response

[53] [5] [88]

Severe toxicity Reduced survival Poor response Better tolerance Better tolerance Reduced efficacy Efficacy, toxicity Reduced efficacy Efficacy, toxicity

[56] [57] [64] [67,68,70] [69] [83] [71] [83] [73]

Expression 538G>A 538G>A

Reduced efficacy Reduced efficacy Reduced efficacy

[82] [83] [82]

Tamoxifen 5-FU


Capecitabine

Gemcitabine

Cyclophosphamide

Paclitaxel

Docetaxel Doxorubicin

Pemetrexed Methotrexate

Ang1/Tie2 CYP2D6 DPD ABCC11 DPD CDA CDA hENT1 hCNT3 CYP2B6 CYP3A4 GSTP1 CYP1B1 CYP2C8 ABCB1 SLCO1B3 ABCB1 GSTM1 GSTP1 GSTT1 ABCG2 ABCC11 ABCC11

Severe toxicity

CDA: Cytidine deaminase; DPD: Dihydropyrimidine dehydrogenase.

Tulsyan et al. have suggested using multi-analytical approaches how genetic polymorphisms affecting GST Phase II enzyme could have an impact on the clinical outcome in anthracycline-treated patients. In particular, GSTM1 and GSTP1 Ile105Val were found to be associated with treatment efficacy, GSTM1 and GSTT1 with severe anemia and GSTT1 and GSTP1 Ile105Val again with treatment discontinuation or cut in dosing due to neutropenia [80]. Confirmatory studies are awaited to better understand the role GSTs polymorphisms could play in doxorubicin-treated patients. A focus on drug transport Dysregulations in transporters are more and more under scrutiny as putative causes for poor clinical outcome in oncology. In particular, genetic polymorphisms affecting ABC transporter genes are related to both risk for breast cancer and decrease in drug efficacy. For instance, ABCC11 (a.k.a. MRP8) is implicated in the efflux of several nucleotidic analogs. ABCC11 mRNA levels in breast cancer cells are correlated with ER a status. Because tamoxifen blocks estradiol, it may thus increase ABCC11 expression. However, tamoxifen being often used as maintenance therapy, its impact on co-administered drugs should be limited [81]. Increase in 3.5

6

ABCC11 expression could lead to loss of 5-FU efficacy because active metabolite FdUMP is believed to efflux cancer cells through MRP8. Similarly, ABCC11 538G>A (A/A variant) has been associated with resistance to methotrexate and pemetrexed [82]. Besides ABCC11, ABCB1 polymorphisms have also been associated with decreased efficacy in breast cancer patients treated with docetaxel, anthracyclines, paclitaxel and FAC regimen, whereas increase in ABCG2 (a.k.a. BCRP) reduces the efficacy of doxorubicin and lapatinib [83,84]. Of note, the exact role ABCB1 plays in the clinical outcome of breast cancer patients remains controversial, because Brooks et al. failed to evidence the impact of ABCB1 status on efficacy of FAC or FEC regimen [85] and Jabir et al. on the efficacy of taxane-based therapy [72]. Finally, and beyond the issue of efficacy, genetic polymorphisms affecting transporters could impact on tolerance as well. Of interest, the study of Chaturvedi et al. [86] evaluated the influence of ABCB1 status in breast cancer patients treated with FAC/FEC regimen. The T allele of 1236C>T was associated with higher toxicity, whereas the CT genotype was linked to treatment response [86]. Besides active transporters, changes in tumor expression of equilibrative and concentrative transporters may impact as well on clinical outcome. Although



solely demonstrated in pancreatic cancer patients, loss in hENT1 and hCNT3 expression has been repeatedly associated with poor clinical outcome in gemcitabine-treated patients, thus stressing out how addressing changes in transport is critical to better predict efficacy [87,88].


4.

Conclusion

Breast cancer treatment has benefited from the approval of a rising number of drugs, including targeted therapies and biotherapies. Several major drugs are affected by genetic polymorphisms of different nature, ranging from the target itself (e.g., trastuzumab and Her2, bevacizumab and VEGF-A, respectively) to metabolic pathways and transport systems (e.g., tamoxifen and CYP2D6, gemcitabine and CDA, 5-FU and DPD), as summarized in Table 1. Bioguided medicine is based upon preliminary investigations at the tumor level of molecular and genetic characteristics associated with response, whether germ-line polymorphisms are likely to impact on drug metabolism and distribution. Both strategies are mandatory to achieve precision medicine in clinical oncology. Implementing routine screening for genetic polymorphisms affecting both the tumor and the host could help indeed to better tailor treatment of breast cancer patients. Of note, the issue of pharmacokinetics variability of anticancer agents used in breast cancer should not be underestimated and left as an unaddressed issue. For instance, the current failure in identifying a biomarker with bevacizumab is probably due, at least in part, to the large variability in drug exposure observed among patients, thus acting as a major confounding factor when trying to predict clinical outcome and searching for relevant biomarkers [89]. 5.

Expert opinion

We have not yet reached the time of precision medicine for cancer care. Much efforts and attention have focused so far on the tumor itself (genetic characteristics, intrinsic variability and molecular profile). Another dimension for precision medicine is to pay attention now to the patient, by taking into account his/her own germinal variability. Breast cancer is an illustrating example of this necessary multidimensional approach (i.e., somatic plus constitutive) in order to improve significantly patient care in terms of both efficacy and safety. Several breast cancer treatments can potentially benefit of pharmacogenetic markers to improve its management. An unanswered question that remains to be fully addressed is

how to incorporate this knowledge from academic studies to routine clinical practice so as to further stretch the clinical benefits achieved in this setting. In addition, biomarker-based medicine can appear as an underpowered strategy without therapeutic drug monitoring. For instance, and despite systematic prescreening for HER2 expression, trastuzumab administration remains ineffective in about half of the patients. This may be partly due to the lack of knowledge and the lack of control of the drug exposure levels through therapeutic drug monitoring strategies in patients treated with biotherapies, an issue largely unaddressed at the bedside. When dealing with hormone therapy or cytotoxics, routine practice tells us that germinal pharmacogenetics has not yet impacted on therapeutic strategy for breast cancer as once expected, as for instance irinogenetics (i.e., adaptive dosing of irinotecan depending on UGT1A1 status [90]) did in digestive oncology. Failing to reach routine application of fully bioguided therapy in breast cancer is partly due to the lack of prospective, controlled trials demonstrating the clinical benefits of genetically- or phenotypically driven dosing strategies of 5-FU or other drugs, despite the number of clinical reports based upon retrospective or monocentric studies. Also, the fact that most breast cancer patients are treated with several drugs given in combination is a confounding factor likely to interfere with the understanding of the actual impact of a given genetic polymorphism on the clinical outcome (toxicity, response, survival). Other difficulties include time-consuming, labor intensive and expensive testing plus complicated algorithms required to custom dosing and integrating genetic status as covariates in sophisticated Pharmacokintics/Pharmacodynamics (PK/PD) models. In this respect, a collaborative effort is needed, which may involve multiple disciplinary fields and different academic centers with complementary expertise. For instance, the Pharmacogenetics Research Network in the US, which includes 12 institutes nationwide [91], opens the paths of a new era in the field of breast cancer genomics, genetics and pharmacokinetics.

Declaration of interest The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.


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Available from: http://www.pharmgkb. org 2014

Affiliation Joseph Ciccolini1, Raphaelle Fanciullino1, Cindy Serdjebi2 & Gerard Milano†2 † Author for correspondence 1 SMARTc Pharmacokinetics Unit, UMR S_911 CRO2, AMU, Marseille, France 2 Centre antoine Lacassagne, Oncopharmacology Laboratory, 33 av. de Valombrose 06189 Nice 02, France. E-mail: [email protected]

11

Circulating tumor cells in breast cancer--current status and perspectives.

Flecainide: Current status and perspectives in arrhythmia management.

MicroRNAs in Cancer Biology and Therapy: Current Status and Perspectives.

Anal cancer treatment: current status and future perspectives.

Current status and future perspectives in differentiated thyroid cancer.

Pharmacotherapy for recurrent ovarian cancer: current status and future perspectives.

Cancer biomarker discovery: current status and future perspectives.

Exercise after breast cancer treatment: current perspectives.

Multidrug-resistant breast cancer: current perspectives.

Neuroendocrine tumor biomarkers: current status and perspectives.

Congenital hyperinsulinism: current status and future perspectives.

SaudiVeg ecoinformatics: Aims, current status and perspectives.

Management of locally advanced breast cancer-perspectives and future directions.

Individual Monitoring and Occupational Dose Record Management in China: History, Current Status and Perspectives.

Optimal management of breast cancer in the elderly patient: current perspectives.

Targeted therapies with companion diagnostics in the management of breast cancer: current perspectives.

Evaluation and management of dyspepsia - current perspectives.

Peripartum cardiomyopathy: current management and future perspectives.

Optimal breast cancer screening strategies for older women: current perspectives.

Current perspectives on CHEK2 mutations in breast cancer.

The management of cognitive impairment in bipolar disorder: current status and perspectives.

Intraoperative radiation therapy for breast cancer patients: current perspectives.

Orofacial pain management: current perspectives.

Nitric oxide and phytohormone interactions: current status and perspectives.