Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics

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Chemotherapy-inducedperipheralneurotoxicityintheeraofpharmacogenomics

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www.thelancet.com/oncology Vol 12 November 2011 1151

Review

Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomicsGuido Cavaletti, Paola Alberti, Paola Marmiroli

Development of advanced and high-throughput methods to study variability in human genes means we can now use pharmacogenomic analysis not only to predict response to treatment but also to assess the toxic action of drugs on normal cells (so-called toxicogenomics). This technological progress could enable us to identify individuals at high and low risk for a given side-eff ect. Pharmacogenomics could be very useful for stratifi cation of cancer patients at risk of developing chemotherapy-induced peripheral neurotoxicity, one of the most severe and potentially permanent non-haematological side-eff ects of modern chemotherapeutic agents. However, study data reported so far are inconsistent, which suggests that methodological improvement is needed in clinical trials to obtain reliable results in this clinically relevant area.

IntroductionVariability of drug response and toxic eff ects are common features in oncology and several other areas of medicine, and the notion that one dose fi ts all patients is now generally accepted to be untenable, particularly with respect to highly eff ective but severely toxic drugs. Pharmacogenomics has been identifi ed as a powerful and eff ective method to obtain reliable answers about the genetic basis of interindividual diff erences in drug response, potentially leading to personalised treatment.1–3 Single nucleotide polymorphisms (SNPs) account for more than 90% of genetic variations in the human genome, and the remaining alterations are caused by insertions and deletions, tandem repeats, and microsatellites. Millions of SNPs have been reported, and availability of high-throughput technologies makes pretreatment genotyping a realistic possibility.4 One of the most obvious applications of pharmacogenomics in oncology is to assess before treatment a patient’s probability not only of seeing a benefi t but also of having adverse events from an anticancer drug. However, the gene or genes that cause a specifi c eff ect are, as yet, unidentifi ed.

In recent years, the pharmacogenomic approach has been proposed for identifi cation of people at high and low risk of development of chemotherapy-induced peripheral neurotoxicity (CIPN).5–9 The term peripheral neurotoxicity is actually more appropriate to describe the pathogenesis of nervous-system damage induced by anticancer drugs, rather than the more commonly used peripheral neuropathy, since peripheral neurotoxicity refl ects the important and sometimes overlooked fact that anticancer drugs can act on peripheral nerves and the dorsal root ganglia. CIPN is frequently recorded in patients treated with platinum drugs, antitubulins, thalidomide, and bortezomib, representing one of the most severe and potentially dose-limiting non-haematological toxic eff ects. Although clinical symptoms and signs are diff erent, all these drugs can induce neurological impairment so severe and persistent that patients’ daily activities are restricted and, in some cases, quality of life is greatly impaired, thus reducing the benefi t of an eff ective treatment for the underlying

malignant disease.10 However, CIPN induced by a given schedule is severe in only a proportion of individuals exposed to the treatment, indicating that individual characteristics might aff ect susceptibility.

Despite several attempts over the past 20 years to identify reliable risk factors for development of severe CIPN, pretreatment assessment of patients is still unable to predict neurological course. Therefore, the remarkable advances in pharmacogenomic techniques have been accepted with enthusiasm by researchers working to prevent CIPN. However, interpretation of data is diffi cult11 because they are somewhat confl icting and inconclusive overall. Here, we have undertaken an extensive review of pharmacogenomic and neurological data reported so far and have compared achievements, highlighted correlations, and discussed confl icting results. We have tried to off er possible interpretations of contradictions between diff erent pharmacogenomic studies, focusing on chronic CIPN.

Identifi cation of genes of interestIn any pharmacogenomic or toxicogenomic analysis, selection and identifi cation of the target gene or genes is the fi rst important step. Selection should be supported by a sound rationale based on what is known about the mechanism of action and the metabolic fate of the drug under investigation in relation to target cell types. However, in the case of CIPN, most studies selected by us for analysis identifi ed gene targets on the basis of mechanistic hypotheses relevant mainly to cancer cells, not to cells of the peripheral nervous system. Therefore, genes that have a role in drug disposition, metabolism, and detoxifi cation, DNA repair, and cancer-cell resistance have been studied much more extensively than genes implicated directly in the activity of neurons and glial cells. Since detailed description of all the various SNPs, deletions, and other gene variants investigated so far that have negative results would be virtually impossible (a complete list of such studies is included in the webappendix pp 1–5), we have focused our Review on variants identifi ed in specifi c genes that have been associated with CIPN course or severity (fi gure).

Lancet Oncol 2011; 12: 1151–61

Published OnlineJune 29, 2011 DOI:10.1016/S1470-2045(11)70131-0

Department of Neuroscience and Biomedical Technologies, University of Milano-Bicocca, Monza, Italy (Prof G Cavaletti MD, P Alberti MD, P Marmiroli MD)

Correspondence to:Prof Guido Cavaletti, Department of Neuroscience and Biomedical Technologies, University of Milano-Bicocca, via Cadore 48, 20900, Monza, [email protected]

See Online for webappendix

1152 www.thelancet.com/oncology Vol 12 November 2011

Review

Genes that correlate with CIPNMost relevant pharmacogenomic and toxicogenomic studies reported so far have been undertaken in patients treated with oxaliplatin and other platinum drugs. However, neurotoxic eff ects associated with specifi c gene variants have also been noted in individuals receiving taxanes, thalidomide, and bortezomib (table).12–47

GSTP1 geneGlutathione S-transferases are a family of enzymes that have an important role in detoxifi cation because they catalyse conjugation of many hydrophobic and electrophilic compounds with reduced glutathione. Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. At present, eight separate classes of soluble cytoplasmic mammalian glutathione S-transferases have been identifi ed: α (alpha), κ (kappa), μ (mu), ω (omega), π (pi), � (sigma), � (theta), and � (zeta). GSTP1 (glutathione S-transferase P1) belongs to the π class and plays a part in detoxifi cation of platinum drugs.48–50 A SNP in GSTP1 (562A→G; rs1695; NM_000852.3) causing substitution of isoleucine for valine diminishes the enzyme’s activity, whereas homozygous deletion of the entire gene abolishes its action. These eff ects might be relevant to CIPN in view of the possible importance of oxidative stress in this disorder’s onset and course.51–54 Moreover, administration of reduced glutathione partly decreased the severity of CIPN in patients treated with platinum drugs55–57 and in animal models.58,59

The GSTP1 Ile105Val SNP (rs1695; NP_000843.1) has been investigated in relation to peripheral neurotoxicity of platinum drugs in 23 studies. In ten of these, a positive association of this SNP with course or severity of CIPN was reported, but in the remaining 13 studies, no correlative evidence was recorded. In 2006, Lecomte and colleagues33 described a cohort of white European, African, and Asian patients with colorectal, pancreatic, or gastric cancer, who

were receiving treatment with oxaliplatin-based chemo-therapy. In these individuals, a signifi cant association was noted between occurrence of the A/A genotype and grade 3 CIPN, assessed with an oxaliplatin-specifi c scale.60,61 The number of patients available for comparison was very low and the result was soon challenged by fi ndings of a study undertaken in a larger cohort of patients aff ected by colorectal cancer and treated with oxaliplatin.22 The result of Lecomte’s work33 was made more unclear when, in another study, a correlation with CIPN severity was established, but with the G rather than the A allele.42 Subsequently, Oldenburg and co-workers39 used a symptom questionnaire to identify an association between more severe long-term CIPN and the A/A or A/G versus G/G genotype. In a study done in 2009 in 134 patients with gastric cancer, the A/A genotype was associated signifi cantly with grade 3 CIPN, although only 12 patients were eventually available for comparison.23 In 2010, a signifi cant association was described in three independent studies between the A/A genotype and either more severe CIPN25,35 or earlier onset of grade 1 CIPN scored with the National Cancer Institute’s common toxicity criteria (NCI-CTC) without any eff ect on development of more severe CIPN grades;26 however, as in previous work, only a few patients were available for comparison. In the largest study reported so far in individuals with colorectal cancer treated with oxaliplatin, McLeod and colleagues37 studied two GSTP1 SNPs—Ile105Val and Ala114Val (rs1138272; NP_000843.1 [590C→T, NM_000852.3]). They stated that the T/T genotype was a predictor for more frequent discontinuation of FOLFOX (leucovorin, fl uorouracil, oxaliplatin) and for more severe CIPN after treatment with irinotecan and oxaliplatin (but, rather surprisingly, not FOLFOX). The Ala114Val SNP was not associated with CIPN in a study by Khrunin and co-workers.31

In disagreement with these positive results, negative fi ndings of an investigation of the GSTP1 Ile105Val SNP in

ERCC1

ERCC2

AGXT

MPO

ABCC1

ABCG1

GSTA1

GSTP1GSTT1

OATP1ABCB1

ABCC1

ABCG1

CYP1B1

CYP3A4

CYP3A5

CYP1B1CYP3A4

CYP2C8

GSTM1/3

XRCC1XPA

Excision repair

Nucleus

Platinum drugs

Pt/DNA

Detoxification

Oxaliplatin

Pt

Docetaxel

Metabolites

Metabolites

Taxanes

Paclitaxel

Figure: Metabolism and transport of platinum drugs and taxanes, and relevant candidate genes investigatedPt=platinum.


Review

patients treated with a platinum drug22 were replicated in several subsequent studies.30,40,43 In 2010, four independent clinical trials undertaken in individuals aff ected either by colorectal cancer and treated with oxaliplatin-based chemotherapy14,29,47 or by ovarian cancer and treated with

cisplatin31 also had negative results. These prospective data accorded with those described in a previous retrospective study done in a mixed population of white European, Hispanic, Asian, and African individuals with colorectal cancer treated with oxaliplatin.46

Tumour (n) CT regimen Previous exposure to neurotoxic CT

Ethnic origin

Neurological assessment

Target studied for toxic eff ects

Association with CIPN?

Type of association with CIPN

Number of patients with CIPN used for comparison

Antonacopoulou (2010)12

Colorectal (55)

FOLFOX-4 CT naive Not stated

TNSc ITGB3 Leu59Pro Yes Association with CIPN severity for T/T genotype (p=0·044 vs C/T and C/C)

C/C=3; T/T=18; C/T=13 (any grade)

Bergmann (2011)13†

Ovarian (119) Paclitaxel (175 mg/m²); carboplatin AUC 5 or 6

Not stated Not stated

NCI-CTC (version not specifi ed)

ABCB1 Ser893Ala/ThrCYP2C8*3 (exon 3)CYP3A5*3

No

No

No

·· Sensory neuropathy: grade 1=58, grade 2=20, grade 3=3; neuropathy (ataxia): grade 1=25, grade 2=9, grade 3=1

Boige(2010)14

Colorectal (346)

FOLFOX-6 CT naive and previous CT patients (no previous neurotoxic CT)

Not stated

NCI-CTC version 2

GSTP1 Ile105ValGSTM1 deletionERCC1 Asn118Asn

NoNoNo

·· Grades 2/3/4=111 (fi rst-line treatment); grades 2/3/4=112 (second-line treatment); grades 2/3/4=31 (third-line treatment)

Booton(2006)15

NSCLC(118)

Docetaxel (75 mg/m²) with or without cisplatin (50 mg/m²) or carboplatin AUC 6, every 3 weeks, to a maximum of four cycles

CT naive Not stated

NCI-CTC version 2

GSTP1 Ile105Val No ·· Not reported

Broyl(2010)16

Multiple myeloma (329 for gene expression, 369 for SNP analysis)

Bortezomib (1·3 mg/m²) on days 1, 4, 8, 11; vincristine (0·4 mg) on days 1–4

CT naive Not stated

NCI-CTC version 3

See reference 16 for complete list of genes and SNPs

40 genes diff erentially expressed in early vs late onset CIPN in bortezomib-treated or vincristine-treated patients;† 59 SNPs associated with bortezomib or vincristine CIPN†

·· Bortezomib: CIPN after one cycle grade 2–4=20, CIPN after 2–3 cycles=63; vincristine: CIPN after one cycle grade 2–4=11, CIPN after 2–3 cycles=17

Caponigro (2009)17

Colorectal (12)

FOLFOX-4 plus bortezomib in escalating dose (1·0, 1·3, 1·6 mg/m²)

CT naive and previous CT patients (no oxaliplatin-based CT)

Not stated

NCI-CTC version 3

ERCC1 (SNPs not stated)

No ·· Total=12

Chang(2009)18

Breast(121)

Paclitaxel (175 mg/m²) every 3 weeks

CT naive and previous CT patients (no previous neurotoxic CT)

Not stated

NCI-CTC version 3

ABCB1 Ser893Ala/Thr

No ·· Grade 3=12

Chen(2010)19

Colorectal (166)

FOLFOX-4 CT naive Asian NCI-CTC (version not specifi ed)

GSTP1 Ile105ValERCC1 Asn118Asn

YesNo

Signifi cant association with higher incidence of grade 3–4 CIPN for GSTP1 Ile105Val G/G+A/G vs A/A (p=0·02 after eight cycles and p<0·01 after 12 cycles)

GSTP1 Ile105Val: A/A=116, A/G and G/G=33 (grade 0–2 after eight cycles); A/A=9, A/G and G/G=8 (grade 3–4 after eight cycles); A/A=107, A/G and G/G=26 (grade 0–2 after 12 cycles); A/A=18, A/G and G/G=15 (grade 3–4 after 12 cycles)

Cho(2010)20

B-cell lymphoma (94)

R-CHOP CT naive Asian NCI-CTC version 3

GSTP1 Ile105ValGSTM1 deletion

NoNo

·· Grade 3/4=2

(Continues on next page)


Review


Ethnic origin






(Continued from previous page)

Favis(2011)21

Multiple myeloma (351)

Bortezomib (1·3 mg/m² on days 1, 4, 8, 11)

CT naive Not stated



Five genes diff erentially expressed in patients with earlier onset of CIPN‡

·· Total number with peripheral sensory neuropathy=227

Gamelin(2007)22

Colorectal (135)

FOLFOX-4 CT naive or previous CT patients (no oxaliplatin-based CT)

White European

NCI-CTC version 1 and oxaliplatin-specifi c scale

AGXT Pro11LeuAGXT Ile340MetGSTP1 Ile105Val

YesYesNo

Signifi cant association (p<0·001) with CIPN severity for AGXT Pro11Leu C/T and T/T vs C/C, and for AGXT Ile340Met A/G and G/G vs A/A

AGXT Pro11Leu: C/C=42, C/T and T/T=12 (grade 1); C/C= 4, C/T and T/T=14 (grade 2); C/C =0, C/T and T/T=6 (grade 3) AGXT Ile340Met: A/A=41, A/G and G/G=12 (grade 1); A/A=4, A/G and G/G=13 (grade 2); A/A=0, A/G and G/G=6 (grade 3)

Goekkurt (2009)23

Gastric(134)

FLO or FLP Neurotoxic CT was an exclusion criterion

Not stated

Oxaliplatin-specifi c scale

ERCC1 Asn118AsnGSTM1 deletionGSTP1 Ile105Val

No

NoYes

Signifi cant association with higher incidence of grade 3–4 CIPN for GSTP1 Ile105Val A/A vs A/G or G/G (p=0·028)

GSTP1 Ile105Val: A/A=54, A/G=46, G/G=20 (grade 0–2); A/A=10, A/G=0, G/G=2 (grade 3–4)

Green(2009)24

Ovarian (30), peritoneal (5), uterus (1), cervix (1), uncertain (1)

Paclitaxel (175 mg/m²), carboplatin AUC 5 or 6

Not declared White European

NCI-CTC version 2, N score, and self-created questionnaire

ABCB1 Ser893Ala/ThrCYP2C8*3 (exon 3)

No

Yes

Patient heterozygous for CYP2C8*3 had higher risk of motor neuropathy (p=0·034)

Not reported

Hong(2010)25

Colorectal (52)

Oxaliplatin 85 mg/m²every 2 weeks

CT naive and previous CT patients

Asian NCI-CTC version 3

ERCC1 Asn118AsnGSTP1 Ile105ValAGXT Ile340Met

No

YesNo

Signifi cant association (p=0·03) with higher incidence of grades 2–3 CIPN for GSTP1 Ile105Val A/G or G/G vs A/A

GSTP1 Ile105Val: A/G and G/G=5, A/A=3 (grades 2–4)

Inada(2010)26

Colorectal (51)

FOLFOX-6 CT naive Asian NCI-CTC version 3

ERCC1 Asn118Asn; GSTP1 Ile105Val

Yes

Yes

Grade 1 CIPN developed earlier in patients with ERCC1 Asn118Asn C/T and T/T vs C/C (p=0·016) and in those with GSTP1 Ile105Val A/A than in those with A/G and G/G (p=0·032), but no increased risk of grade 2 or higher CIPN was reported

ERCC1 Asn118Asn: C/C=20, C/T and T/T=16 (grade 1); C/C=7, C/T and T/T=8 (grade 2–3) GSTP1 Ile105Val: A/A=27, A/G and G/G=9 (grade 1); A/A=11, A/G and G/G =4 (grade 2–3)

Isla(2004)27

NSCLC(62)

75 mg/m² of both docetaxel and cisplatin every 3 weeks


WHO ERCC1 Asn118Asn

No ·· 36 patients developed grade 2–4 neurological toxic eff ect

Johnson(2011)28

Multiple myeloma (1495)

Vincristine (0·4 mg) on days 1–4; thalidomide (100, 200, or 400 mg)


NCI-CTC version 2 (assessed only in induction phase)


Five SNPs were cross-validated in two diff erent series of thalidomide-treated patients and nine SNPs were cross-validated in two diff erent series vincristine-treated patients†

·· Signifi cant association with grade ≥2 CIPN (number of patients not reported but overall patients with CIPN=446)

Kanai(2010)29§

Colorectal (82)

Modifi ed FOLFOX-6

CT naive and previous CT patients (no oxaliplatin-based CT)

Asian Oxaliplatin-specifi c scale

GSTP1 Ile105ValAGXT Pro11LeuAGXT Ile340Met

NoNoNo

·· Grade 1=38, grade 2=43, grade 3=1



Review


Ethnic origin







Keam(2008)30

Gastric(73)

Modifi ed FOLFOX-6


Not stated

NCI-CTC version 3

GSTP1 Ile105ValERCC1 Asn118Asn

NoNo

·· Grade 1/2=12, grade 3/4=1

Khrunin(2010)31

Ovarian (104) Cisplatin (100 mg/m²) every 3 weeks for maximum of six cycles

CT naive White European


GSTM1 deletionGSTM3 (intron 6) 3-bp deletionGSTP1 Ile105ValERCC1 Asn118Asn

YesYes

NoNo

Patients with GSTM1 null or GSTM3 AGG/AGG genotypes had decreased risk of CIPN (p=0·031 and p=0·055, respectively)

Grade 0–1=64, grade 2–3=31 (no data available about distribution)

Kim(2009)32†

Ovarian (118) Paclitaxel (175 mg/m²), carboplatin AUC 5, docetaxel (75 mg/m²), cisplatin (75 mg/m²)

CT naive Asian NCI-CTC version 2

GSTP1 Ile105ValERCC1 8092C→AGSTM1 deletion

NoYes

No

Higher rate of grade 3/4 sensory or motor CIPN for ERCC1 8092C→A C/C genotype vs C/A or A/A (p=0·019)

Grade 3/4=18

Lecomte (2006)33

Colorectal (59), pancreas (4), stomach (2)

FOLFOX-4, FOLFOX-6, FOLFOX-7, GEMOX, TOMOX

CT naive and pretreated patients (no previous neurotoxic CT)

White European (59), African (4), Asian (1)


GSTP1 Ile105Val; GSTM1 deletion

YesNo

Signifi cant association with CIPN grade 3 severity for GSTP1 Ile105Val A/A vs A/G and G/G (p=0·02)

GSTP1 Ile105Val: A/A=13 (grade 3), A/G and G/G=2 (grade 3)

Leskela(2011)34

Lung (39), breast (38), ovarian (24), uterus (6), head and neck (4), other (7)

Several paclitaxel schemes (80 or 90 mg/m² every week, 150 or 175 mg/m² every 21 days)


White European

NCI-CTC version 2

CYP2C8*3CYP2C8 haplotype CCYP3A5*3ABCB1 Ser893Ala/Thr

YesYes

YesNo

Signifi cant association for increased risk of CIPN with polymorphisms CYP2C8*3 (p=0·049) and reduced risk for CYP2C8 haplotype C (p=0·049) and CYP3A5*3 (p=0·010)

Sensory neuropathy: grade 1=17, grade 2=44, grade 3=14; motor neuropathy: grade 1=7, grade 2=5, grade 3=2

Li(2010)35

Gastric(85)


NCI-CTC version 2

GSTP1 Ile105Val Yes More severe CIPN severity for GSTP1 Ile105Val A/A vs A/G and G/G (p=0·005)

Grade 1=29, grade 2=14, grade 3=12

Marsh(2007)36

Ovarian (914) Carboplatin AUC 5, paclitaxel (175 mg/m²), docetaxel (75 mg/m²)


Not stated

NCI-CTC version 2

CYP2C8*3CYP3A5*5ABCB1 Ser893Ala/ThrGSTP1 Ile105ValERCC1 Asn118Asn

NoNoNo

NoNo

·· Grade 0–1=710, grade 2–4=204

McLeod(2010)37

Colorectal (520)

FOLFOX-4, IROX CT naive and previous CT patients

White European (450), black (36), Asian (9), Hispanic (16), other (9)

NCI-CTC version 2 (adapted for paresthesias)

GSTP1 Ile105ValABCB1 Ser893Ala/ThrERCC1 Asn118AsnCYP3A5*3

YesNo

No

No

T/T genotype¶ was more likely to discontinue FOLFOX treatment (p=0·01); IROX (but not FOLFOX) patients with T/T genotype had more grade 3–4 CIPN (p=0·003)

FOLFOX discontinuation rate 24% vs 10%; 8/43 vs 0/54 IROX patients (grade 3–4)

Mir(2009)38

Breast (16), non-small cell cancer (14), prostate (16), other (12)

Docetaxel (75 or 100 mg/m²)


NCI-CTC version 2

GSTM1 deletionGSTP1 Ile105Val

NoYes

Signifi cant association (p=0·03 with univariate, p=0·01 with multivariate analysis) with increased incidence of grade 2 or higher CIPN for GSTP1 Ile105Val A/A or A/G vs G/G

GSTP1 Ile105Val: A/A=17, A/G and G/G=29 (grade 0–1), A/A=8, A/G and G/G=2 (grade 2 or higher)



Review

Rates of the GSTP1 Ile105Val polymorphism were also investigated in patients treated with docetaxel,38 taxane and platinum regimens,15,32,36 and vincristine.20 In these studies, the A/A genotype was associated positively with a higher incidence of NCI-CTC grade 2 CIPN only in docetaxel-treated patients, whereas no association was reported in those treated with taxane and carboplatin regimens or with vincristine.

GSTM1 and GSTM3 genesThe μ class of glutathione S-transferases is crucial for detoxifi cation through glutathione conjugation of electro philic compounds, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress. Genes encoding the μ class of enzymes are organised in a cluster on chromosome 1p13.3 and are highly polymorphic. These genetic variations


Ethnic origin







Oldenburg (2007)39

Testicular (238)

Cisplatin combined with bleomycin, etoposide, or vinblastine (median cumulative dose 397 mg/m²)

Diff erent lines of treatment (up to four), neurotoxic eff ects undetermined

Not stated

SCIN GSTM1 deletionGSTP1 Ile105Val

NoYes

More severe long-term CIPN for GSTP1 Ile105Val A/A (p=0·012) or A/G (p=0·003) vs G/G

GSTP1 Ile105Val: A/A=23 moderate and 16 severe CIPN, A/G=29 moderate and 20 severe CIPN, A/A=10 moderate without severe CIPN

Parè(2008)40

Colorectal (126)



GSTP1 Ile105Val No ·· Grade 1=42, grade 2=66, grade 3=5

Rizzo(2010)41

Breast(95)

Paclitaxel (80 mg/m²) weekly, docetaxel (75 or 100 mg/m²) every 3 weeks


White European

NCI-CTC version 3

ABCB1 Ser893Ala/ThrCYP2C8*3

No

No

·· Grade 1=1, grade 2=6

Ruzzo(2007)42

Colorectal(166)

FOLFOX-4 CT naive and previous CT patients

Not stated


ERCC1 Asn118AsnGSTP1 Ile105ValGSTM1 deletion

No

YesNo

Signifi cant association with CIPN severity GSTP1 Ile105Val G/G>A/G>A/A (p<0·001)

GSTP1 Ile105Val: A/A=49, A/G=27, G/G=2 (grade 1–2); A/A=4, A/G=5, G/G=8 (grade 3)

Seo(2009)43

Gastric(94)

Modifi ed FOLFOX CT naive and previous CT patients

Not stated



No

NoNo

.. Grade 3/4=12

Sissung(2006)44

Advanced solid (26)

Paclitaxel Not stated Not stated

Not stated ABCB1 Ser893Ala/Thr

No .. 22 patients (not reported CIPN incidence, severity, and type)

Sissung(2008)45

Prostate (73) Docetaxel (30 mg/m²), thalidomide (200 mg daily)


NCI-CTC version 2

ABCB1 Ser893Ala/Thr

Yes More rapid onset of CIPN only in patients co-treated with docetaxel and thalidomide ABCB1 Ser893Ala/Thr G/T and G/A and T/T vs G/G (p=0·007)

73 patients (not reported CIPN incidence, severity, and type)

Stoehlmacher (2002)46†

Colorectal (107)

Oxaliplatin (130 mg/m²) every 2 weeks

Previous CT patients (excluded neurotoxic CT)

White European (77), Hispanic (14), African (5), Asian (11)

Not stated GSTP1 Ile105ValGSTM1 deletionGSTT1 deletion

NoNoNo

.. 10 patients with grade 3–4 (not indicated lower grades)

Zarate(2010)47

Colorectal (60)

Oxaliplatin (85 mg/m²) every 2 weeks

CT naive Not stated



No

NoNo

Grade 1=25, grade 2=15, grade 3=1

AUC=area under the curve. CIPN=chemotherapy-induced peripheral neurotoxicity. CT=chemotherapy. FLO=fl uorouracil, leucovorin, oxaliplatin. FLP=fl uorouracil, leucovorin, cisplatin. FOLFOX=leucovorin, fl uorouracil, oxaliplatin. GEMOX=gemcitabine, oxaliplatin. IROX=irinotecan, oxaliplatin. NCI-CTC=National Cancer Institute common toxicity criteria. NSCLC=non-small-cell lung cancer. R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone. SCIN=scale for chemotherapy-induced neurotoxicity. SNPs=single nucleotide polymorphisms. TNSc=total neuropathy score, clinical version. TOMOX=raltitrexed, oxaliplatin. †Retrospective study. ‡None of the reported associations refers to other targets described in this table. §Leu11 allele was not found in this population of Japanese patients. ¶See text.

Table: Summary of studies describing gene variants associated with CIPN severity or course


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can change an individual’s susceptibility to carcinogens and toxins and aff ect toxic eff ects and eff ectiveness of specifi c drugs. Null mutations in the μ class of genes have been linked with a rise in frequency of several cancers, probably due to increased susceptibility to environ mental toxins and carcinogens.46,49

Deletion of the gene encoding glutathione S-transferase M1 (GSTM1) has been investigated in many studies of platinum-based chemotherapy. In individuals with ovarian cancer treated with cisplatin,31 GSTM1 deletion was identifi ed as a predictor of decreased risk of CIPN. However, no correlation was noted in other independent prospective studies14,23,33,38,39,42,43,47 and a retrospective series.46 Khrunin and colleagues31 also noted that the AGG/AGG genotype in glutathione S-transferase M3 (GSTM3) SNPs on intron 6 (rs1799735; NM_000849.4) was associated with less frequent occurrence of CIPN. Up to now, no other studies have investigated this specifi c GSTM3 genotype in patients treated with platinum drugs. No association between GSTM1 deletion and a more severe course of CIPN has been detected in people treated with docetaxel or a taxane and platinum regimen,32,38 nor in those treated with vincristine.20

ERCC1 geneExcision repair cross-complementing group 1 (ERCC1) is part of the nucleotide excision-repair pathway and is required for repair of DNA lesions, such as those induced by ultraviolet light or formed by electrophilic compounds including cisplatin. Polymorphisms that alter expression of ERCC1 might have a role in carcinogenesis, and this gene has been investigated extensively for its role in cancer-cell resistance to platinum drugs.62 The ERCC1 Asn118Asn SNP (rs11615; NP_973730.1) has been the target of several studies designed to disclose a possible role in development of CIPN. Inada and colleagues26 reported a small series of patients belonging to an initial cohort of 51 Asian people aff ected by colorectal cancer and treated with oxaliplatin. Those with either C/T or T/T genotypes had earlier (but not more severe) CIPN compared with those with a C/C genotype (542T→C; rs11615; NM_202001.2). However, in several prospective studies undertaken in Asian and white European populations, no association was described between any genotype and CIPN in more than 1000 patients treated with oxaliplatin14,19,23,25,30,43,47 and 104 treated with cisplatin.31 Furthermore, no association was reported between the ERCC1 Asn118Asn polymorphism and CIPN in patients treated with combined taxane and platinum regimens.27,36 Caponigro and colleagues17 noted no link between ERCC1 variants and CIPN in a population treated with oxaliplatin and escalating doses of bortezomib, but the SNPs investigated were not declared.

In a retrospective series of patients with ovarian cancer who received diff erent chemotherapy combinations (either paclitaxel and docetaxel or cisplatin and carboplatin), the ERCC1 8092C→A SNP (located in the 3 non-translated region; rs3212986; NM_012099.1) was investigated. Higher

rates of grade 3–4 sensory or motor CIPN were reported for individuals with the C/C compared with the C/A or A/A genotypes.32

AGXT geneAlanine-glyoxylate aminotransferase (AGXT) prevents accumulation of glyoxylate in the cytosol by converting it into glycolate, which is subsequently metabolised into oxalate by lactate dehydrogenase.63 Because of this role in oxalate metabolism, the AGTX Ile340Met polymorphism (rs4426527; NP_000021.1) has been investigated in two studies of patients with colorectal cancer treated with oxaliplatin. First, Gamelin and colleagues22 studied patients of white European background and recorded a signifi cant association between CIPN severity and the A/G or G/G genotype (1141A→G; rs4426527; NM_000030.2), although only 17 individuals with grade 2 and six with grade 3 CIPN (scored according to a modifi ed version of Levi’s scale plus the NCI-CTC score) were available for comparison.22,61,64 However, this result was not confi rmed in the second study by Kanai and co-workers,29 in a cohort of 82 Japanese patients. Work by Gamelin’s group22 with Pro11Leu SNPs (rs34116584; NP_000021.1) indicated a positive correlation between the C/T or T/T genotype (153C→T; NM_000030.2) and more severe CIPN. However, the Leu allele was not detected in Kanai’s Japanese cohort,29 therefore data cannot be compared between these two studies.

ABCB1 geneATP-binding cassette proteins transport various molecules across extracellular and intracellular membranes. Genes that encode these proteins are divided into seven distinct subfamilies: ABC1 (sub family A), MDR/TAP (subfamily B), MRP (subfamily C), ALD (subfamily D), OABP (subfamily E), GCN20 (sub family F), and WHITE (subfamily G).65,66 The membrane-associated protein ABCB1 (also known as P-gp or MDR1) is part of the MDR/TAP subfamily that reduces drug accumulation in multidrug-resistant cells. Paclitaxel and docetaxel are known substrates of ABCB1-mediated effl ux from cancer cells,67 and the ABCB1 Ser893Ala and Ser893Thr SNPs (rs2032582; NP_000918.2) have been investigated in patients treated with taxanes. However, most participants in such studies were co-treated with other neurotoxic drugs and, therefore, results are diffi cult to interpret. First, a study was undertaken in a few patients with advanced solid tumours treated with paclitaxel, but no correlation between SNPs and CIPN severity was recorded.44 This negative result was confi rmed subsequently in more than 1000 patients aff ected by ovarian cancer who were treated either with paclitaxel monotherapy18 or with paclitaxel or docetaxel in combination with carboplatin13,36 and in individuals with diff erent types of solid cancers treated with paclitaxel and carboplatin.24 However, in 2008, Sissung and colleagues45 reported that patients co-treated with docetaxel and thalidomide with G/T, G/A, and T/T genotypes (2677G→T; rs2032582;


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NM_000927.3) had more rapid onset of CIPN than did those with the G/G genotype. In two studies from 2010, no correlation was detected either in patients aff ected by several diff erent types of solid cancer who were treated with a regimen of a taxane and carboplatin34 or in those with breast cancer treated with paclitaxel or docetaxel.41

CYP2C8 and CYP3A5 genesThe cytochrome P450 superfamily is a large group of enzymes that play a part in oxidation of organic substances and xenobiotics such as drugs and other toxic chemicals. They are the major enzymes of drug metabolism and bioactivation, accounting for about 75% of total metabolic reactions.67,68 Although no clear data are available for their distribution and activity in the peripheral nervous system, their possible contribution to development of CIPN due to altered pharmacokinetics of taxanes has been suggested.69 The enzymes CYP2C8 and CYP3A5 help to eliminate paclitaxel through successive hydroxylation reactions and they have been investigated in several studies, with some positive results.67

In a study of white European people with diff erent solid tumours, those heterozygous for the CYP2C8*3 allele (rs11572080; NM_000770.3) were at high risk of motor CIPN after paclitaxel and carboplatin co-treatment.24 Furthermore, the CYP2C8*3 polymorphism was signifi cantly associated with CIPN in another group of patients aff ected by several diff erent types of cancer who were treated with a highly non-homogenous series of chemotherapy regimens based mainly on a combination of a taxane and carboplatin.70 However, this result was not confi rmed by fi ndings of a study of white European women with breast cancer treated with paclitaxel or docetaxel41 nor by retrospective analysis of a series of ovarian-cancer patients.13 A correlation was noted in one study between the CYP3A5*3 polymorphism (rs776746; NR_033807.1) and reduced risk of developing CIPN,24 although in the retrospective series of ovarian-cancer patients previously mentioned,13 and in the largest cohort with ovarian cancer investigated so far,36 both CYP2C8*3 and CYP3A5*3 variants were not associated with any aspect of CIPN. CYP2C8 haplotype C (rs1113129; NM_000770.3) seemed to be associated with less severe CIPN in one study.70

ITGB3 geneIntegrin B3 (ITGB3) belongs to the large family of integrins, which are integral cell-surface proteins composed of an α and β chain and known to participate in cell adhesion and cell-surface-mediated signalling. The ITGB3 Leu59Pro polymorphism (rs5918; NP_000203.2) has been associated with diff erent activation of the MAPK3 and MAPK1 subgroup of mitogen-activated protein kinases, and reduced activation of MAPK3 and MAPK1 has been seen in in-vitro models of neurotoxic eff ects of platinum drugs.71 Therefore, in a cohort of 55 colorectal-cancer patients treated with oxaliplatin, Antonacopoulou and colleagues12 investigated the diff erent genotypes of this

variant for an association with CIPN severity. After assessment for neurotoxic eff ects with the clinical version of the total neuropathy scale,61 34 people developed CIPN, and the T/T genotype (196T→C; rs5918; NM_000212.2) was associated with the most severe toxic eff ects, although the diff erence was so close to the limit of signifi cance (p=0·044) that the researchers themselves viewed their results as encouraging yet preliminary.

Other SNPsResearchers on two pharmacogenomic studies inves-tigated 3404 SNPs in large populations of patients with multiple myeloma who were treated with diff erent chemotherapy schedules, incorporating bortezomib, thalidomide, or vincristine;16,28 in a third study, 2016 SNPs were looked at in people with myeloma who received a polychemotherapy schedule that included bortezomib.21 In these cohorts, none of the previously cited SNPs and variants were associated with CIPN, but data supported many other signifi cant associations, including genes that play a part in absorption, distribution, metabolism, and excretion and those that encode proteins linked to ion-channel activity, neuronal development and function, activity of Schwann cells, infl ammation and immunity, apoptosis, and oxidative stress. Despite the large sample sizes and the scientifi c validity of the technical approach used in the analysis, we should consider that neurological assessment and identifi cation of concurrent possible risk factors for peripheral neuropathy (eg, diabetes, alcohol consumption, etc) could be limited. In one study,28 several SNPs associated with CIPN were confi rmed in two diff erent study populations (table); however, the relatively low-quality neurological data—linked to the overall high number of reported associations—aff ect the reliability of the reported associations with CIPN course and severity and the possibility of transferring this screening method to clinical practice.

Methodological considerationsPharmacogenomics has now been used in several studies to identify gene variants related to diff erent aspects of CIPN severity and course; however, the ability of this methodological approach to improve our capacity to identify patients at high versus low risk is still unclear. Currently available technical methods and the expertise of investigators are defi nitely suffi cient to achieve reliable results;72–74 therefore, the main reason for this uncertainty could reside in the methodological approach used to select, defi ne, and assess CIPN features and the populations investigated. Besides evident diff erences in ethnic factors (webappendix, pp 6–7), which can be detected by comparison of studies (although not all reports include this crucial information), several methodological features could have biased clinical trials and contributed to discrepancies in CIPN assessment.


Review

The fi rst major diff erence between studies is selected neurological endpoints: CIPN severity, time of onset, or need for treatment discontinuation have all been used, although they are clearly not equivalent. Second, in several studies, a mixed population of patients was included, in which participants were treated with diff erent chemo-therapy regimens (sometimes with a combination of two neurotoxic drugs), and baseline neurological conditions were frequently omitted, even in second-line patients previously faced with potential neurotoxic treatment schedules. Third, incidence, type, and severity of possible risk factors (eg, diabetes, age, alcohol intake, concurrent diseases aff ecting peripheral nerves) were assessed rarely. In most studies, the planned neurotoxic schedule was described clearly but not the dose actually received by patients in relation to CIPN. Therefore, establishment of a correlation between treatment intensity and CIPN severity in every patient was not possible. Fourth, in general, neurological assessment of CIPN in trials was not suffi cient to properly assess its features. The most frequently used method was the NCI-CTC scale (diff erent versions) but, in general, no formal neurological examination was undertaken and reported. Questionnaires and specifi c or self-created scales were also used,24,60,64,75 although reliability of these assessment types has been challenged repeatedly, and agreement is growing among researchers that we need a more eff ective and standardised method.76–79 Finally, although in most cases the sample size of the study seemed appropriate at baseline, the subgroup of patients with CIPN was remarkably sparse in several cohorts, thus raising the possibility that studies were statistically underpowered.

Several improvements should be considered for future studies, to achieve reliable risk stratifi cation of cancer patients who are candidates for potentially neurotoxic chemotherapy. First, since laboratory methods are already valid, careful assessment of the neurological status of patients before, during, and after chemotherapy will be most important, and to this end, we believe that a formal neurological examination (although restricted to the peripheral nervous system) should be done. This assessment should be simple and reasonably fast to undertake, yet be accurate. Preferably, it should have already been compared with the most frequently used common toxicity scale (ie, NCI-CTC) so that results can be translated easily into daily clinical practice. None of the currently available neurological methods have been formally validated for accuracy, reproducibility, and responsiveness in patients with CIPN, but the total neuropathy scale (clinical version) is currently regarded by some researchers as one of the most suitable candidates for reliable assessment of non-painful CIPN.76 Second, as a possible complementary approach, formal assessment of a patient’s perspective by means of specifi c quality-of-life scales80 or questionnaires to assess the eff ect of CIPN on activities of daily life81,82 could be considered to properly assess CIPN, once they are formally validated. Finally, particularly in the case of antineoplastic drugs associated

with painful CIPN (eg, bortezomib), pain assessment with a validated scale would be necessary.83

A further step could be not only to investigate genes proposed on the basis of either the known anticancer activity of the antineoplastic drug under investigation or the drug’s pharmacokinetic and pharmacodynamic properties but also to identify and study candidate genes most closely related to activity of the peripheral nervous system under normal and pathological conditions. As an example, according to scant scientifi c data available so far, many drug transporters seem to be expressed unequally and have discrepant activity in cancer cells and neurons and glial cells of the peripheral nervous system, and so drug transporters could be targeted in studies to better understand an important step in pathogenesis of CIPN. Moreover, the combined eff ect of diverse gene variants on CIPN features should be analysed, since several events (and, therefore, several gene products and variants) are probably implicated in the complex and incompletely elucidated process that eventually results in CIPN.

ConclusionsAnalysis of pharmacogenomic data reported so far in patients at high versus low risk of CIPN has shown not only that this approach is technically feasible on a large scale but also that substantial improvement in selection, characterisation, and clinical assessment of study populations and sample size calculation is needed to avoid chance correlations potentially leading to discrepancies in study results. Findings also indicate a need, in future clinical trials, for detailed and formal neurological assessment of cancer patients undergoing potentially neurotoxic chemotherapy, coupled with highly advanced pharmacogenomic analysis, to obtain useful and reliable data that can aff ect daily clinical practice and development of eff ective neuroprotective strategies.

ContributorsAll authors contributed to the literature search and wrote the report.

Confl icts of interestGC received research grants from Bayer Healthcare, Merck Serono, Biogen

Dompè, and Pfi zer and has acted as consultant for Bristol-Myers Squibb,

Debiopharm, Sigma-Tau, EOS, and Johnson & Johnson. PA and PM

declare that they have no confl icts of interest.

AcknowledgmentsGC received an unrestricted research grant from Fondazione Banca

del Monte di Lombardia. We thank L Dalprà and A Bentivegna for

Search strategy and selection criteria

Data for this Review were identifi ed by searching Medline, Current Contents, PubMed, and Scopus, and relevant articles were retrieved with the search terms: “genomic”, “genetic”, “neuropathy”, “cancer”, “chemotherapy”, “pharmacogenetic”, “pharmacogenomic”, “cisplatin”, “carboplatin”, “oxaliplatin”, “epothilone”, “paclitaxel”, “docetaxel”, “vincristine”, “thalidomide”, and “bortezomib”. Abstracts were not included. Only papers published in English between January, 1990, and March, 2011, were considered. 42 studies were identifi ed (webappendix pp 1–5), and 36 reports relating to any genes for which a correlation with some aspect of CIPN has been recorded are listed in the table.


Review

critical revision of genetic data, and A Canta for help with preparation

of the fi gure.

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Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics