kras mutation in nsclc - oncologypro | educational...

KRAS mutation in NSCLC

Mir Alireza Hoda, MD

Clinical director Surgical Thoracic Oncology Program &

Translational Thoracic Oncology Laboratory Division of Thoracic Surgery

Department of Surgery Comprehensive Cancer Center

Medical University Vienna


COI

I have nothing to declare with my role in this presentation


Outline

Short overview

Biological background

Evidence so far in lung cancer

- epidemiology

- prognostic value

- predictive value for EGFR-TKI/ mAB and chemotherapy

Recently published data from our group

Future perspectives

Summary & Take home messages


Collaborative effort

Translational Thoracic Oncology Program Department of Thoracic Surgery Medical University of Vienna

National Koranyi Institute of Pulmonology, Budapest

2nd Department of Pathology and Department of Thoracic Surgery, Semmelweis University, Budapest

Division of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna

Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna


Epidemiology of lung cancer

• Lung cancer is a leading cause of cancer mortality in men and women.

• The most frequent histological type is adenocarcinoma.

• Platinum-based doublet chemotherapy is the most common treatment in advanced lung adenocarcinoma.

Number of cancer deaths per 100,000 persons in the EU countries

Courtesy of G. Ostoros


Oncogenic driver mutations and „drugable targets” in lung adenocarcinoma


Biology of KRAS mutations


Kirsten ras oncogene homolog from the mammalian ras gene family (KRAS)

proto-oncogene -> central regulator of growth factor receptor tyrosine kinase signaling cascades

important downstream component of the epidermal growth factor receptor (EGFR) signaling pathway

germline KRAS mutations are associated with cardio-facio-cutaneous syndrome and Noonan syndrome

oncogenic somatic KRAS mutations are frequently identified in leukemia, colorectal and pancreatic cancers and in lung adenocarcinoma

KRAS and EGFR activating mutations have been described to be usually mutually exclusive

Courtesy of G. Ostoros


Involved signaling cascades

Suda et al. Cancer Metastasis Rev, 2010

Oncogenic KRAS mutations

• The KRAS oncogene in certain malignant

tumors is present in one third of cases

• KRAS mutations in codon 12, 13 or 61

• KRAS mutation in CRC is a negative

prognostic factor

• Prognostic and predictive role in lung

adenocarcinoma is the most intensively

studied question

Roberts, Stinchcombe JCO 2013


The most frequent oncogenic subtype mutations of KRAS in lung adenocarcinoma

Dogan S et al, Clin Cancer Res. 2012

Nukleotid

change

Amino acid change Mutation sign

GGT>TGT

Glycin Cystein G12C

GGT>GTT Glycin Valin G12V

GGT>GAT Glycin Aspartat G12D

GGT>GCT Glycin Alanin G12A

GGT>AGT Glycin Serin G12S

GGT>CGT Glycin Arginin G12R

GGC>GAC

Glycin Aspartat G13D


Effect of different KRAS oncogene substitutions on downstream signaling

Ihle N et al, J Natl Cancer Inst. 2012


Biological and pharmacologic effect of amino acid change in NSCLC cell lines

Garassino MC et al, Ann Oncol. 2011


Epidemiology of KRAS mutations


Incidence of double mutations (EGFR and KRAS)

Number of EGFR mutation test N= 2250

Number of KRAS mutation tests N=5482

Incidence of double mutations 1.15%

Kovalszky, I. SOTE I. Pathol. Inst. Méhes, G. DEOEC Pathol. Inst. Peták, I. KPS Molekular Diagn. Sükösd, F. University of Szegedi Szőke, J. National Oncol. Inst. Tímár, J. SOTE II. Pathol. Inst. Ostoros et al, unpublished data


Incidence of KRAS mutation/smoking habits

Incidence of KRAS mutation in smokers and in non-smokers

Study No. of

smokers No. of non-

smokers KRAS mutation in

smokers KRAS mutation in

non-smokers P-value

Nelson 180 16 44 (24%) 0 0,028

Marchetti 35 35 12 (34%) 0 0,00016

De Gregorio

160 23 47 (29%) 0 0,0013

Gealy 32 23 8 (25%) 2 (9%) 0,18

Westra 84 27 36 (31%) 2 (7%) 0,017

Ahrendt 92 14 40 (43%) 0 0,0014

All 583 138 177 (30%) 4 (2,9%) <0,001

Incidence of KRAS mutation in smoker adenocarcinoma patients: 24-43%

Strong correlation with number of cigarettes during lifetime and with pack-year

Ahrendt et al. Cancer 2001 Mitzudomi t al. Int J Clin Oncol 2006 Kosaka at al. Cancer Res 2004


KRAS mutation subtypes and smoking history

Dogan S et al, Clin Cancer Res. 2012


Different mutational status of distinct genes according to geographical location and smoking status in lung cancer patients

Couraud et al. Eur Journal Canc. 2012.


Incidence of KRAS c12 and c13 mutations

All patients data

KRAS Patients number

Patients % Mutations %

Total

1125

100

-

Wild type 764 67.91 -

KRAS c12 mutations

335 29.78 92.8

KRAS c13 mutations

26 2.31 7,2

Cserepes, Ostoros, Lohinai et. al. Eur. J. Cancer 2014 Stepherd et al. JCO 2013

Stepherd et al. ESMO 2014.

7 % RADIANT

8.7 % Metaanalysis

7 – 8 %


Yu et al, ASCO 2013

Prognostic significance of Codon 13 mutations


Comparison of KRAS and EGFR mutations in lung cancer

Suda et al. Cancer Metastasis Rev, 2010


Prognostic value of KRAS mutations


KRAS mutation – prognostic value in early and advanced NSCLC patients

Karachaliou N et al,Clinical Lung Cancer. 2013


Prognostic effect of KRAS mutation subtypes

G12V/G12C : longer overall survival G12D/G12S G12A/G12R: shorter overall survival

Zer A et al. ESMO 2014 Abstr. 1680

Pooled analysis of 4 trials of E-TKIs v placebo was conducted to clarify the prognostic/predictive roles of KRAS M+ and to explore the importance of M+ subtype.


Predictive effect of KRAS mutation subtypes

Zer A et al. ESMO 2014 Abstr. 1680

Pooled analysis of 4 trials of EGFR-TKIs vs placebo was conducted to clarify the prognostic/predictive roles of KRAS M+ and to explore the importance of M+ subtype.

G12V/G12C better prognosis worse predictive (EGFRTKI treatment could be harmful) G12D/G12S and G12A/G12R poor prognosis better predictive (EGFRTKI)


Predictive value of KRAS mutations


No response to EGFR-TKI treatment in KRAS mutant lung adenocarcinoma

Agent n Responses

Pao 2005 Gefitinib/Erlotinib 9 0

Tsao 2006 Erlotinib 20 1

Fujimoto 2006 Gefitinib 6 0

van Zandwijk 2006 Gefitinib 3 0

Han 2006 Gefitinib 9 0

Hirsch 2006 Gefitinib 6 0

Miller 2006 Erlotinib 19 0

Giaccone 2006 Erlotinib 10 0

Jackman 2007 Erlotinib 6 0

Douillard 2007 Gefitinib 20 0

Total 108 1 (< 1%) Courtesy of G. Ostoros


KRAS: no predictive value in EGFR monoclonal antibody treatment of NSCLC



Predictive significance of KRAS in other anti-cancer therapy



Recently published data from our group


Response to Platinum-Based Chemotherapy and Subtype-Specific KRAS Mutations in Advanced Lung

Adenocarcinoma

Cserepes, Ostoros, Lohinai et. al. Eur. J. Cancer 2014


Background & objective

- In advanced-stage lung adenocarcinoma, the clinical significance of amino acid substitution-specific KRAS mutational status in terms of tumor recurrence after chemotherapy and OS has not yet been clearly established.

- In order to better understand the influence of KRAS mutations in the this setting, we analyzed the largest cohort of patients with platinum-based chemotherapy treated KRAS mutant stage III-IV lung adenocarcinoma.


Population and enrollment criteria

1125 patient

KRAS mutation analysis

01/01/2009 - 31/12/2012

505 patients met the requirements of inclusion criteria:

III-IV stage lung adenocarcinoma

ECOG: 0-1

platinum based chemotherapy

(adjuvant chemo treatment was exclusive)

KRAS mutation analysis

• RFLP

Detection of wild-type and mutant

alleles.

• Direct sequencing

validation of the mutation and the

accurate nucleotide change

detection

wt wt mut wt wt wt mut wt


Entire patient population

KRAS status Number

of

patients

Patients

%

Mutations

%

Entire

population

1125 100 -

Wild type 764 67.91 -

KRAS12 mut 335 29.78 92.8

KRAS13 mut 26 2.31 7.2

Patients with full clinical follow-up

Number of patients 505

Wild type 338

Codon13 mutation 20

Codon12

mutation

all 147

G12C 61

G12V 29

G12D 27

G12A 8

G12S 6

G12R 3

Not identified 11

COSMIC* Current cohort

G12C 42% 38,61%

G12V 20% 18,35%

G12D 15% 17,09%

G12A 7% 5,06%

*COSMIC: Catalogue of Somatic Mutations in Cancer

Prevalence of KRAS mutations


Prognostic / predictive factors

SD+PD: stable disease + progressive disease (RECIST)

CR+MR+PR: complete+mixed+partial response (RECIST)

p= 0.002 p<0.001

p<0.001 p=0.69

p=0.54


KRAS mutation subtype and smoking history

0,00%

5,00%

10,00%

15,00%

20,00%

25,00%

30,00%

35,00%

40,00%

45,00%

50,00%

Never smoker Ex smoker Current smoker Ever smoker

Asp

Cys

Val

Other

G12V

G12V


Clinical relevance of G12V KRAS subtype mutation

RR, 66% vs 47% Median PFS, 5.8 vs 7.8 months P=0.016 P=0.077 P=0.14

G12V: KRAS subtype mutation with valin amino acid substitution

G12x: all other codon 12 KRAS mutations

SD+PD: stable and progressive disease (RECIST 1.1)

CR+PR: complete and partial response (RECIST 1.1)


Summary & Conclusion of study

Among 338 non-KRAS mutant (67%), 147 codon 12 mutant (29%) and 20 codon 13 mutant (4%) patients, there were no mutation-related significant differences in PFS or OS (P values were 0.534 and 0.917, respectively). ECOG status and clinical stage were significant independent prognostic factors. KRAS mutation showed a significant correlation with ever-smoker status (P=0.0189). Importantly, however, G12V KRAS mutant patients were significantly more frequent among never-smokers than other codon 12 KRAS mutant (G12x) subtypes (P=0.016). G12V KRAS mutant patients tended to have a higher response rate (66% versus 47%, P=0.077). A modest increase was also found in the median PFS of the G12V mutant cohort (from 175 of G12x patients to 233 days; P=0.145).

Conclusion: While KRAS mutation status per se is not a prognostic or predictive biomarker in stage III-IV lung adenocarcinoma, subtype-specific analysis may indeed identify clinically relevant subgroups of patients that ultimately may influence treatment decisions.


Future perspectives


Future perspective: pathway cross-talk



Future perspective: trials



Future Perspective: Mutant allele specific imbalance (MASI)

Combination of mutation and copy number change result in an imbalance between the wild type allele and the mutant allele

There was a marked difference in RFS based on the presence of MASI in univariate and multivariate analysis

Villaruz L et al,Cancer. 2013


Summary & Take home messages


Summary & Take home messages I

Mainly in adenocarcinoma

30% in Caucasian patients

< 10% in Asian patients

Typically related to smoking habits

Rare in never smokers

Prognostic and predictive value is debated

KRAS mutation is heterogenous

Different KRAS mutation subtypes could be prognostic


G12V and G12C with good prognostic value

G12D/G12S and G12A /G12R with poor prognostic value

KRAS mutant adenocarcinoma: no benefit from EGFR-TKI treatment in overall survival

No predictive effect of different KRAS mutations (codon12 versus codon 13) in advanced adenocarcinoma patients treated with platinum based chemotherapy

The predictive effect of KRAS mutation may differ according to codon 12 subtypes (EGFR-TKI treatment)

G12C and G12 V no survival benefit from EGFR-TKI treatment, G12D and G12S and G12A and G12R could have a benefit from EGFR-TKI treatment

Summary & Take home messages II


Acknowledgements

Translational Thoracic Oncology Program Department of Thoracic Surgery Medical University of Vienna

Gyula Ostoros, M. Cserepes, Zoltan Lohinai

Balazs Döme, Balazs Hegedüs, Viktoria Laszlo, Anita Rozsas, Thomas Klikovits, Walter Klepetko

Walter Berger, Michael Grusch

Ferenc Renyi-Vamos, Gyorgy Lang


Looking forward to see you in Vienna!

Thank you for your attention!

kras mutation in nsclc - oncologypro | educational...

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