Open Access

Systematic analysis of overall survival and interactions between tumor mutations and drug treatment

Journal of Hematology & Oncology20169:15

https://doi.org/10.1186/s13045-016-0249-2

Received: 28 January 2016

Accepted: 24 February 2016

Published: 2 March 2016

Abstract

Background

Few exceptional responses in cancer treatment were attributed to a genetic predisposition of the tumor.

Methods

We analyzed a cohort of 3105 patients from 12 different cancer types and systematically sought the existence of a correlation between overall survival and the interaction of 21 antineoplastic treatments with 6 tumor mutations.

Results

We identified a single significant correlation resulting in increased overall survival from temozolomide in lower-grade glioma with IDH1 R132H mutations. The trend could not be attributed to either the treatment or the mutation alone. Univariate and multivariate Cox regression demonstrated that this interaction stood as an independent prognostic predictor of survival.

Conclusion

Our results suggest infrequent instances of exceptional responses ascribable to tumor genomics yet corroborate the existence of an interaction of temozolomide with IDH1 mutations in lower-grade glioma.

Keywords

Cancer genomics Exceptional response Large-scale data analysis Systems biology Lower-grade glioma

Findings

The cancer genome can elicit sensitivity to certain drugs not specifically designed to target the underlying genetic aberrations. To this end, genomic markers of drug sensitivity have been systematically assessed in cancer cell lines [1, 2]. Ideally, these markers can identify patients who may better benefit from a certain antineoplastic drug [3, 4]. In contrast to the increasing availability of data about genomics of drug sensitivity in vitro [5], the association with improved patient survival is so far limited to few clinical cases, e.g., exceptional responses to everolimus in bladder cancers with TSC1 mutations [6].

Here, we sought to systematically assess if the chances of overall survival in patients with a certain cancer type and treated with a given antineoplastic drug correlate with the presence of a certain genetic mutation in the tumor. The examined cohort comprised 3105 patients, spanning 12 cancer types (with 81–731 samples for each cancer type). Collectively, 21 antineoplastic drugs were administered each in at least 20 patients (median 82; IQR 29–150). Six cancer-associated mutations were detected in at least 20 patients in this cohort: V600E in BRAF (n = 29), R132H in IDH1 (n = 108), G12V in KRAS (n = 49), H1047R in PIK3CA (n = 89), R175H in TP53 (n = 45), and V777 deletion in ZFHX3 (n = 22). After binning samples by cancer type, out of 1512 potential associations, 9 associations between overall survival, drug treatment, and tumor mutation had sufficient sample size for each covariate and were hereby tested. The hazard ratio (HR) for each interaction between drug treatment and tumor mutation in a cancer type was estimated in a multivariate analysis using a nested Cox proportional hazard regression model. We adopted a likelihood ratio test to test whether there is a significant effect of the interaction on overall survival on top of the tumor mutation and administered drug alone (Additional file 1: Table S1).

We observed a significant effect only in one scenario, the interaction between temozolomide (TMZ) and R132H mutations in IDH1 on the overall survival of lower-grade glioma (LGG) (likelihood ratio test p = 0.026). This test suggests that the correlation with survival is specific to the interaction between TMZ and R132H mutations in IDH1 and not associated with the drug treatment or the mutation per se, as demonstrated by the Kaplan-Meier curves generated for patients stratified upon these features (log-rank test p = 0.047, Fig. 1). The median overall survival for patients with the interaction was 95 months (95 % CI, 63—N.E.) and for patients without the interaction was 62 months (95 % CI, 49–87).
Fig. 1

Kaplan-Meier survival plots for patients with or without an interaction between temozolomide and R132H mutations in IDH1 in lower-grade glioma

We detected a significant prognostic value for the interaction using a univariate Cox proportional hazard regression model (p = 0.016, Table 1). However, the interaction violated the proportional hazard assumption and showed a time-dependent effect. The univariate analysis was also run on validated prognostic factors in LGG [7] and additional clinical features (Table 1). A multivariate analysis based on significant factors from the univariate analysis and including a time-dependent effect for the interaction revealed an independent positive correlation between the interaction and overall survival (HR 0.09, 95 % CI 0.01–0.58, p = 0.012), which tends to diminish over time (Additional file 1: Figure S1).
Table 1

Hazard ratio (HR) for clinical factors in the overall survival of lower-grade glioma

Factors

N [n death]

HR

Univariate

Multivariate

95 % CI

p

HR

95 % CI

p

Age

261

1.07

1.05–1.09

5e−10

1.07

1.05–1.09

6e−9

Gender

 

 Female

117 [30]

1

     

 Male

144 [33]

0.88

0.54–1.45

0.620

   

Temozolomide

 No

41 [24]

1

     

 Yes

220 [39]

0.80

0.47–1.35

0.398

   

R132H in IDH1

 Undetected

166 [45]

1

     

 Detected

95 [18]

0.74

0.43–1.29

0.292

   

Interaction drug-mutation

 Absent

181 [57]

1

  

1

  

 Present

80 [6]

0.35

0.15–0.83

0.016

0.09

0.01–0.58

0.012

Histology

 Astrocytoma

107 [27]

1

     

 Oligoastrocytoma/oligodendroglioma

154 [36]

0.67

0.40–1.10

0.112

   

Tumor grade

 Grade II

77 [18]

1

  

1

  

 Grade III

184 [45]

2.06

1.18–3.61

0.011

1.52

0.85–2.71

0.159

Laterality

 N.A.

1

      

 Left

131 [28]

1

     

 Midline

5 [1]

0.34

0.04–2.64

0.304

   

 Right

123 [33]

0.82

0.49–1.37

0.443

   

Tumor site

 N.A./other

3

   

1

  

 Supratentorial, frontal lobe

160 [36]

1

     

 Supratentorial, occipital lobe

5 [1]

0.71

0.10–5.20

0.736

   

 Supratentorial, parietal lobe

23 [4]

0.84

0.30–2.38

0.748

   

 Supratentorial, temporal lobe

70 [21]

1.86

1.08–3.22

0.026

1.22

0.70–2.11

0.481

Symptoms at diagnosis

 

 N.A./other

19

      

 Headaches

62 [18]

1

     

 Mental status changes

22 [8]

1.84

0.80–4.27

0.153

   

 Motor/movement changes

22 [6]

1.20

0.47–3.06

0.698

   

 Seizures

119 [23]

0.58

0.31–1.08

0.087

   

 Sensory changes

11 [2]

1.07

0.24–4.66

0.929

   

 Visual changes

6 [2]

0.69

0.16–2.98

0.617

   

In conclusion, we identified one genomic marker of drug sensitivity that was associated with better survival in patients, in contrast to patients treated with the same drug but with no detected mutation or vice versa. Indeed, mutations in IDH1 were previously implicated with good prognosis in brain tumors treated with TMZ [8, 9]. Our results independently validate these findings and further extend the reach of this correlation beyond some previous limitations [10]. First and foremost, the cohort size allowed discerning that an increase in patient survival was exquisitely associated with the interaction between IDH1 mutations and TMZ, suggestive of a synergy between treatment and tumor genomics. Second, it specifically correlated with R132H mutations. Finally, we recovered a negative time-dependent effect of the interaction, which is reminiscent of emergence of drug resistance and in line with the genetic evolution of lower-grade glioma attributed to TMZ treatment [11].

Declarations

Acknowledgements

The authors acknowledge Knut and Alice Wallenberg Foundation for financing this work.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Biology and Biological Engineering, Chalmers University of Technology

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Copyright

© Gatto and Nielsen. 2016

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