Re-establishing Responsiveness in a Case of Refractory Metastatic Rectal Cancer with a Personalized de novo Combination Regimen Case Report

Abstract

Introduction: Encyclopedic Tumor Analysis (ETA) is multi-analyte, molecular and functional interrogation to identify latent vulnerabilities in solid tumors which can then be targeted in organ-and label-agnostic combination treatment regimens.
Case Presentation: We describe here a case of metastatic rectal cancer in a 61-year-old male who was progressed on all prior Standard of Care (SoC) treatment modalities including surgery, chemotherapy and radiotherapy. We addressed disease recurrence via personalized therapy guided by ETA which revealed characteristic molecular heterogeneity in primary and metastatic lesions in terms of single nucleotide variations (SNVs) and gene copy number variations (CNVs). Notably, a novel TBL1XR1 (Exon1) – PIK3CA (Exon 2) gene fusion was identified in the tumor along with gene copy number gains in TERT, IGF-1R, MYC, FGFR1 and EGFR genes.
Conclusion: ETA based molecular analysis with synchronous in vitro chemo-sensitivity profiling strategy helped to define de novo combinatorial therapy regimen of targeted and cytotoxic drugs which countered disease progression at each instance and led to the durable regression of primary as well as metastatic lesions.

Full text

Bose C et al. American Journal of Cancer Case Reports 2021, 9:1-8 Page 1 of 8
Ivy Union Publishing | http: //www.ivyunion.org March 10, 2021 | Volume 9, Issue 1
Re-establishing Responsiveness in a Case of Refractory Metastatic Rectal
Cancer with a Personalized de novo Combination Regimen
Chirantan Bose, Pradip Devhare, Dadasaheb Akolkar*, Darshana Patil, Vineet Datta, Ashwini Ghaisas,
Revati Patil, Sanket Patil, Sachin Apurwa, Navin Srivastava, Raja Dhasarathan, Shabista Khan,
Shankar Somashekar, Kiran Bendale, Jinumary John, Rahul Gosavi, Ajay Srinivasan, Rajan Datar.
Datar Cancer Genetics, Nasik, India.
American Journal ofCancer Case Reports
http://ivyunion.org/index.php/ajccr/
Case Report
Keywords: Colorectal Cancer; TBL1XR1-PIK3CA; Abiraterone; Cetuximab; Everolimus
Received: October 7, 2020; Accepted: November 14, 2020; Published: March 10, 2021
Competing Interests: The authors have declared that no competing interests exist.
Consent: Consent was taken from the patient’s next of kin for publication of this case report.
Copyright: 2020 Akolkar
D et al. This is an open-access article distributed under the terms of the Creative
Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,
provided the original author and source are credited.
*Correspondence to: Dadasaheb Akolkar
Email: dadasaheb.akolkar@datarpgx.com
Abstract:
Introduction
: Encyclopedic Tumor Analysis (ETA) is multi-analyte, molecular and functional interrogation to
identify latent vulnerabilities in solid tumors which can then be targeted in organ- and label-agnostic combination
treatment regimens.
Case Presentation
: We describe here a case of metastatic rectal cancer in a 61-year-old male who was progressed
on all prior Standard of Care (SoC) treatment modalities including surgery, chemotherapy and radiotherapy.
We
addressed disease recurrence via personalized therapy guided by ETA which revealed characteristic molecular
heterogeneity in primary and metastatic lesions in terms of single nucleotide variations (SNVs) and gene copy
number variations (CNVs).
Notably, a novel TBL1XR1 (Exon1) – PIK3CA (Exon 2) gene fusion was identified
in the tumor along with gene copy number gains in TERT, IGF-1R, MYC, FGFR1 and EGFR genes.
Conclusion
: ETA based molecular analysis with synchronous in vitro chemo-sensitivity profiling strategy helped
to define de novo combinatorial therapy regimen of targeted and cytotoxic drugs
which countered disease
progression at each instance and led to the durable regression of primary as well as metastatic lesions.

Bose C et al. American Journal of Cancer Case Reports 2021, 9:1-8 Page 2 of 8
Ivy Union Publishing | http: //www.ivyunion.org March 10, 2021 | Volume 9, Issue 1
Introduction
Current Standard of Care (SoC) modalities for management of colorectal cancer (CRC) are surgery,
chemotherapy, radiotherapy and targeted therapy mainly comprising anti-EGFR and anti-VEGF
agents [1]. However, the treatment of metastatic CRC remains challenging with limited options after
progression on SoC measures. Surgery is rarely feasible in metastatic disease and may be further
restricted owing to patient’s health and other co-morbidities. Chemotherapy regimens with
fluoropyrimidines (e.g., FOLFOX, FOLFIRI, FOLFIRINOX) which form the backbone of initial line
therapies have limited utility in advanced refractory cancers with onset of resistance [2]. There appears
to be limited utility of tyrosine kinase inhibitors (TKI) in CRC; Regorafenib, though indicated in SoC
has low response rates. The use of anti-EGFR monoclonal antibody (mAb) Cetuximab is restricted to
RAS wild type CRC, that too to left sided CRC where outcomes are better than right sided CRC [1].
EGFR inhibitors in combination with chemotherapy agents have shown limited efficacy in treatment
of advanced CRC and the clinical use of such combinations are not common [3]. Finally, though
Checkpoint Inhibitor Therapies (CIT) are approved for advanced CRC, these are limited to use in a
setting of deficient mismatch repair (dMMR) / high microsatellite instability (MSI-high) / high tumor
mutation burden (TMB), the prevalence rates of which have been reported to be <5% in colorectal
cancers [4].
Molecular heterogeneity accounts for the large variations in prognosis and response to
chemotherapy in (CRC) patients [5]. Presently, molecular investigations in CRC are restricted to
variations in RAS and RAF for the purposes of prognostication. A recent effort identified 4 consensus
molecular subtypes of biological relevance that were associated with different patient outcomes (CRC
ESMO guidelines) [6]. However, such investigations have limited therapeutically actionable
relevance in CRC. Multi-gene variant profiling panels for Next Generation Sequencing (NGS) have no
application in SoC, and are considered for personalized or label-agnostic therapy selection as
physician’s choice of treatment.
We have previously described the clinical benefits of a multi-analyte, molecular and
functional interrogation (ETA: Encyclopedic Tumor Analysis) to identify latent vulnerabilities in solid
tumors which can then be targeted in organ- and label-agnostic combination treatment regimens [7-8].
In the present case report, we describe the case of an advanced refractory metastatic rectal cancer
where personalized de novo combination regimen based on the findings of ETA yielded durable
response.
Case presentation
The case described in this manuscript is a retrospective observational report of a single patient who
opted to receive ETA-guided personalized treatment [7]. The patient consented for publication of
deidentified data and results.
Clinical history of this case is traceable to 2007 when the patient was diagnosed with
Adenocarcinoma of the Rectum. The patient underwent abdominoperineal resection followed by
standard dose chemotherapy with FOLFOX followed by external beam radiotherapy (EBRT) and 2
fractions of high dose-rate (HDR) brachytherapy. Limited molecular profiling indicated that the tumor
was KRAS wild-type (wt). The patient was asymptomatic for 4 years until recurrence was detected in
July 2011 as appearence of enlarged hypermatabolic periprostatic nodules on PET-CT. The patient

Bose C et al. American Journal of Cancer Case Reports 2021, 9:1-8 Page 3 of 8
Ivy Union Publishing | http: //www.ivyunion.org March 10, 2021 | Volume 9, Issue 1
underwent radiofrequency ablation (RFA) in July 2011 as well as in Dec 2011, both of which showed
complete metabolic response. Between 2012 and 2017, the patient reported recurrent urinary
symptoms associated with periprostatic nodules for which he underwent RFA and other palliative
procedures.
Between February 2016 and February 2017, follow-up PET-CT scans documented increase
in size of the persistent mass in retro-prostatic region which was infiltrating the base of urinary bladder
along with perilesional necrotic deposits. Between February and August 2017, the patient was
administered 6 cycles of FOLFIRI. A subsequent PET-CT scan in September 2017 showed increase in
size of the necrotic retro-prostatic lesion which was extending into the obturator muscles and also
infiltrating into the base of urinary bladder.
A detailed exploratory workup in December 2017 via cystoscopy revealed necrosis in the
prostatic fossa and evidence of cystitis. A whole-body PET-CT scan revealed further increase in tumor
activity in the retroprostatic area along with evidence of necrosis along with persistent pelvic and
inguinal lymphadenopathy. The patient was administered oral Tab Capecitabine (500 mg, 3 – 0 – 2
daily) until March 2018, when a follow-up PET-CT revealed further increase in the size of the tumor,
stemming from the retroprostatic site, involving the anorectal and pre-sacral regions adjacent to the
base of urinary bladder, and extension of the lesion into bilateral obturator muscles along with
metastatic iliac lymph nodes.
Encyclopedic tumor analysis and personalized regimen
In March 2018, the patient underwent a biopsy at the left inguinal node to obtain tumor tissue sample.
The freshly biopsied tissue sample along with 15 mL of peripheral blood was provided to the study
sponsor to perform ETA. Evaluation of mononucleotide repeat markers (NR-21, BAT-26, BAT-25,
NR-24, MONO-27) in tumor tissue DNA showed stable microsatellites (MS-S). There were no
detectable actionable or significant gene variations in tumor tissue by NGS; APC p.L1489fs*18
variant (MAF 3.7%) was detected in NGS profiling of mutations in cell free tumor DNA (ctDNA)
(Table 1). Differential gene expression profiling of the tumor transcriptome indicated significant
overexpression of CYP17A1 indicating potential benefit from Abiraterone. In vitro chemo-resistance /
sensitivity profiling of viable tumor cells indicated sensitivity towards several drugs including
Methotrexate and Vinorelbine. Based on these findings the patient received a combination regimen of
Methotrexate (70 mg; D1 and D8, 21-day cycle), Vinorelbine (40 mg; D1 and D8, 21-day cycle) and
Abiraterone (250 mg, 1 OD), between March and September 2018 (7 cycles). Radiological follow-up
(PET-CT) between March and September 2018 showed stable disease indicating that the treatment
regimen had effectively halted further disease progression for up to 6 months along with stable serum
CEA and CA19-9 levels. The regimen was well tolerated with minimal toxicity profile. Therapy
related Adverse Events (AEs) were moderate (Grade II), transient and included Fatigue, Anorexia and
Mucositis, all of which were clinically managed.
In September 2018, increase in serum CEA levels (278 ng/ml) was observed even though
there were no radiological or clinical indications of progression. The patient underwent a second
biopsy to obtain tumor tissue from the Pelvic mass for ETA re-evaluation of the tumor. NGS mutation
profiling of ctDNA showed persistence of the previously detected APC.pL1489fs*18 mutation (MAF
1.9%) and emergence of new mutations in TP53. NGS mutation profiling of tumor tissue DNA
revealed other single nucleotide variations (SNV) in TP53 p.T125T (MAF 66%), NOTCH3 p.R1190C
(MAF 18%) and ATR p.R177* (MAF 3.9%) as well as copy number alterations (CNA, gain) in TERT
(n = 17), IGF-1R (n = 15), MYC (n = 14), FGFR1 (n = 9) and EGFR (n = 8). Transcriptome analysis

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Ivy Union Publishing | http: //www.ivyunion.org March 10, 2021 | Volume 9, Issue 1
showed overexpression of MMP7, MMP9, VEGFA, MAPK15, PTGS2 gene transcripts. Notably, a
TBL1XR1-PIK3CA (T1:P2) gene fusion (209 transcript reads) was also detected in tumor tissue
(Table 1). In vitro chemosensitivity profiling of viable tumor cells indicated low response towards
Vinorelbine and Methotrexate, but increased response towards Pemetrexed.
Table 1 Molecular alterations identified after encyclopaedic tumor analysis (ETA) of blood and tumor
tissue samples.
ETA
(Month/Year)
Gene Name
Molecular alteration
MAF / Fold / gain
Source
Method
ETA-1
Feb 2018
APC
p.L1489fs*18
MAF 3.7%
ctDNA
NGS
CYP17A1
Overexpression
10 fold
tissue
Transcriptome
IL-6
Overexpression
5 fold
tissue
Transcriptome
MAP2K2
Overexpression
2.2 fold
tissue
Transcriptome
PTGS2
Overexpression
2.4 fold
tissue
Transcriptome
ETA-2
Sept 2018
APC
p.L1489fs*18
MAF 3.7%
ctDNA
NGS
TP53
p.C141Y
MAF 0.9%
ctDNA
NGS
TP53
p.V216M
MAF 0.2%
ctDNA
NGS
TP53
p.T125T
MAF 66%
tissue
NGS
NOTCH3
p.R1190C
MAF 18%
tissue
NGS
ATR
p.R177*
MAF 3.9%
tissue
NGS
TERT
CNV
17 gain
tissue
NGS
IGF1R
CNV
15 gain
tissue
NGS
MYC
CNV
14 gain
tissue
NGS
FGFR1
CNV
9 gain
tissue
NGS
EGFR
CNV
8 gain
tissue
NGS
TBL1XR1 –
PIK3CA
Fusion (T1:P2)
209 reads
tissue
NGS
MMP7
Overexpression
9.9 fold
tissue
Transcriptome
MMP9
Overexpression
3.7 fold
tissue
Transcriptome
MAPK15
Overexpression
4.6 fold
tissue
Transcriptome
VEGFA
Overexpression
4.2 fold
tissue
Transcriptome
IL-6
Overexpression
2.4 fold
tissue
Transcriptome
PTGS2
Overexpression
2.2 fold
tissue
Transcriptome
CHP – Cancer hotspot panel; NGS – Next Generation Sequencing; MAF – Mutant allele frequency;
ctDNA – circulating tumor DNA; Fold – Upregulation of target gene compared to expression in normal RNA
control.

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Based on these findings, the patient was advised a combination regimen of Cetuximab
(EGFR gain), Everolimus (chemo-sensitivity and TBL1XR1-PIK3CA fusion) and Pemetrexed
(chemo-sensitivity). The patient was administered weekly Cetuximab (700 mg loading dose, 450 mg
maintenance dose), Pemetrexed (500 mg, 21 day cycle) and Everolimus (5 mg, 1 OD) between
October 2018 to March 2019. Administration of this regimen led to Partial Response (PR) during the
same period (shown in Figure 1). There were no significant therapy related AEs with the exception of
transient Anemia (Grade 3) as well as transient Anorexia and Fatigue, both Grade 2.
Figure 1 Significant regression of malignant rectal mass revealed in positron emission tomography-
computed tomography (PET-CT) transverse sections. Compare follow-up scan after ETA guided therapy in right
panel (B) Vs baseline scan left panel (A).
Follow-up radiological data for the patient was available until April 2019, following which
only telephonic follow-up data was available. During a recent (May 2020) telephonic follow-up, the
patient was surviving and asymptomatic. However, therapy and disease status are presently unknown.
Discussion
The present study describes the case of an advanced refractory colorectal cancer where ETA revealed
latent molecular and functional vulnerabilities that could be targeted with personalized de novo
combination regimens. Prior lines of therapy received by this patient were based on SoC and included
locoregional (surgery, RFA, EBRT) as well as systemic (FOLFOX, FOLFIRI, Capecitabine)
treatments. The inability of prior treatments to yield objective and durable response highlights the
limitations of SoC approaches to treat cancers, especially those which are advanced and refractory.
Such futile treatment are also associated with accumulated adverse effects which thus indirectly
increase the costs of cancer care with no benefits to patient. This is a common dilemma faced by
oncologists during routine clinical practice where treatments are assigned on the basis of limited
profiling or sidedness and lead to varying outcomes.
Administration of the first iteration of ETA guided treatment regimen to the patient was
beneficial in immediately halting further progression of the tumor. The use of Abiraterone [9] in this
regimen was based on expression of CYP17A1 which is a target in prostate cancer therapy. While

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Objective Response (OR) was not achieved, this regimen yielded a PFS of 6 months. Gene copy
number gain of TERT , MYC and FGFR1 genes in subsequently biopsied tumor tissue indicates
variations associated with poor prognosis in CRC [10-12]. The gain of EGFR gene copy number
indicated potential benefit from Cetuximab, while gain of IGF-1R gene copy number indicated
potential resistance to Cetuximab [13]. The tumor was found to harbour a novel gene fusion:
TBL1XR1-PIK3CA since it has been reported to drive activation of PIK3CA [14]. Based on these
findings, combination regimen included Cetuximab and Everolimus to achieve tandem targeting of
multiple (EGFR, mTOR) pathways to improve treatment efficacy and Pemetrexed based on in vitro
functional vulnerability. This multi-targeting de novo combination regimen led to durable partial
response with significant regression in malignant rectal mass (shown in Fig. 1). The response to
combination regimen is remarkable since recent clinical trials in metastatic KRAS-wt CRC have
shown no benefit from the combination of anti-EGFR and anti-IGF1-R therapies over anti-EGFR
monotherapy [15-16].
Traditional integration of univariate molecular data of the tumor into clinical practice have
limited benefits in CRC. Similarly prior studies considering molecular indications have focussed on
use of single agents such as Cetuximab in the NCI CCTG CO 17 trial [17], anti-EGFR antibody [17-
23], or anti-VEGF Bevacizumab [20] despite possible availability of multiple indications. The utility
of patient-specific combination therapies in advanced cancers has remained largely unexplored except
the RESILIENT trial [7]. The present case study provides evidence of benefit to patients in routine
clinical practice from combination treatment strategies guided by multi-analyte tumor profiling.
Conclusion
This trajectory of response in this case of recurrent metastatic rectal cancer proves utility of ETA
guided personalized therapy and superiority of such treatments over SoC regimens. Personalized
combination regimen in this patient was based on de novo patient-derived evidence and was associated
with improved treatment efficacy, response rates and survival. It is pertinent to mention that though
Cetuximab was approved by the FDA approval for CRC in 2004, the same could not be administered
to the patient owing to non-availability in India. Though it was considered for administration at a later
date, the decision to avoid it was based on the presence of potential resistance mechanism (IGF1R
copy gain).
Acknowledgements
The Authors acknowledge the contribution of HCG-Manavata Cancer Centre, Nasik, India and their
staff and thank them for the clinical management of the patient.
Statement of ethics
Written informed consent was obtained from the patient for the publication (including images) of
deidentified data and results. A copy of the written consent is available for review by the Editor-in-
chief of this journal on request.
Sample collections and therapeutic interventions were carried out at HCG Manavata Cancer
Centre, Nasik, India. Cellular and molecular investigations on the patient’s samples were carried out at
the College of American Pathologists (CAP)-accredited and International Organization for
Standardization (ISO)-compliant facilities of Datar Cancer Genetics Limited (DCGL), Nasik, India.

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All interventional procedures including therapy administration were approved as per standard hospital
practices and in concordance with existing ethical, medical and legal requirements. In addition, the
research was conducted ethically in accordance with the World Medical Association Declaration of
Helsinki.
Conflict of interest
All enlisted authors are employees of DCGL which offers commercial services for onco-diagnosis and
therapy management. R.D. is the Founder and Chairman and Managing Director of DCGL.
Funding sources
No external funding was received for the present study.
Author contributions
C.B., P.D. and A.S.: Writing – Original Draft Preparation, Review and Editing; D.A., D.P., V.D., A.G.,
S.S., K.B.: Conceptualization, Supervision, Project administration; R.P., J.J., S.P., N.S., Raja. D., S.K.,
R.G.: Methodology, Data Curation; S.A.: Bioinformatics Analysis; R.D.: Resources, Project
Administration and Review.
References
1. Xie Y, Chen Y, Fang J. Comprehensive review of targeted therapy for colorectal cancer. Sig
Transduct Target Ther. 2020, 5:22
2. Van der Jeught K, Xu HC, Li YJ, et al. Drug resistance and new therapies in colorectal cancer.
World J Gastroenterol. 2018, 24(34):3834-3848
3. Sobani ZA, Sawant A, Jafri M, et al. Oncogenic fingerprint of epidermal growth factor receptor
pathway and emerging epidermal growth factor receptor blockade resistance in colorectal cancer.
World J Clin Oncol. 2016, 7(5):340‐351
4. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of Pembrolizumab in Patients With
Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From
the Phase II KEYNOTE-158 Study. J Clin Oncol. 2020, 38(1):1-10
5. Albanese I, Scibetta AG, Migliavacca M, et al. Heterogeneity within and between primary
colorectal carcinomas and matched metastases as revealed by analysis of Ki-ras and p53
mutations. Biochem Biophys Res Commun. 2004, 325(3):784-791
6. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of
patients with metastatic colorectal cancer. Ann Oncol. 2016, 27(8):1386-1422
7. Nagarkar R, Patil D, Crook T, et al. Encyclopedic tumor analysis for guiding treatment of
advanced, broadly refractory cancers: results from the RESILIENT trial. Oncotarget. 2019 Sep
24, 10(54):5605-5621
8. Ranade A, Patil D, Bhatt A, et al. Adaptive, Iterative, Long-Term Personalized Therapy
Management in a Case of Stage IV Refractory NSCLC. J Pers Med. 2019, 9(3):34
9. Vasaitis TS, Bruno RD, Njar VC. CYP17 inhibitors for prostate cancer therapy. J Steroid
Biochem Mol Biol. 2011, 125(1-2):23-31.
10. Bertorelle R, Rampazzo E, Pucciarelli S, et al. Telomeres, telomerase and colorectal cancer.
World J Gastroenterol. 2014, 20(8):1940-50

Bose C et al. American Journal of Cancer Case Reports 2021, 9:1-8 Page 8 of 8
Ivy Union Publishing | http: //www.ivyunion.org March 10, 2021 | Volume 9, Issue 1
11. Lee KS, Kwak Y, Nam KH, et al. c-MYC Copy-Number Gain Is an Independent Prognostic
Factor in Patients with Colorectal Cancer. PLoS ONE. 2015, 10(10): e0139727
12. Kwak Y, Nam SK, Seo AN, et al. Fibroblast Growth Factor Receptor 1 Gene Copy Number and
mRNA Expression in Primary Colorectal Cancer and Its Clinicopathologic Correlation.
Pathobiology. 2015, 82(2):76-83
13. Vigneri PG, Tirrò E, Pennisi MS, et al. The Insulin/IGF System in Colorectal Cancer
Development and Resistance to Therapy. Front Oncol. 2015, 5:230
14. Stransky N, Cerami E, Schalm S, et al. The landscape of kinase fusions in cancer. Nat Commun.
2014, 5:4846
15. Reidy DL, Vakiani E, Fakih MG, et al. Randomized, phase II study of the insulin-like growth
factor-1 receptor inhibitor IMC-A12, with or without cetuximab, in patients with cetuximab- or
panitumumab-refractory metastatic colorectal cancer. J Clin Oncol. 2010, 28(27):4240-4246
16. Van Cutsem E, Eng C, Nowara E, et al. Randomized phase Ib/II trial of rilotumumab or
ganitumab with panitumumab versus panitumumab alone in patients with wild-type KRAS
metastatic colorectal cancer. Clin Cancer Res. 2014, 20(16):4240-4250
17. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in
advanced colorectal cancer. N Engl J Med. 2008, 359(17):1757-1765
18. Modest DP, Ricard I, Heinemann V, et al. Outcome according to KRAS-, NRAS- and BRAF-
mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in
metastatic colorectal cancer by the AIO colorectal cancer study group. Ann Oncol.
2016;27(9):1746-1753
19. Arnold D, Lueza B, Douillard JY, et al. Prognostic and predictive value of primary tumour side in
patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR
directed antibodies in six randomized trials† Ann Oncol. 2017, 28(8):1713-1729
20. Sinicrope FA, Okamoto K, Kasi PM, Kawakami H. Molecular Biomarkers in the Personalized
Treatment of Colorectal Cancer. Clin Gastroenterol Hepatol. 2016, 14(5):651-658
21. Moretto R, Cremolini C, Rossini D, et al. Location of Primary Tumor and Benefit From Anti-
Epidermal Growth Factor Receptor Monoclonal Antibodies in Patients With RAS and BRAF
Wild-Type Metastatic Colorectal Cancer. Oncologist. 2016, 21(8):988-994
22. Brulé SY, Jonker DJ, Karapetis CS, et al. Location of colon cancer (right-sided versus left-sided)
as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer.
2015, 51(11):1405-1414
23. Chen KH, Shao YY, Chen HM, et al. Primary tumor site is a useful predictor of cetuximab
efficacy in the third-line or salvage treatment of KRAS wild-type (exon 2 non-mutant) metastatic
colorectal cancer: a nationwide cohort study. BMC Cancer. 2016, 16:327