Targeted pharmacotherapy after somatic cancer mutation screening

Thomas M. Polasek; Karen Ambler; Hamish S. Scott; Michael J. Sorich; Peter A. Kaub; Andrew Rowland; Michael D. Wiese; Ganessan Kichenadasse

doi:10.12688/f1000research.9040.2

Home Browse Targeted pharmacotherapy after somatic cancer mutation screening

ALL Metrics

Views

Downloads

Get PDF

Get XML

Export

▬

✚

Research Article

Revised

Targeted pharmacotherapy after somatic cancer mutation screening

[version 2; peer review: 2 approved]

Thomas M. Polasek ¹, Karen Ambler², Hamish S. Scott², [...] Michael J. Sorich¹, Peter A. Kaub², Andrew Rowland¹, Michael D. Wiese³, Ganessan Kichenadasse⁴

Thomas M. Polasek ¹, Karen Ambler², [...] Hamish S. Scott², Michael J. Sorich¹, Peter A. Kaub², Andrew Rowland¹, Michael D. Wiese³, Ganessan Kichenadasse⁴

PUBLISHED 20 Sep 2016

Author details Author details

¹ Department of Clinical Pharmacology, Flinders Medical Centre and Flinders University, Adelaide, Australia
² Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia
³ School of Pharmacy and Medical Science, University of South Australia, Adelaide, Australia
⁴ Department of Medical Oncology, Flinders Centre for Innovation in Cancer, Adelaide, Australia

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Many patients with solid tumours are treated with targeted pharmacotherapy based on the results of genetic testing (‘precision medicine’). This study investigated the use of targeted drugs after OncoFOCUS™+KIT screening in patients with malignant melanoma, non-small cell lung cancer and metastatic colorectal cancer, and then audited the results against the National Comprehensive Cancer Network (NCCN) guidelines. Patients who were not indicated for targeted pharmacotherapy did not receive such treatment (99%, 100/101). Of the patients indicated for targeted drugs, 79% (33/42) received treatment according to NCCN guidelines. In 48% (20/42) of these patients the results from OncoFOCUS™+KIT screening were required for targeted drug selection, with the remaining 52% (22/42) prescribed drugs independent of the screening results for various reasons. This study highlights the growing importance of precision medicine approaches in directing pharmacotherapy in medical oncology.

Keywords

: targeted pharmacotherapy, oncology, precision medicine, dabrafenib erlotinib,, bevacizumab, malignant melanoma, non-small cell lung cancer, metastatic colorectal cancer

Corresponding author: Thomas M. Polasek

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2016 Polasek TM 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 work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

How to cite: Polasek TM, Ambler K, Scott HS et al. Targeted pharmacotherapy after somatic cancer mutation screening [version 2; peer review: 2 approved]. F1000Research 2016, 5:1551 (https://doi.org/10.12688/f1000research.9040.2) First published: 30 Jun 2016, 5:1551 (https://doi.org/10.12688/f1000research.9040.1) Latest published: 20 Sep 2016, 5:1551 (https://doi.org/10.12688/f1000research.9040.2)

Revised Amendments from Version 1

The major change is a new Figure 2, which splits data into cohorts of patients who A) received or B) did not receive targeted pharmacotherapy according to NCCN guidelines after OncoFocus+KIT screening. The raw data are now also included in the figure.

See the authors' detailed response to the review by Andrew A. Somogyi

Introduction

Over the last 20 years the molecular profiles of many solid tumours have been characterised. The discovery of specific variants in critical proteins that influence cancer pathogenesis has seen the development of ‘targeted pharmacotherapy’ – drugs that selectively inhibit unique molecular targets in tumour cells. Compared to traditional cytotoxic agents, targeted drugs have considerable benefits in the treatment of cancer, including improved response rates and less toxicity¹.

This field of cancer therapeutics is rapidly evolving with several hundred ongoing clinical trials. However, there are no local guidelines in Australia to inform the prescribing of targeted pharmacotherapy. As a consequence, clinicians often use resources from pharmaceutical companies, conference presentations, journal publications or recommendations from other countries, such as the US National Comprehensive Cancer Network (NCCN) guidelines, for their clinical practice. Although the NCCN guidelines are not always directly applicable for practice in Australia, these are reviewed annually, are freely available (www.nccn.org), and have best practice recommendations for targeted pharmacotherapy use in selected cancers.

In addition to the well documented role of estrogen/progesterone receptor and HER-2 testing in selecting therapies for breast cancer, three other important cancers in Australia, malignant melanoma, non-small cell lung cancer (NSCLC) and metastatic colorectal cancer (mCRC), now have targeted drugs available for treatment based on genetic testing. Dabrafenib, with or without trametinib, is used for malignant melanoma with activating BRAF mutations (‘BRAF positive’)², whereas imatinib can be used for KIT-mutated melanoma. Patients with NSCLC that harbours activating EGFR mutations (‘EGFR positive’) are recommended the EGFR inhibitors erlotinib or gefitinib³. Two monoclonal antibodies that also inhibit EGFR (cetuximab and panitumumab) significantly improve survival in patients with mCRC that is RAS wild-type (WT), whereas those with mutations in RAS are essentially insensitive⁴. Bevacizumab is a selective inhibitor of VEGR that is also used in mCRC but response rates are independent of RAS status i.e., genetic testing is often not necessary for treatment decisions. Bevacizumab is frequently used first-line in combination with chemotherapy regimens such as FOLFOX, FOLFIRI and CapeOX⁵. Figure 1 shows the 2015 NCCN recommendations for targeted pharmacotherapy based on the molecular profiles of the cancers investigated in this study^6–9.

Figure 1. OncoFOCUS™+KIT results, molecular cancer classifications, and the 2015 NCCN guideline recommendations for targeted pharmacotherapy.

OncoFOCUS™+KIT is a somatic cancer mutation screen offered by SA Pathology (www.sapathology.sa.gov.au) for clinicians in South Australia. The test analyses the oncogenes KRAS, NRAS, EGFR, BRAF and KIT. Clinically significant mutations in these genes are reported as either ‘no mutation detected’ (WT) or as a specific mutation e.g., BRAF V600E. Screening with OncoFOCUS™+KIT has recently been introduced at the Flinders Centre for Innovation in Cancer (FCIC), an academic healthcare centre located in the southern suburbs of Adelaide that specialises in research and treatment of cancer. Given this introduction into clinical practice, and the lack of local prescribing guidelines, the aim of this study was to audit targeted pharmacotherapy use after screening against the latest NCCN recommendations.

Methods

A retrospective chart-based audit of OncoFOCUS™+KIT results and targeted pharmacotherapy use was conducted. Ethics approval for the study was granted by the Southern Adelaide Human Research Ethics Committee (application 137.15). Inclusion criteria were: ≥ 18 years, diagnosis of malignant melanoma, advanced NSCLC or mCRC, record of attendance at the FCIC in 2014, and OncoFOCUS™+KIT results reported in 2014. The electronic patient system OACIS was searched for genetic test results and relevant discharge summaries, multi-disciplinary team meeting summaries and electronic and/or hardcopy case notes were reviewed to determine pharmacotherapy use. In a small number of cases (21), information about medications used in private practice was confirmed with the treating oncologist. Retrieval of data was conducted over a 3 month period between June–August 2015. Results were presented as descriptive data or as a percentage.

Results

Sixty percent (90/149) of the cohort were male and 40% (59/149) were female, with a mean average age of 67.6 years (range 34 to 91 years). At the audit cut-off date, 48.3% (72) were alive, 49.7% (74) were deceased and the living status of 2.0% (3) could not be determined. There were similar numbers of patients with NSCLC (68) and mCRC (63) but a smaller number of patients with malignant melanoma (18).

OncoFOCUS™+KIT results for patients with malignant melanoma, NSCLC and mCRC are shown in Figures 1A–C, respectively. All patients were KIT WT. Importantly, the cohort had similar cancer mutation rates as previously reported. Forty four percent with malignant melanoma had an activating BRAF mutation (40–60% reported¹⁰), 17.6% had EGFR-positive NSCLC (10–20% reported¹¹), and 46% had RAS mutant mCRC (40% reported¹²). These data suggest that the FCIC cohort is representative of the wider population.

Of the 149 patients included, only 6 patients (3.8%) were excluded from the analysis of targeted pharmacotherapy use due to incomplete records. Figure 2 shows the percentage of patients who received or did not receive a targeted drug according to NCCN guidelines. Appropriately, almost all patients not indicated for targeted pharmacotherapy did not receive targeted pharmacotherapy (99%, 100/101). Of the 42 patients in the total cohort indicated for targeted therapy, 79% (33/42) received such treatment according to NCCN guidelines (Figure 2). Of the 25 patients with mCRC that was RAS WT, 36% (9/25) had targeted pharmacotherapy directed by OncoFOCUS™+KIT with an anti-EGFR drug (8 cetuximab, 1 panitumumab), 52% (13/25) received bevacizumab, and 12% (3/25) did not receive a targeted drug in contrast to NCCN guidelines. If bevacizumab in RAS WT mCRC is excluded, 48% (20/42) of the total indicated cohort received appropriate targeted drugs following OncoFOCUS™+KIT screening i.e., required genetic test results for a targeted drug to be prescribed.

Figure 2.

Percentage of patients who (A) did not receive targeted pharmacotherapy or (B) did receive targeted pharmacotherapy according to NCCN guidelines after OncoFOCUS™+KIT screening.

Number	Request comment	Tissue Type	Age	Gender	Cancer	Stage	Test Date	Tissue Source (lab)	ng/ul	KRAS	NRAS	BRAF	MSI Result	ODG Result	IDH1 result	IDH2 result	MGMT result	EGFR	MLM result	KIT	Drug	Dose (mg)	Notes	FLT3 ITD size	FLT3 allelic ratio	FLT3 D835	CEBPA	Histo Number	Block return date	Sample Status	Dose (mg)	Current Status	Notes	OncoFocus Advice
1		FFPE	72	M	Melanoma	advanced	17/09/2014	SAPath	0.5	wt	wt	wt						wt		wt	none									Validation Complete		alive	ipilimumab	Melanoma patients with BRAF wild-type tumours are UNLIKELY to benfit from BRAF kinase inhibitor therapy
2		FFPE	63	M	Melanoma	advanced	unknown	SAPath	10	wt	wt	wt						wt		wt	none									Validation Complete		alive	ipilimumab	G - BRAF WT - ipilimumab and anti-PD
3		FFPE	88	M	Melanoma	advanced	10/09/2014	SAPath	24	wt	wt	wt						wt		wt	none									Validation Complete		alive	ipilimumab
4		FFPE	72	M	Melanoma	advanced	23/09/2014	SAPath	4	wt	wt	wt						wt		wt	none									Validation Complete		deceased	previous OncoFocus result V600K positive treated with dibrafanib, after this result switched to ipilimumab
5		FFPE	74	F	Melenoma	advanced	25/03/2014	SAPath	19	wt	wt	wt						wt		wt	none									Validation Complete		alive	ipilumumab
6		FFPE	67	F	Melanoma	advanced	19/11/2014	SAPath	7.3	wt	wt	wt						wt		wt	none									Validation Complete		deceased	ipilumumab
7		FFPE	64	M	Melanoma	advanced	5/06/2014	SAPath	51	wt	Q61H	wt						wt		wt	none									Validation Complete		alive	ipilimumab	The role of NRAS mutations in selecting treatment, including targeted therapy, is uncertain at this time
8		FFPE	81	F	Melanoma	advanced	7/10/2014	SAPath	181	wt	Q61K	wt						wt		wt	none									Validation Complete		alive		G - clinical trial and c-KIT positive imatinib
9		FFPE	51	M	Melanoma	advanced	28/11/2014	SAPath	9	wt	Q61R	wt						wt		wt	none									Validation Complete		deceased 4/12/2014	deceased 10 days post OncoFocus testing.
10		FFPE	62	M	Melanoma	advanced	7/10/2015	SAPath	125	wt	Q61R	wt						wt		wt	none									Validation Complete		alive
11		FFPE	67	M	Melanoma	advanced	1/01/2014	SAPath	N/A	wt	wt	V600K						wt		wt	debrafanib									Validation Complete	150 mg bd	deceased 31/8/2014		Patients with tumours harbouring mutations in BRAF may benefit from BRAF kinase inhibitor therapy
12		FFPE	58	M	Melanoma	advanced	16/01/2014	SAPath	18	wt	wt	V600K						wt		wt	debrafanib									Validation Complete	150 mg bd	alive		G - BRAF inhibitor +/- MEK inhibitor
13		FFPE	71	M	Melanoma	advanced	18/01/2014	SAPath	51	wt	wt	V600E						wt		wt	debrafanib									Validation Complete	150 mg bd	?	NT patient
14		FFPE	69	F	Melanoma	advanced	20/01/2014	SAPath	111	wt	wt	V600E						wt		wt	debrafanib/tramatinib									Validation Complete	150 mg bd	alive
15		FFPE	72	M	Melanoma	advanced	11/02/2014	SAPath	0.2	wt	wt	V600K						wt		wt	debrafanib									Validation Complete	150 mg bd	deceased	discharged to palliative care 20/10/2014
16		FFPE	81	M	Melenoma	advanced	25/03/2014	SAPath	49	wt	wt	V600K						wt		wt	none									Validation Complete		deceased 27/3/2014	died 2 days after Oncofocus test
17		FFPE	80	F	Melanoma	advanced	23/06/2014	SAPath	63	wt	wt	V600K						wt		wt	none									Validation Complete		deceased	patient requested symptom management only
18		FFPE	84	F	Melanoma	advanced	8/09/2014	SAPath	10	wt	wt	V600E						wt		wt	?									Validation Complete		alive	alive, followed up at RAH melenoma clinics so no record at FMC


Number	Request comment	Tissue Type	Age	Gender	Cancer	Stage	Test Date	Tissue Source (lab)	ng/ul	KRAS	NRAS	BRAF	MSI Result	ODG Result	IDH1 result	IDH2 result	MGMT result	EGFR	MLM result	KIT	Drug	Dose (mg)	Notes	FLT3 ITD size	FLT3 allelic ratio	FLT3 D835	CEBPA	Histo Number	Block return date	Sample Status	Dose (mg)	Current Status	Notes	OncoFocus Advice
1		other	49	M	NSCLC	advanced	9/01/2014	SAPath	9	wt	wt	wt						wt		wt	none									Validation Complete		deceased		Patients with EGFR wild-type tumours are UNLIKELY to benefit from EGFR inhibitors
2		FFPE	65	M	NSCLC	advanced	29/01/2014	SAPath	20	wt	wt	wt						wt		wt	none									Validation Complete		deceased
3		FFPE	55	F	NSCLC	advanced	29/01/2014	SAPath	2.4	wt	wt	wt						wt		wt	none									Validation Complete		alive
4		FFPE	79	M	NSCLC	advanced	28/01/2014	SAPath	28	wt	wt	wt						wt		wt	none									Validation Complete		alive	chemotherapy	GT - if EGFR negative, then test for ALK and ROS 1 = crizotinib
5		FFPE	61	M	NSCLC	advanced	13/02/2014	SAPath	90	wt	wt	wt						wt		wt	none									Validation Complete		alive	chemotherapy
6		FFPE	80	M	NSCLC	advanced	24/03/2014	SAPath	3.5	wt	wt	wt						wt		wt	none									Validation Complete		alive	paclitaxel + carboplatin
7		FFPE	77	M	NSCLC	advanced	28/03/2014	SAPath	12	wt	wt	wt						wt		wt	none									Validation Complete		deceased 7/4/2014
8		FFPE	77	M	NSCLC	advanced	23/04/2014	SAPath	2.1	wt	wt	wt						wt		wt	none									Validation Complete		deceased
9		FFPE	73	M	NSCLC	advanced	12/05/2014	SAPath	19	wt	wt	wt						wt		wt	none									Validation Complete		deceased
10		FFPE	68	M	NSCLC	advanced	16/05/2014	SAPath	1.2	wt	wt	wt						wt		wt	none									Validation Complete		deceased	too deconditioned for chemotherapy at time of diagnosis
11		FFPE	81	M	NSCLC	advanced	6/06/2104	SAPath	8	wt	wt	wt						wt		wt	none									Validation Complete		deceased
12		FFPE	86	M	NSCLC	advanced	5/06/2014	SAPath	3	wt	wt	wt						wt		wt	none									Validation Complete		deceased
13			65	M	NSCLC	advanced	3/06/2014		6	wt	wt	wt						wt		wt	none									To extract		?
14		FFPE	90	F	NSCLC	advanced	13/06/2014	SAPath	1.9	wt	wt	wt						wt		wt	none									Validation Complete		deceased
15		FFPE	69	M	NSCLC	advanced	3/09/2014	SAPath	2.5	wt	wt	wt						wt		wt	none									Validation Complete		deceased	radiotherapy
16		FFPE	62	M	NSCLC	advanced	20/10/2014	SAPath	8	wt	wt	wt						wt		wt	none									Validation Complete		deceased
17		FFPE	68	F	NSCLC	advanced	22/10/2014	SAPath	10	wt	wt	wt						wt		wt	none									Validation Complete		deceased	gemcitabine + carboplatin
18		FFPE	66	F	NSCLC	advanced	21/10/2014		1	wt	wt	wt						wt		wt	none									Validation Complete		alive	chemotherapy
19		FFPE	69	F	NSCLC	advanced	2/04/2014	SAPath	N/A	wt	wt	wt						wt		wt	none									Validation Complete		deceased 5/2/2015
20		FFPE	70	M	NSCLC	advanced	unknown	SAPath	15	wt	wt	wt						wt		wt	none									Validation Complete		deceased
21		FFPE	72	M	NSCLC	advanced	3/06/2014	SAPath	2	wt	wt	wt						wt		wt	none									Validation Complete		deceased 3/8/2014	chemotherapy
22		FFPE	62	M	NSCLC	advanced	24/06/2014	SAPath	1.2	wt	wt	wt						wt		wt	none									Validation Complete		deceased	gemcitabine + carboplatin
23		FFPE	67	F	NSCLC	advanced	30/06/2014	SAPath	22	wt	wt	wt						wt		wt	none									Validation Complete		alive
24		FFPE	84	F	NSCLC	advanced	2/07/2014	SAPath	15	wt	wt	wt						wt		wt	none									Validation Complete		deceased
25		FFPE	66	F	NSCLC	advanced	2/07/2014	SAPath	2	wt	wt	wt						wt		wt	none									Validation Complete		deceased 14/7/2014	deceased post emergency surgery, lung cancer discovered as incidental finding
26		FFPE	80	F	NSCLC	advanced	4/08/2014	SAPath	5.3	wt	wt	wt						wt		wt	none									Validation Complete		alive	gemcitabine + carboplatin, then pemetrexed
27		FFPE	67	M	NSCLC	advanced	unknown	SAPath	21	wt	wt	wt						wt		wt	none									Validation Complete		deceased	chemotherapy, stroke then palliative care
28		FFPE	77	F	NSCLC	advanced	19/08/2014	SAPath	3.9	wt	wt	wt						wt		wt	none									Validation Complete		deceased 20/11/2014	chemotehrapy
29		FFPE	75	F	NSCLC	advanced	17/07/2014	SAPath	57	wt	wt	wt						wt		wt	none									Validation Complete		deceased
30		FFPE	58	M	NSCLC	advanced	1/09/2014		1.6	wt	wt	wt						wt		wt	none									Validation Complete		alive	chemotherapy, vinorelbine + cisplatin
31		FFPE	60	F	NSCLC	advanced	21/08/2015	SAPath	N/A	wt	wt	wt						wt		wt	none									Validation Complete		alive	chemotherapy
32		FFPE	83	F	NSCLC	advanced	5/09/2014	SAPath	1	wt	wt	wt						wt		wt	none									Validation Complete		alive
33		FFPE	81	F	NSCLC	advanced	17/09/2014	SAPath	3	wt	wt	wt						wt		wt	none									Validation Complete		alive
34		FFPE	45	M	NSCLC	advanced	5/12/2014	SAPath	23	wt	wt	wt						wt		wt	none									Validation Complete		deceased	declined chemotherapy
35		FFPE	83	M	NSCLC	advanced	30/09/2014	SAPath	1	wt	wt	wt						wt		wt	none									Validation Complete		deceased	radiotherapy
36		FFPE	82	F	NSCLC	advanced	7/10/2014	SAPath	44	wt	wt	wt						wt		wt	none									Validation Complete		alive	pemetrexed
37		FFPE	66	M	NSCLC	advanced	22/10/2014	SAPath	3	wt	wt	wt						wt		wt	none									Validation Complete		deceased
38		FFPE	85	M	NSCLC	advanced	14/11/2014	SAPath	4	wt	wt	wt						wt		wt	none									Validation Complete		deceased
39		FFPE	67	M	NSCLC	advanced	21/11/2014	SAPath	0.2	wt	wt	wt						wt		wt	none									Validation Complete		alive	chemotherapy
40		FFPE	49	F	NSCLC	advanced	28/11/2014	SAPath	1.7	wt	wt	wt						wt		wt	none									Validation Complete		alive	chemotherapy
41		FFPE	68	F	NSCLC	advanced	20/11/2014	SAPath	1.7	wt	wt	wt						wt		wt	none									Validation Complete		alive	chemotherapy
42		FFPE	85	M	NSCLC	advanced	5/12/2014	SAPath	22	wt	wt	wt						wt		wt	none									Validation Complete		deceased
43		FFPE	62	F	NSCLC	advanced	30/09/2014	SAPath	28	G12C	wt	wt						wt		wt	none									Validation Complete		alive	cisplatin + etoposide	Patients with EGFR wild-type tumours are UNLIKELY to benefit from EGFR inhibitors. KRAS mutations are usually found in tumours that are wild type for EGFR, ALK, and other driver mutations
44		FFPE	57	M	NSCLC	advanced	5/11/2014	SAPath	1.2	G12V	wt	wt						wt		wt	none									Validation Complete		deceased 12/11/2104	unfit for chemotherapy at diagnosis
45		FFPE	72	F	NSCLC	advanced	16/12/2014	SAPath	N/A	G12C	wt	wt						wt		wt	none									Validation Complete		deceased	deceased shortly after OncoFocus result
46		FFPE	83	M	NSCLC	advanced	23/102014	SAPath	6	G12R	wt	wt						wt		wt	none									Validation Complete		alive	chemotherapy
47		FFPE	67	F	NSCLC	advanced	4/12/2014	SAPath	0	G13A	wt	wt						wt		wt	none									Validation Complete		deceased
48		FFPE	72	F	NSCLC	advanced	16/01/2014	SAPath	2.2	G12C	wt	wt						wt		wt	none									Validation Complete		deceased
49		FFPE	79	M	NSCLC	advanced	29/01/2014	SAPath	24	G12V	wt	wt						wt		wt	none									Validation Complete		deceased	pemetrexed 2nd line chemo
50		FFPE	64	F	NSCLC	advanced	5/02/2014	SAPath	2	G12D	wt	wt						wt		wt	none									Validation Complete		deceased 2/5/2014
51		FFPE	62	F	NSCLC	advanced	29/05/2014	SAPath	3	Q61H	wt	wt						wt		wt	none									Validation Complete		deceased
52		FFPE	58	F	NSCLC	advanced	28/05/2014	SAPath	4	G12C	wt	wt						wt		wt	none									Validation Complete		alive
53		FFPE	68	M	NSCLC	advanced	21/10/2014	SAPath	0	G13D	wt	wt						wt		wt	none									Validation Complete		deceased	gemcitabine + carboplatin
54		FFPE	69	M	NSCLC	advanced	8/08/2014	SAPath	6	G12R	wt	wt						wt		wt	none									Validation Complete		deceased	chemostherapy
55		FFPE	85	M	NSCLC	advanced	18/09/2014	SAPath	2.5	wt	wt	V600E						wt		wt	none									Validation Complete		deceased 18/11/2014		Patients with EGFR wild-type tumours are UNLIKELY to benefit from EGFR inhibitors. The BRAF gene is mutated in < 5% of non-small cell lung cancer.
56		FFPE	75	F	NSCLC	advanced	N/A	SAPath	0	wt	wt	K601N						wt		wt	none									Validation Complete		deceased 14/10/2014
57		FFPE	79	M	NSCLC	advanced	4/02/2014	SAPath	1.5	wt	wt	wt						c.2307-2308ins9 (p.V769_D770insPAC		wt	gefitinib									Validation Complete		alive
58		FFPE	71	F	NSCLC	advanced	1/07/2014	SAPath	3.9	wt	wt	wt						2236-2249del		wt	erlotinib									Validation Complete		alive		Mutation is associated with INCREASED sensitivity to EGFR inhibitors
59		FFPE	66	F	NSCLC	advanced	21/08/2014	SAPath	0.7	wt	wt	wt						L858R		wt	none									Validation Complete		alive		G - erlotinib or gefitinib
60		FFPE	70	F	NSCLC	advanced	12/09/2014	SAPath	2	wt	wt	wt						L858R		wt	?									Validation Complete		N/A	flew back to China after diagnosis
61		FFPE	71	F	NSCLC	advanced	18/09/2014	SAPath	3	wt	wt	wt						E746_A750del		wt	none									Validation Complete		alive
62		FFPE	63	M	NSCLC	advanced	16/09/2014	SAPath	13	wt	wt	wt						L858R		wt	gefitinib									Validation Complete		alive	progressed so planned for emcitabine and carboplatin
63		FFPE	70	F	NSCLC	advanced	23/09/2014	SAPath	1.1	wt	wt	wt						L858R		wt	none									Validation Complete		alive	gemcitabine + carboplatin
64		FFPE	69	F	NSCLC	advanced	9/10/2014	SAPath	1	wt	wt	wt						E746_A750del		wt	gefitinib									Validation Complete		deceased		This mutation is associated with INCREASED sensitivity to EGFR inhibitors in patients with non small cell lung cancer
65		FFPE	33	M	NSCLC	advanced	6/11/2014	SAPath	11	wt	wt	wt						E746_A750del		wt	erlotinib									Validation Complete		alive
66		FFPE	70	M	NSCLC	advanced	24/11/2014	SAPath	21	wt	wt	wt						L858R and T790M		WT	gefitinib									Validation Complete		deceased	L858R increased sensitivity to EGFR inhibitors (from test in 2013) but T790M confers decreased sensitivity
67		FFPE	91	M	NSCLC	advanced	18/12/2014	SAPath	0	WT	WT	WT						L858R		WT	?									To extract		alive
68		FFPE	59	M	NSCLC	advanced	18/12/2014	SAPath	4	WT	WT	WT						L858R		WT	none									To extract		alive


Number	Request comment	Tissue Type	Age	Gender	Cancer	Stage	Test Date	Tissue Source (lab)	ng/ul	KRAS	NRAS	BRAF	MSI Result	ODG Result	IDH1 result	IDH2 result	MGMT result	EGFR	MLM result	KIT	Drug	Dose (mg)	Notes	FLT3 ITD size	FLT3 allelic ratio	FLT3 D835	CEBPA	Histo Number	Block return date	Sample Status	Dose (mg)	Current Status	Notes	OncoFocus Advice
1		FFPE	67	F	mCRC	advanced	9/01/2014	SAPath	82	wt	wt	wt						wt		wt	bevacizumab									Validation Complete		alive	capecitabine plus oxaliplatin, bevacizumab - showing stable disease so not started on targetted drugs yet	Patients with KRAS wild-type tumours may benefit from EGFR antagonist based therapy
2		FFPE	59	M	mCRC	advanced	16/01/2014	SAPath	28	wt	wt	wt						wt		wt	bevacizumab									Validation Complete		alive	On capecitabine
3		FFPE	62	F	mCRC	advanced	10/01/2014	SAPath	8	wt	wt	wt						wt		wt	bevacizumab									Validation Complete		deceased		G - KRAS and NRAS WT - cetuximab, pan - 2014 second line with chemo, third line as monotherapy
4		FFPE	58	M	mCRC	advanced	16/01/2014	SAPath	72	wt	wt	wt						wt		wt	?									Validation Complete		alive	seen at Modbury so can't get notes	G - audit year, the practice was to test Oncogocus when disease progress after first treatment, now more frequently testing at time of diagnosis of stage 4 disease
5		FFPE	61	F	mCRC	advanced	unknown	Southpath	7	wt	wt	wt						wt		wt	none									Validation Complete		deceased	deceased within days of test result
6		FFPE	49	F	mCRC	advanced	5/03/2014	SAPath	62	wt	wt	wt						wt		wt	cetuximab									Validation Complete		deceased
7		FFPE	52	F	mCRC	advanced	24/03/2014	SAPath	10	wt	wt	wt						wt		wt	panitmumumab									Validation Complete		deceased	capecitabine plus oxaliplatin, bevacizumab
8		FFPE	50	M	mCRC	advanced	28/03/2014	SAPath	12	wt	wt	wt						wt		wt	cetuximab									Validation Complete		alive
9		FFPE	85	M	mCRC	advanced	29/04/2014	SAPath	9.2	wt	wt	wt						wt		wt	cetuximab									Validation Complete		deceased
10		other	57	F	mCRC	advanced	8/05/2014	SAPath	4.8	wt	wt	wt						wt		wt	cetuximab									Validation Complete		deceased
11		FFPE	73	F	mCRC	advanced	16/05/2014	SAPath	4.4	wt	wt	wt						wt		wt	cetuximab									Validation Complete		alive	irenotecan
12		FFPE	42	M	mCRC	advanced	22/05/2014	SAPath	14	wt	wt	wt	neg					wt		wt	bevacizumab									Validation Complete		alive	capecitabine + oxaliplatin, bevacizumab
13		FFPE	77	M	mCRC	advanced	28/05/2014	SAPath	159	wt	wt	wt						wt		wt	bevacizumab									Validation Complete		alive
14		FFPE	68	F	mCRC	advanced	6/06/2014	SAPath	25	wt	wt	wt						wt		wt	bevacizumab									Validation Complete		alive
15		FFPE	80	M	mCRC	advanced	12/06/2014	SAPath	5	wt	wt	wt						wt		wt	none									Validation Complete		deceased	offered cetuximab but declined for best supportive care
16		FFPE	54	M	mCRC	advanced	13/06/2014	SAPath	4.4	wt	wt	wt						wt		wt	none									Validation Complete		deceased
17		FFPE	56	M	mCRC	advanced	20/06/2014	SAPath	55	wt	wt	wt						wt		wt	bevacizumab									Validation Complete		deceased
18		FFPE	79	M	mCRC	advanced	5/09/2014	SAPath	3	wt	wt	wt						wt		wt	bevacizumab									Validation Complete		deceased	after 3rd line chemotherapy palliative care
19		FFPE	66	M	mCRC	advanced	10/09/2014	SAPath	7	wt	wt	wt						wt		wt	cetuximab									Validation Complete		alive	FOLFOX + bevacizumab
20		FFPE	82	M	mCRC	advanced	16/09/2014	SAPath	23	wt	wt	wt						wt		wt	bevacizumab									Validation Complete		deceased	capecitabine + oxaliplatin, bevacizumab
21		FFPE	34	F	mCRC	advanced	15/08/2014	SAPath	8	wt	wt	wt						wt		wt	bevacizumab									Validation Complete		deceased	FOLFOX + bevacizumab, then capcitabine + bevacizumab. KRAS wild-type tumours may benefit from EGFR antagonist based therapy
22		FFPE	70	M	mCRC	advanced	13/10/2015	SAPath	N/A	wt	wt	wt						wt		wt	bevacizumab									Validation Complete		deceased	chemotherapy
23		FFPE	50	F	mCRC	advanced	31/10/2014	SAPath	1	wt	wt	wt						wt		wt	bevacizumab									Validation Complete		alive	FOLFOX + bevacizumab, then 5FU + bevacizumab
24		FFPE	40	F	mCRC	advanced	4/11/2014	SAPath	15	wt	wt	wt						wt		wt	cetuximab									Validation Complete		alive	FOLFOX + bevacizumab
25		FFPE	70	M	mCRC	advanced	5/11/2014	SAPath	1.8	wt	wt	wt						wt		wt	cetuximab									Validation Complete		alive
26		FFPE	65	M	mCRC	advanced	29/12/2014	SAPath	10	wt	wt	wt						wt		wt	bevacizumab									Validation Complete		alive	FOLFOX + bevacizumab
27		FFPE	61	M	mCRC	advanced	5/11/2014	SAPath	4	wt	wt	wt						wt		wt	?									Validation Complete		alive
28		FFPE	65	F	mCRC	advanced	16/01/2014	SAPath	25	G12V	wt	wt						wt		wt	none									Validation Complete		alive		Tumours harbouring mutations in KRAS are UNLIKELY to benefit from EGFR antagonist based therapy
29		FFPE	57	F	mCRC	advanced	20/01/2014	SAPath	62	G13D	wt	wt						wt		wt	none									Validation Complete		alive		G - chemo without EGFR targetted drug
30		FFPE	83	M	mCRC	advanced	17/01/2014	SAPath	2.3	G12V	wt	wt						wt		wt	none									Validation Complete		deceased
31		FFPE	77	M	mCRC	advanced	28/01/2014	Southpath	7	G12D	wt	wt						wt		wt	none									Validation Complete		alive	completed course of chemo July 2015
32		FFPE	44	F	mCRC	advanced	21/02/2014	SAPath	2.9	G12V	wt	wt						wt		wt	none									Validation Complete		alive	FOLFOX + bevacixumab
33		FFPE	80	M	mCRC	advanced	3/03/2014	SAPath	184	G12C	wt	wt						wt		wt	none									Validation Complete		deceased
34		FFPE	91	M	mCRC	advanced	28/04/2014	SAPath	44	G12S	wt	wt						wt		wt	none									Validation Complete		deceased
35		FFPE	70	M	mCRC	advanced	29/04/2014	SAPath	35	A146T	wt	wt						wt		wt	none									Validation Complete		deceased 14/4/2015
36		other	74	M	mCRC	advanced	7/05/2014	SAPath	13	G12C	Q61L	wt						wt		wt	none									Validation Complete		alive	mutations in KRAS are UNLIKELY to benefit from EGFR antagonist based therapy
37		FFPE	45	M	mCRC	advanced	14/05/2014	SAPath	8.4	G12D	wt	wt						wt		wt	none									Validation Complete		alive	mutations in KRAS are UNLIKELY to benefit from EGFR antagonist based therapy
38		FFPE	83	M	mCRC	advanced	8/05/2014	SAPath	26	G13D	wt	wt						wt		wt	none									Validation Complete		alive	capecitabine plus oxaliplatin, bevacizumab
39		FFPE	45	M	mCRC	advanced	18/06/2014	SAPath	122	G13D	wt	wt						wt		wt	none									Validation Complete		deceased, 24/7/2014
40		FFPE	67	M	mCRC	advanced	19/06/2014	SAPath	1.7	G12D	wt	wt						wt		wt	cetuximab then regorafenib									Validation Complete		deceased	first sample said KRAS MT, then said not enough tissue for testing. Cetuximab given inspite of KRAS MT. Regorafenib a multiple PKI
41		FFPE	62	F	mCRC	advanced	17/06/2014	SAPath	12	G12C	wt	wt						wt		wt	none									Validation Complete		deceased	FOLFOX + bevacizumab
42		FFPE	75	M	mCRC	advanced	14/07/2014	SAPath	63	G12V	wt	wt						wt		wt	none									Validation Complete		alive	chemotherapy
43		FFPE	75	M	mCRC	advanced	22/07/2014	SAPath	35	G12D	wt	wt						wt		wt	none									Validation Complete		alive	chemotherapy
44		FFPE	43	F	mCRC	advanced	29/07/2014	SAPath	13	G12D	wt	wt	neg					wt		wt	none									Validation Complete		alive
45		FFPE	54	F	mCRC	advanced	24/07/2014	SAPath	21	G13D	wt	wt						wt		wt	none									Validation Complete		alive	FOLFOX + bevacizumab
46		FFPE	60	M	mCRC	advanced	17/09/2014	SAPath	3	G12D	wt	wt						wt		wt	none									Validation Complete		deceased	chemotherapy
47		FFPE	72	M	mCRC	advanced	17/09/2014	SAPath	10	G12D	wt	wt						wt		wt	none									Validation Complete		alive
48		FFPE	61	M	mCRC	advanced	5/11/2014	SAPath	0	G13D	wt	wt						wt		wt	none									Validation Complete		deceased
49		FFPE	67	M	mCRC	advanced	unknown	SAPath	N/A	A59T	wt	wt						wt		wt	none									Validation Complete		deceased	capecitabine + oxaliplatin, bevacizumab
50		FFPE	73	M	mCRC	advanced	24/11/2014	SAPath	4	A146V	wt	wt						wt		wt	none									Validation Complete		alive
51		FFPE	58	M	mCRC	advanced	27/11/2014	SAPath	13	A146T	WT	WT						WT		WT	none									Validation Complete		alive
52		FFPE	56	M	mCRC	advanced	3/12/2014	SAPath	N/A	G12V	WT	WT						WT		WT	none									Validation Complete		alive	capecitabine + oxaliplatin
53		FFPE	83	F	mCRC	advanced	23/12/2014	SAPath	N/A	G13D	WT	WT						WT		WT	none									Validation Complete		deceased	deceased shortly after OncoFocus result
54		FFPE	42	M	mCRC	advanced	18/12/2014	SAPath	6.3	G12C	WT	WT						WT		WT	none									To extract		alive
55		FFPE	52	M	mCRC	advanced	18/02/2014	SAPath	19	wt	G12C	wt						wt		wt	none									Validation Complete		alive	capecitabine and bevacizumab on 19/4/2015, treated at Lyell McEwin. KRAS WT may benefit from EGFR Mabs	Tumours harbouring mutations in KRAS are UNLIKELY to benefit from EGFR antagonist based therapy
56		FFPE	77	F	mCRC	advanced	13/08/2014	SAPath	4	wt	G13R	wt						wt		wt	none									Validation Complete		deceased, 12/3/2015
57		FFPE	73	M	mCRC	advanced	9/02/2014	SAPath	3.5	wt	wt	V600E						wt		wt	none									Validation Complete		deceased		V600E negatively impacts treatment outcomes for anti-EGFR monoclonal antibodies in mCRC patients with KRAS wild-type tumours
58		FFPE	48	F	mCRC	advanced	2/06/2014	SAPath	8	wt	wt	V600E						wt		wt	none									Validation Complete		deceased 6/8/2014	FOLFOX + bevacizumab	G - poor prognosis, BRAF not a predictive factor for response or lack of response to EGFR drugs - treated as RAS WT
59		FFPE	71	M	mCRC	advanced	22/08/2014	SAPath	8	wt	wt	V600E						wt		wt	none									Validation Complete		alive
60		FFPE	71	M	mCRC	advanced	26/08/2014	SAPath	N/A	wt	wt	G469A						wt		wt	none									Validation Complete		alive		The sensitivity of this mutation to EGFR and BRAF inhibitors is currently unknown.
61		FFPE	74	M	mCRC	advanced	5/09/2014	SAPath	N/A	wt	wt	V600E						wt		wt	none									Validation Complete		alive
62		FFPE	62	F	mCRC	advanced	7/10/2014	SAPath	2	wt	wt	K601E						wt		wt	?									Validation Complete		alive
63		FFPE	76	F	mCRC	advanced	unknown	SAPath	8	WT	WT	V600E						WT		WT	none									Validation Complete		decreased












































This is a portion of the data; to view all the data, please download the file.

Dataset 1.OncoFOCUS screening raw data.

Frequency of oncogene mutations and targeted pharmacotherapy in malignant melanoma, advanced non-small cell lung cancer, and metastatic colorectal cancer.

Discussion

This study is the first to report utilisation rates of targeted pharmacotherapy after OncoFOCUS™+KIT screening. As expected, patients who were not indicated for targeted pharmacotherapy did not receive such treatment. In contrast, the use of targeted drugs directed by OncoFOCUS™+KIT screening was relatively low (48%).

This result may be explained by factors that are independent of OncoFOCUS™+KIT results. First, the use of bevacizumab in mCRC does not require genetic testing – it is considered equivalent to cetuximab and panitmumumab in RAS WT mCRC and was given first-line to most patients with mCRC at FCIC⁶. This is confusing because bevacizumab is a targeted drug by definition, selectively inhibiting VEGR. Second, targeted drugs for NSCLC and mCRC were subsidised by the Australian Pharmaceutical Benefits Scheme (PBS) in 2014 as second-line only. Thus, patients on first-line chemotherapy appropriately did not receive targeted drugs, despite having mutations suggesting they may benefit from such treatment. During 2014, anti-EGFR drugs became indicated for first-line treatment of EGFR-positive NSCLC and were funded by the PBS¹³. Likewise, cetuximab and panitumumab are now PBS-subsidised as first-line treatment in RAS WT mCRC¹³. Not differentiating between first- and second-line targeted pharmacotherapy is a major limitation of the study (note that half the cohort was still alive at the audit cut-off date, precluding a more complete analysis of the temporal relationships between screening and targeted pharmacotherapy use). Third, a number of patients had genetic testing close to the end of life. These patients were considered too unwell for further oncology treatment, or declined targeted drugs when offered, preferring to transfer to palliative care.

The exact role of targeted drugs for some of the cancer mutations reported by OncoFOCUS™+KIT is unclear. For example, approximately 5–9% of colorectal cancers (7.9% in this study) are characterised by a specific mutation in the BRAF gene (V600E) which causes constitutive activity, in theory bypassing inhibition by cetuximab and panitumumab and potentially making them insensitive¹⁴. In the colon cancer NCCN guidelines, BRAF mutation testing is currently optional and not part of decision making for anti-EGFR drugs⁶. A recent meta-analysis suggests that there is currently insufficient evidence to conclude that patients with mCRC harbouring BRAF mutations should be denied anti-EGFR therapy over concerns of poor efficacy¹⁵. However, there are conflicting views on whether BRAF status should influence use of anti-EGFR therapy^16,17, and hence some clinicians may potentially utilise BRAF status to make treatment decisions. This highlights the difficulty of auditing medical oncology prescribing where guidelines and the underlying evidence are rapidly evolving.

The OncoFOCUS™+KIT screening panel is currently limited to five oncogenes. The status of other oncogenes that may influence treatment decisions is determined separately. For example, patients with NSCLC are also tested for ALK rearrangements, and if positive are eligible for treatment with crizotinib (although it is not currently PBS-subsidised for this indication)⁸. Once the importance of emerging genetic alternations is established in these cancers, such as MET amplifications, ROS1 and RET rearrangements, and HER2 mutations, the OncoFOCUS™+KIT screening panel could be expanded to facilitate more complete molecular diagnosis.

In conclusion, this study showed that most patients at the FCIC receive pharmacotherapy for their cancer according to NCCN guidelines (93%), and that the results of a somatic cancer mutation screening test are applied reasonably well to drug selection. Precision medicine approaches are of increasing importance when directing pharmacotherapy in medical oncology.

Data availability

F1000Research: Dataset 1. OncoFOCUS screening raw data, 10.5256/f1000research.9040.d127508¹⁸

Author contributions

Participated in research design: Polasek and Kichenadasse

Collected data: Polasek and Ambler

Performed data analysis: Polasek

Wrote or contributed to writing of the manuscript: Polasek, Scott, Sorich, Kaub, Rowland, Wiese and Kichenadasse

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no supporting grants were involved in this work.

Acknowledgements

We thank Glenice Cheetham, Musei Ho and Madelyn Zawitkowski at SA Pathology for assay development and conducting the genetic analyses.

Faculty Opinions recommended

References

1. Simon R, Rowchowdhury S: Implementing personalized cancer genomics in clinical trials. Nat Rev Drug Discov. 2013; 12(5): 358–369. PubMed Abstract | Publisher Full Text
2. Atkinson V: Medical management of malignant melanoma. Aust Prescr. 2015; 38(3): 74–78. PubMed Abstract | Publisher Full Text | Free Full Text
3. Giaconne G: Epidermal growth factor receptor inhibitors in the treatment of non-small-cell lung cancer. J Clin Oncol. 2005; 23(14): 3235–3242. PubMed Abstract | Publisher Full Text
4. Sorich MJ, Wiese MD, Rowland A, et al.: Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. 2015; 26(1): 13–21. PubMed Abstract | Publisher Full Text
5. Lv C, Wu S, Zheng D, et al.: The efficacy of additional bevacizumab to cytotoxic chemotherapy regimens for the treatment of colorectal cancer: an updated meta-analysis for randomized trials. Cancer Biother Radiopharm. 2013; 28(7): 501–509. PubMed Abstract | Publisher Full Text | Free Full Text
6. NCCN. NCCN Clinical Practice Guidelines in Oncology. Colon Cancer Version 3. 2015. 2015.
7. NCCN. NCCN Clinical Practice Guidelines in Oncology. Melanoma Version 3. 2015. 2015.
8. NCCN. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer Version 7. 2015. 2015.
9. NCCN. NCCN Clinical Practice Guidelines in Oncology. Rectal Cancer Version 3. 2015. 2015.
10. Menzies AM, Haydu LE, Visintin L, et al.: Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res. 2012; 18(12): 3242–3249. PubMed Abstract | Publisher Full Text
11. Hirsch FR, Bunn PA Jr: EGFR testing in lung cancer is ready for prime time. Lancet Oncol. 2009; 10(5): 432–433. PubMed Abstract | Publisher Full Text
12. Roth AD, Tejpar S, Delorenzi M, et al.: Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2010; 28(3): 466–474. PubMed Abstract | Publisher Full Text
13. Health Do: Pharmaceutical Benefits Scheme. 2015. Accessed 31/7/2015. Reference Source
14. Tol J, Nagtegaal ID, Punt CJ: BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009; 361(1): 98–99. PubMed Abstract | Publisher Full Text
15. Rowland A, Dias MM, Wiese MD, et al.: Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br J Cancer. 2015; 112(12): 1888–1894. PubMed Abstract | Publisher Full Text | Free Full Text
16. Cremolini C, Di Maio M, Petrelli F, et al.: BRAF-mutated metastatic colorectal cancer between past and future. Br J Cancer. 2015; 113(11): 1634–1635. PubMed Abstract | Publisher Full Text | Free Full Text
17. Rowland A, Dias MM, Wiese MD, et al.: Reply: Comment on 'Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal-antibody therapy for RAS wild-type metastatic colorectal cancer'. Br J Cancer. 2015; 113(11): 1635. PubMed Abstract | Publisher Full Text | Free Full Text
18. Polasek T, Ambler K, Scott H, et al.: Dataset 1 in: Targeted pharmacotherapy after somatic cancer mutation screening. F1000Research. 2016. Data Source

Comments on this article Comments (0)

Version 2

VERSION 2 PUBLISHED 30 Jun 2016

Author details Author details

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

Article Versions (2)

version 2

Revised

Published: 20 Sep 2016, 5:1551

https://doi.org/10.12688/f1000research.9040.2

version 1

Published: 30 Jun 2016, 5:1551

https://doi.org/10.12688/f1000research.9040.1

© 2016 Polasek TM 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 work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

Download

Export To

metrics

	Views	Downloads
F1000Research	-	-
PubMed Central Data from PMC are received and updated monthly.	-	-

Citations

SEE MORE DETAILS

CITE

how to cite this article

Polasek TM, Ambler K, Scott HS et al. Targeted pharmacotherapy after somatic cancer mutation screening [version 2; peer review: 2 approved] F1000Research 2016, 5:1551 (https://doi.org/10.12688/f1000research.9040.2)

NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.

track

receive updates on this article

Track an article to receive email alerts on any updates to this article.

Open Peer Review

Current Reviewer Status: ?

Key to Reviewer Statuses VIEW HIDE

ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions

Version 2

VERSION 2

PUBLISHED 20 Sep 2016

Revised

Views

Reviewer Report 19 Jan 2017

Nimit Singhal, Cancer Centre, Royal Adelaide Hospital, Adelaide, SA, Australia

Approved

https://doi.org/10.5256/f1000research.10374.r19477

The article was updated and edited as per suggestions of primary reviewer. The updated article ... Continue reading

CITE

Report a concern

Respond or Comment

Views

Reviewer Report 21 Sep 2016

Andrew A. Somogyi, Discipline of Pharmacology, School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia

Approved

https://doi.org/10.5256/f1000research.10374.r16463

I confirm that I have read this submission and believe that I have an ... Continue reading

CITE

Report a concern

Respond or Comment

Version 1

VERSION 1

PUBLISHED 30 Jun 2016

Views

Reviewer Report 24 Aug 2016

Andrew A. Somogyi, Discipline of Pharmacology, School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia

Approved

https://doi.org/10.5256/f1000research.9728.r15849

The title suitably addresses the content of the article; in the Abstract, after the second last line, a comment should be made regarding the 52% who were screened by the test but did not receive the targeted drugs. The content of the article in general is of a high standard, it could be improved to the casual and inexpert reader by clarifying where KIT, KRAS and NRAS fit within the overall picture as BRAF deals with MM, EGFR with NSCLC and RAS with mCRC; and of the 6 exclusions the number in each cohort (targeted versus no targeted) could be stated. Finally, Figure 2 is unclear and a disconnect between the figure (BRAF, EGFR, RAS positive, negative) and the legend (…received or did not receive targeted pharmacotherapy), to include actual numbers and not just percentages would also make it clearer. The conclusions are most appropriate and it succinctly highlights the complex interplay between testing, prescribing, guidelines, evidence and funding all of which are rapidly changing but are not connected, all of which have universal implications.

Competing Interests: No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

CITE

Report a concern

Author Response 13 Sep 2016

Thomas Polasek, Department of Clinical Pharmacology, Flinders Medical Centre and Flinders University, Adelaide, Australia

13 Sep 2016

Author Response
We thank Prof Somogyi for these very useful comments and suggestions regarding our manuscript. We have now uploaded version 2 to incorporate changes based on the review as described below: ... Continue reading
We thank Prof Somogyi for these very useful comments and suggestions regarding our manuscript. We have now uploaded version 2 to incorporate changes based on the review as described below:

‘after the second last line, a comment should be made regarding the 52% who were screened by the test but did not receive the targeted drugs’. We have now added the following in the abstract, ‘with the remaining 52% (22/42) prescribed drugs independent of the screening results for various reasons.’

‘by clarifying where KIT, KRAS and NRAS fit within the overall picture’. In the introduction we have now added that KIT testing is used for selecting imatinib for metastatic melanoma e.g. ‘whereas imatinib can be used for KIT-mutated melanoma’. We have not added further comments about the differences between KRAS and NRAS, since they are considered together in targeted drug selection for mCRC (as already described in the manuscript by referring to RAS), and mutations in these for metastatic melanoma and NSCLC are not currently indications for targeted drug selection.

‘and of the 6 exclusions the number in each cohort (targeted versus no targeted) could be stated’. We have already stated that these 6 could not be included in the analysis due to incomplete records (Results first line paragraph 3).

‘Figure 2 is unclear and a disconnect between the figure (BRAF, EGFR, RAS positive, negative) and the legend (…received or did not receive targeted pharmacotherapy), to include actual numbers and not just percentages would also make it clearer’. We have added a new Figure 2 to make the distinction clearer, including raw data.
We thank Prof Somogyi for these very useful comments and suggestions regarding our manuscript. We have now uploaded version 2 to incorporate changes based on the review as described below:

‘after the second last line, a comment should be made regarding the 52% who were screened by the test but did not receive the targeted drugs’. We have now added the following in the abstract, ‘with the remaining 52% (22/42) prescribed drugs independent of the screening results for various reasons.’

‘by clarifying where KIT, KRAS and NRAS fit within the overall picture’. In the introduction we have now added that KIT testing is used for selecting imatinib for metastatic melanoma e.g. ‘whereas imatinib can be used for KIT-mutated melanoma’. We have not added further comments about the differences between KRAS and NRAS, since they are considered together in targeted drug selection for mCRC (as already described in the manuscript by referring to RAS), and mutations in these for metastatic melanoma and NSCLC are not currently indications for targeted drug selection.

‘and of the 6 exclusions the number in each cohort (targeted versus no targeted) could be stated’. We have already stated that these 6 could not be included in the analysis due to incomplete records (Results first line paragraph 3).

‘Figure 2 is unclear and a disconnect between the figure (BRAF, EGFR, RAS positive, negative) and the legend (…received or did not receive targeted pharmacotherapy), to include actual numbers and not just percentages would also make it clearer’. We have added a new Figure 2 to make the distinction clearer, including raw data.
Competing Interests: No competing interests to declare. Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 13 Sep 2016

Thomas Polasek, Department of Clinical Pharmacology, Flinders Medical Centre and Flinders University, Adelaide, Australia

13 Sep 2016

Author Response
We thank Prof Somogyi for these very useful comments and suggestions regarding our manuscript. We have now uploaded version 2 to incorporate changes based on the review as described below: ... Continue reading
We thank Prof Somogyi for these very useful comments and suggestions regarding our manuscript. We have now uploaded version 2 to incorporate changes based on the review as described below:

‘after the second last line, a comment should be made regarding the 52% who were screened by the test but did not receive the targeted drugs’. We have now added the following in the abstract, ‘with the remaining 52% (22/42) prescribed drugs independent of the screening results for various reasons.’

‘by clarifying where KIT, KRAS and NRAS fit within the overall picture’. In the introduction we have now added that KIT testing is used for selecting imatinib for metastatic melanoma e.g. ‘whereas imatinib can be used for KIT-mutated melanoma’. We have not added further comments about the differences between KRAS and NRAS, since they are considered together in targeted drug selection for mCRC (as already described in the manuscript by referring to RAS), and mutations in these for metastatic melanoma and NSCLC are not currently indications for targeted drug selection.

‘and of the 6 exclusions the number in each cohort (targeted versus no targeted) could be stated’. We have already stated that these 6 could not be included in the analysis due to incomplete records (Results first line paragraph 3).

‘Figure 2 is unclear and a disconnect between the figure (BRAF, EGFR, RAS positive, negative) and the legend (…received or did not receive targeted pharmacotherapy), to include actual numbers and not just percentages would also make it clearer’. We have added a new Figure 2 to make the distinction clearer, including raw data.
We thank Prof Somogyi for these very useful comments and suggestions regarding our manuscript. We have now uploaded version 2 to incorporate changes based on the review as described below:

‘after the second last line, a comment should be made regarding the 52% who were screened by the test but did not receive the targeted drugs’. We have now added the following in the abstract, ‘with the remaining 52% (22/42) prescribed drugs independent of the screening results for various reasons.’

‘by clarifying where KIT, KRAS and NRAS fit within the overall picture’. In the introduction we have now added that KIT testing is used for selecting imatinib for metastatic melanoma e.g. ‘whereas imatinib can be used for KIT-mutated melanoma’. We have not added further comments about the differences between KRAS and NRAS, since they are considered together in targeted drug selection for mCRC (as already described in the manuscript by referring to RAS), and mutations in these for metastatic melanoma and NSCLC are not currently indications for targeted drug selection.

‘and of the 6 exclusions the number in each cohort (targeted versus no targeted) could be stated’. We have already stated that these 6 could not be included in the analysis due to incomplete records (Results first line paragraph 3).

‘Figure 2 is unclear and a disconnect between the figure (BRAF, EGFR, RAS positive, negative) and the legend (…received or did not receive targeted pharmacotherapy), to include actual numbers and not just percentages would also make it clearer’. We have added a new Figure 2 to make the distinction clearer, including raw data.
Competing Interests: No competing interests to declare. Close
Report a concern

Comments on this article Comments (0)

Version 2

VERSION 2 PUBLISHED 30 Jun 2016

Open Peer Review

Reviewer Status

Reviewer Reports

	Invited Reviewers
	1	2
Version 2 (revision) 20 Sep 16	read	read
Version 1 30 Jun 16	read

Andrew A. Somogyi, University of Adelaide, Adelaide, Australia
Nimit Singhal, Royal Adelaide Hospital, Adelaide, Australia

Comments on this article

All Comments(0)

Add a comment

Browse by related subjects

Back to all reports

Reviewer Report

3 Views

19 Jan 2017 | for Version 2

Nimit Singhal, Cancer Centre, Royal Adelaide Hospital, Adelaide, SA, Australia

3 Views Cite this report Responses(0)

Approved

The article was updated and edited as per suggestions of primary reviewer. The updated article has appropriate abstract, content and conclusions. The graphs are easy to understand and clear.

Competing Interests

No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Respond to this report

Responses (0)

Back to all reports

Reviewer Report

8 Views

21 Sep 2016 | for Version 2

Andrew A. Somogyi, Discipline of Pharmacology, School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia

8 Views Cite this report Responses(0)

Approved

Competing Interests

No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Respond to this report

Responses (0)

Back to all reports

Reviewer Report

16 Views

24 Aug 2016 | for Version 1

Andrew A. Somogyi, Discipline of Pharmacology, School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia

16 Views Cite this report Responses(1)

Approved

Competing Interests

No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Respond to this report

Responses (1)

Author Response

13 Sep 2016

Thomas Polasek, Department of Clinical Pharmacology, Flinders Medical Centre and Flinders University, Adelaide, Australia

We thank Prof Somogyi for these very useful comments and suggestions regarding our manuscript. We have now uploaded version 2 to incorporate changes based on the review as described below:

‘after the second last line, a comment should be made regarding the 52% who were screened by the test but did not receive the targeted drugs’. We have now added the following in the abstract, ‘with the remaining 52% (22/42) prescribed drugs independent of the screening results for various reasons.’
‘by clarifying where KIT, KRAS and NRAS fit within the overall picture’. In the introduction we have now added that KIT testing is used for selecting imatinib for metastatic melanoma e.g. ‘whereas imatinib can be used for KIT-mutated melanoma’. We have not added further comments about the differences between KRAS and NRAS, since they are considered together in targeted drug selection for mCRC (as already described in the manuscript by referring to RAS), and mutations in these for metastatic melanoma and NSCLC are not currently indications for targeted drug selection.
‘and of the 6 exclusions the number in each cohort (targeted versus no targeted) could be stated’. We have already stated that these 6 could not be included in the analysis due to incomplete records (Results first line paragraph 3).
‘Figure 2 is unclear and a disconnect between the figure (BRAF, EGFR, RAS positive, negative) and the legend (…received or did not receive targeted pharmacotherapy), to include actual numbers and not just percentages would also make it clearer’. We have added a new Figure 2 to make the distinction clearer, including raw data.

View more View less

Competing Interests

No competing interests to declare.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

Click here to access the data.

Downloaded data do not display as expected? Download the data (83.31KB)

[1] 1. Simon R, Rowchowdhury S: Implementing personalized cancer genomics in clinical trials. Nat Rev Drug Discov. 2013; 12(5): 358–369. PubMed Abstract | Publisher Full Text

[2] 2. Atkinson V: Medical management of malignant melanoma. Aust Prescr. 2015; 38(3): 74–78. PubMed Abstract | Publisher Full Text | Free Full Text

[3] 3. Giaconne G: Epidermal growth factor receptor inhibitors in the treatment of non-small-cell lung cancer. J Clin Oncol. 2005; 23(14): 3235–3242. PubMed Abstract | Publisher Full Text

[4] 4. Sorich MJ, Wiese MD, Rowland A, et al.: Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. 2015; 26(1): 13–21. PubMed Abstract | Publisher Full Text

[5] 5. Lv C, Wu S, Zheng D, et al.: The efficacy of additional bevacizumab to cytotoxic chemotherapy regimens for the treatment of colorectal cancer: an updated meta-analysis for randomized trials. Cancer Biother Radiopharm. 2013; 28(7): 501–509. PubMed Abstract | Publisher Full Text | Free Full Text

[6] 6. NCCN. NCCN Clinical Practice Guidelines in Oncology. Colon Cancer Version 3. 2015. 2015.

[7] 7. NCCN. NCCN Clinical Practice Guidelines in Oncology. Melanoma Version 3. 2015. 2015.

[8] 8. NCCN. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer Version 7. 2015. 2015.

[9] 9. NCCN. NCCN Clinical Practice Guidelines in Oncology. Rectal Cancer Version 3. 2015. 2015.

[10] 10. Menzies AM, Haydu LE, Visintin L, et al.: Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res. 2012; 18(12): 3242–3249. PubMed Abstract | Publisher Full Text

[11] 11. Hirsch FR, Bunn PA Jr: EGFR testing in lung cancer is ready for prime time. Lancet Oncol. 2009; 10(5): 432–433. PubMed Abstract | Publisher Full Text

[12] 12. Roth AD, Tejpar S, Delorenzi M, et al.: Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2010; 28(3): 466–474. PubMed Abstract | Publisher Full Text

[13] 13. Health Do: Pharmaceutical Benefits Scheme. 2015. Accessed 31/7/2015. Reference Source

[14] 14. Tol J, Nagtegaal ID, Punt CJ: BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009; 361(1): 98–99. PubMed Abstract | Publisher Full Text

[15] 15. Rowland A, Dias MM, Wiese MD, et al.: Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br J Cancer. 2015; 112(12): 1888–1894. PubMed Abstract | Publisher Full Text | Free Full Text

[16] 16. Cremolini C, Di Maio M, Petrelli F, et al.: BRAF-mutated metastatic colorectal cancer between past and future. Br J Cancer. 2015; 113(11): 1634–1635. PubMed Abstract | Publisher Full Text | Free Full Text

[17] 17. Rowland A, Dias MM, Wiese MD, et al.: Reply: Comment on 'Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal-antibody therapy for RAS wild-type metastatic colorectal cancer'. Br J Cancer. 2015; 113(11): 1635. PubMed Abstract | Publisher Full Text | Free Full Text

[18] 18. Polasek T, Ambler K, Scott H, et al.: Dataset 1 in: Targeted pharmacotherapy after somatic cancer mutation screening. F1000Research. 2016. Data Source

Targeted pharmacotherapy after somatic cancer mutation screening

Abstract

Keywords

Revised Amendments from Version 1

Introduction

Figure 1. OncoFOCUS™+KIT results, molecular cancer classifications, and the 2015 NCCN guideline recommendations for targeted pharmacotherapy.

Methods

Results

Figure 2.

Discussion

Data availability

Author contributions

Competing interests

Grant information

Acknowledgements

References

Comments on this article Comments (0)

Open Peer Review

Comments on this article Comments (0)

Open Peer Review

Reviewer Status

Reviewer Reports

Comments on this article

Browse by related subjects

The problem

How to fix it

Competing Interests Policy

Stay Updated