A study into the urgent endoscopy referral system for

patients with suspected gastrointestinal cancer

Christopher Jump

3rd Year Medical Student

Background information

• With the aim of improving the detection of cancers at an early stage and therefore survival rates the 2-week referral system was introduced in 2000 by the Department of Health and was revised in 2005 by NICE

• This included a referral form which specified symptoms that needed to be present in order for the patient to be urgently referred to a specialist consultation or directly to endoscopy

Reasons the study was needed

• Many patient’s specimens referred as urgent to the

histopathologist are not diagnosed with malignancy.

This displaces ‘correctly’ referred urgent patients

down the waiting list, potentially causing them a

worse prognosis due to the delay of diagnosis and

subsequent treatment

Reasons the study was needed

• Each colonoscopy costs about £900

• Each oesophagogastroduodenoscopy (OGD) costs about £500-

600

• Histopathology costs are about:

o £67 per single biopsy site

o £100 for 2 biopsy sites

o £133 for 3 biopsy sites

• The PCT pays for each one they refer for, so if they are not

necessary it is a waste of their limited budget

Reasons the study was needed

• There are significant complications associated with

all types of endoscopy, which patients are being

needlessly exposed to if they are incorrectly referred

• E.g. Perforation, haemorrhage, infection, pain and

discomfort, sedation associated (cardio-pulmonary

events), etc.

Current evidence base

• Limited number of studies investigating urgent referral

for endoscopy in GI cancer patients, most of which

look into therapeutic endoscopy

• Many studies looking into the effectiveness of the

guidelines for urgent referral to a specialist in

secondary care. Have shown mixed results regarding

if the guidelines are specific enough to detect early

cancer presentation and their effect on the outcome of

patients

Main aims of the study

• To investigate:

o The number of patients that are correctly and

incorrectly referred for urgent endoscopies

o The differences in outcome between the patients

who were correctly and incorrectly referred

Method

• 50 patients included in the study, 25 who underwent an upper GI

endoscopy and 25 who had a lower GI endoscopy between the

25th February and 17th March 2009 at Southport and Formby

District General Hospital.

• Patients were identified by urgent histopathology referral forms.

• Medical records were then accessed and data collected.

• Urgent referrals were deemed to be correct or incorrect using

‘NICE referral for suspected cancer guidelines’.

• Outcomes were recorded by assessing their progress since their

endoscopy.

Results

• Mean age of 72.1 years

• 25 males and 25 females in total sample

• When divided:

o 14 females and 11 males in upper GI group

o 11 females and 14 males in lower GI group

Results- Source of referrals

• 43 (86%) of the 50 patients were referred from a GP

• 4 from hospital wards

• 1 from A&E, 1 referred by MDT, 1 surveillance

Results- Number of correct and incorrect referrals

• 18 (36%) of 50 patients were referred in accordance with NICE

guidelines

• When divided:

o Upper GI= 4 correct and 21 incorrect referrals

o Lower GI= 14 correct and 11 incorrect referrals

Results- what the upper GI referrals should have been

• Of the 21 incorrect referrals:

o 12 should have been given an urgent outpatient referral

o 5 should have been considered for an urgent outpatient referral

o 4 should have been routinely referred for an outpatient appointment

Results- Outcomes of correct referrals

• Upper GI:

o 1 patient with a benign polyp, now on surveillance

o 1 patient with an oesophageal ulcer and gastritis (PPI and discharged)

o 1 patient with duodenitis, duodenal ulcer, gastritis and 2 gastric ulcers

(PPI and discharged)

o 1 patient with gastritis and duodenitis (PPI and discharged)

• Lower GI:

o 5 cancers; 3 died, 1 is treated palliatively and 1 had surgical excision

and is now under surveillance

o 2 patients with Diverticular Disease discharged

o 2 patients with benign polyps discharged

o 5 patients normal, discharged

Results-Outcome of correct referrals

Results-Outcome of incorrect referrals

• Upper GIo 3 patients died (2 cancers, 1 unknown)o 13 patients treated for an inflammatory condition (oesophagitis,

gastritis or duodenitis) with a PPI and discharged.o 2 patients normalo 2 treated for malignancy (partial gastrectomy, oesophageal stent)o 1 patient continued on surveillance for Barrett’s oesophagus

Results-Outcome of incorrect referrals

• Lower GI:o 3 malignancies detected; 2 had successful surgical excisions,

1 treated palliativelyo 3 patients had adenomatous polyps excised, now under

surveillanceo 2 normal patientso 1 with haemorrhoids, dischargedo 2 treated for ulcerative colitis (both medication, 1 also had a

colectomy)

What has it shown

• Minority (36%) of urgent referrals comply with guidelines

• Majority (81%) of incorrect referrals are from GPs

• There are considerably more upper GI than lower GI incorrect

urgent referrals for endoscopy (21/25- 11/25)

• Minority of patients who are urgently referred for endoscopy

are diagnosed with cancer (24%)

• The incorrect referrals detected more cancers than the correct

referrals (7-5)

What has it shown

• Correct upper GI referrals detected no cancers, incorrect

detected 4

• Correct lower GI referrals detected 5 cancers, incorrect detected

3

• Incorrect lower GI referrals had a higher curative treatment rate

for cancer than correct lower GI referrals (66.7%-20%)

• 3 patients out of 50 had life saving surgical resection of their

cancer over the 3 weeks this study observed

• Equates to 52 patients a year saved at an annual cost of about

£718,363 for endoscopy and histopathology only

Conclusions• The existing guidelines are not effective as originally hoped in detecting patients

with gastrointestinal cancer

• This study suggests that for a cancer to meet the current urgent referral

guidelines it has to be at a late enough stage to exhibit enough symptoms to fulfil

the criteria, with the majority of the time this being too late to cure the patient

• Guidelines need to be reviewed and amended with the aim of detecting more

cancers at an early stage

• Guidelines need to be made compulsory for all GPs as this is where the main

problem lies

Limitations

• Symptoms in urgent referral form not specified,

which meant many patients may have been eligible

for urgent referral but were deemed not, as form not

filled in extensively enough. E.g. ‘rectal bleeding’ but

duration not specified

• Handwriting on some referral forms illegible so

patient may have met criteria

Limitations

• Some patients had missing histology reports in their

medical files so information had to be taken from

consultants letter to GP, which contains less specific

information

• Sample size in this study is not large enough to

draw significant conclusions, so a possible future

study could expand on these findings with more

patients from a wider region

Thank you for listening

Audit of Lung Biopsies Received at Whiston Hospital Histopathology Department in

2009

Dr S Kelly

Dr L Forsyth

Dr S A Melmore

Aim

• To review all lung biopsies received at Whiston

in 2009.• To assess adequacy.• Try to further differentiate the non-small cell

carcinomas (NSCC) into adenocarcinoma (adenoca) and squamous cell carcinoma (SCC)– on morphology, and– with the aid of immunohistochemistry.

Background

• Biopsy interpretation limited by – Sampling error,– Sample size,– Tumour heterogeneity.

• BTS guidelines (2001)recommend 90% adequacy with 5+ biopsies in cases of suspected malignancy.

• Small cell carcinoma (SMCC) → chemotherapy.• NSCC → surgery.

• New medical treatments for adenoca – without squamous differentiation (folate

antimetabolite chemotherapy drugs under assessment by NICE), and

– with EGFR-TK mutations (EGFR-TK inhibitors).

• Immunohistochemistry (IHC) may aid further differentiation.

• Limitations include;– inadequate sample size,– crush artefact,– positive staining of normal lung constituents,– overlapping immunophenotypes, and– previous studies conducted on resection

specimens and cytology but not biopsies.

Immunohistochemistry

• Squamous cell carcinoma; CK5, p63 and 34βE12.

• Adenocarcinoma; CK7, CK20 and TTF1.• P63

– Nuclear, SCC 78-100%, adenoca 1-33%, SMCC 77%.

• CK 5/6– SCC 100%.

• TTF1– Nuclear, adenoca 68-85%, SMCC 84%, 5-21%

SCC.– Poorly differentiated more likely to be negative.

SCC

H & E

TTF -ve

P63 +ve

Adenoca

H & E

TTF +ve

P63 -ve

Method

• Telepath search for all lung biopsies in 2009.• All cases reviewed by 2 consultants and 1 SpR.• Number of biopsy fragments counted.• Morphological diagnosis given.• All carcinoma NOS, 6 adenoca and 6 SCC →

– TTF-1 and p63. • TTF1 and p63 - ve →

– CK5/6– Case notes and reports from RLBUHT

reviewed.

Results• Pieces 1 2 3 4 5 6

• Negative (9) 2 4 2 0 1 0• Suspicious (1) 0 0 1 0 0 0• Malignant (49) 4 12 17 7 5 4

• Total (64) 6 16 20 7 6 4• % of total 9.4 25 31.3 11 9.4

6.3Number of adequate = 15.7 %

• Total 64

• Inadequate 5 • Negative 9• Low grade dysplasia, 1• Adenocarcinoma 9• Squamous cell carcinoma, 17• Carcinoma (NOS) 11 • Small cell carcinoma 8 • Metastatic or other 4

Not satisfactory

TTF1+

p63+

TTF1+

p63-

TTF1 –

p63 +

TTF1-

p63 -

TTF1 +

p63 +/-

Adenoc 0 1 (17%)

5 (83%)

0 0 0

sqcc 2 0 0 4 (100%)

0 0

Carcinoma NOS

2 0 4 (44%)

0 4 (44%)

1 (11%)

• 83% of adenocarcinoma TTF1 + (75-85% in studies).

• 1 adenocarcinoma TTF1 + p63 + (1-33% literature).

• 100% of satisfactory biopsies of sqcc p63 +.• 4 cases of carcinoma NOS TTF1 +, p63 -

probably adenocarcinoma.• 1 case p63 +/- , showed a positive internal

control. (Patient with cerebral metastases so no resection performed).

P63 +/-ve

TTF +ve

CK 5/6 -ve

H & E

• 4 cases TTF1 - ve, p63 – ve, – all internal controls for p63 + ve, and – all CK5/6 – ve. – 1 was small cell marker - ve on biopsy,

• resection showed a squamous cell carcinoma.

– 3 showed possible squamous morphology, • no resection due to the patient’s co-morbidities,

metastases or locally advanced disease.

Conclusion

• We diagnosed 5/64 cases as inadequate on H&E.

• Only 10/64 (15.7%) of the remaining cases contained 5+ fragments of tissue.( vs. 90%).

• We made a morphological diagnosis of malignancy on 49/64 cases, (9/49 had 5+ biopsies), and

• Differentiated type on H&E in 38/49 cases (6/38 had 5+ biopsies).

• 4/23 cases sent for IHC were inadequate. – diagnosed on H&E as 2 x SCC, 2 x carcinoma NOS

• Our cases are comparable with the literature for these robust IHC stains.

• For morphologically classic adenocarcinoma TTF1 and p63 can be used in combination to confirm the absence/presence of squamous differentiation.

• For poorly differentiated NSCC cells the use of TTF1 and p63 may aid further differentiation.

• Immunohistochemistry should be interpreted together with morphology and clinical history.

• Sub classification should be avoided if uncertain.

• Limitations include;

– small sample size, – difficult morphology, – variable immunohistochemical staining and

interpretation,– tumour heterogeneity,– previous studies done on resection

specimens.

The future

• As the prospect of mutational analysis on more/all of these tumours draws closer, and

• The use of IHC is used increasingly to choose the tumours that will benefit from treatment,

• Clinicians will need to be aware of – The need for an adequate sample, and– The impact on turnaround times will mean

• waiting for a delayed report, or

• receiving preliminary and supplementory reports.

Recommendations

• Use TTF1 and p63; – to confirm squamous differentiation in

morphologically diagnosed adenocarcinoma,– in poorly differentiated NSCC but be aware of the

limitations.

• Cut spare sections on all levels for IHC.

• Check results of subsequent resections.

• Comment on BTS adequacy in reports.

• Disseminate this information to all histopathologists and relevant clinicians.

Take Home Message

• For clinicians– An adequate sample is required for accurate

diagnosis, and – extensive IHC and mutational testing is time

consuming. • For pathologists

– Immunohistochemistry should ALWAYS be interpreted together with morphology and clinical history.

Thank you

Any questions?

Cancer Data for Outcomes

Desperately Seeking

Your Support

‘We can only be sure to improve

what we can actually measure’

– Lord Darzi

NHS North West

Supplier Data Report 2010/11

Data Supply

Data Quality

Poor SurvivalKey Questions?

• Stage at Presentation– Does my population have a problem with late stage

presentation? (not amenable to healthcare)– Do I know where and with whom there are delays in

presentation/delays in diagnosis?– Am I able to make informed investment/disinvestment

decisions?

• Access to Diagnosis and Treatment– Does the population and sub-populations of my PCT

access the right services at the right time?

PROVIDER Pathology Comment

AINTREE UNIVERSITY HOSPITALS NHS FOUNDATION TRUST GREEN

 

ALDER HEY CHILDREN'S NHS FOUNDATION TRUST

GREEN

04/10/2010 First electronic send. Received a file from Jan 2009 to June 2010. Receiving monthly sends thereafter

COUNTESS OF CHESTER HOSPITAL NHS FOUNDATION TRUST GREEN

 

ROYAL LIVERPOOL AND BROADGREEN UNIVERSITY HOSPITALS NHS TRUST GREEN

Receipt re-established

SOUTHPORT AND ORMSKIRK HOSPITAL NHS TRUST RED

Still sending paper

ST HELENS AND KNOWSLEY HOSPITALS NHS TRUST GREEN

 

WALTON CENTRE FOR NEUROLOGY AND NEUROSURGERY NHS TRUST RED

Still sending paper

WARRINGTON AND HALTON HOSPITALS NHS FOUNDATION TRUST GREEN

WIRRAL UNIVERSITY TEACHING HOSPITAL NHS FOUNDATION TRUST RED

NO DATA RECEIVED SINCE MARCH 2010

March 2011 – Electronic PathPipe delimited txt files

Pathology Mark Up

Breast

Laterality

Grade

No of Nodes

Size

Timeliness

• Timeliness of Data Supply

• Timeliness of Data Quality Feedback– Don’t want to study history

• Timeliness of commentary on services as they are currently configured and delivered

Summary

• Outcomes Framework a key driver for regular, high quality, timely cancer data

• Informed service planning depends upon high quality data – across patient pathway

• Need to achieve full electronic data supply by March 2011

• Leverage vital for a step change in data capture and reporting

Emerging technologies and targeting treatments: EGFR

JR GosneyConsultant Thoracic Pathologist

Royal Liverpool University Hospital

Epidermal growth factor receptor (EGFR)

• EGFR (HER-1; ErbB1)

• HER-2 (neu; ErbB2)

• HER-3 (ErbB3)

• HER-4 (ErbB4)

EGFR gene mutations and gefitinib

Sensitising mutations of EGFR gene

• Classically in peripheral, well differentiated, acinar, non-mucinous adenocarcinomas with a bronchioloalveolar component

• About 60% of non-smoking, Eastern Asian women with adenocarcinoma

• About 10% of Western subjects with NSCLC

EGFR protein expression

• Immunochemical detection of EGFR protein is not currently a reliable indicator of sensitising mutations nor of sensitivity to TKIs

EGFR gene amplification

• High EGFR gene copy number is an imprecise reflection of mutational status and sensitivity to TKIs and its detection by in situ hybridization is time consuming and technically demanding

Detecting mutations

• Mutations are detectable by screening or targeted detection– Trials of gefitinib employed an

amplification-refractory mutation system (ARMS)-based kit that targets 29 mutations in the EGFR gene

– This technique is sensitive and robust and does not require a high level of technical expertise

EGFR mutational analysis

In the Merseyside & North Cheshire Network

• About 750 new cases of NSCLC diagnosed by histo- or cytopathology per annum

• Paraffin wax block with accompanying report and H&E-stained section sent by referring pathologist to Department of Pathology at RLUH

• Histological assessment with possible microdissection followed by DNA extraction and mutational analysis

• Return of report of analysis to managing oncologist and to referring histopathology laboratory for integration with histopathology report

• Correlation of histopathology with mutational status for quality control, audit and development of service

December 2009-November 2010

• Phillipe Tanière, University of Birmingham

• Funded by AstraZeneca

• Non-small cell lung cancer

• Any stage

• 200 cases sent for analysis

December 2009-November 2010

• 96 male• 190 adenocarcinoma, 9 squamous, 1 LCNEC• 170 tissue biopsies, 15 cytology (10 FNAs (8

EBUS), 4 pleural fluid, 1 washing), 15 from resections

• 11 sensitizing mutations (5%)• 2 mutations conferring resistance (1%)• Mean turnaround time 15 days (8-34)

Eleven sensitizing mutations

• Six male, five female• Two of Chinese, one of Pakistani origin• Eight new diagnoses: three needle cores, two

bronchial biopsies, one lymph node, one bronchial washings, one from wedge resection

• Three recurrent disease: one original needle biopsy, one vertebral metastasis, one from previous resection

• Six point mutations (one 719 exon 18; one 861 exon 21, four 858 exon 21), five deletions (all exon 19)

• Nine adenocarcinoma, two non-small cell carcinoma not otherwise specified

From December 2010

• Mutational analysis at Royal Liverpool University Hospital

• Budget for analysis (and gefitinib) held at Clatterbridge Centre for Oncology

• Locally advanced or metastatic disease (according to license and NICE guidance)

• Non-squamous tumours only

Pooja Jain

Consultant Clinical Oncologist

Clatterbridge Centre for Oncology

• EGFR in NSCLC

• Targeting EGFR– Tyrosine Kinase Inhibitors

• John Gosney

• Key drivers in the process of – Cell growth– Proliferation

• EGFR activating mutation– promotion of tumour cell

growth– blocking of apoptosis– increasing the production of

angiogenic factors– facilitating the processes of

metastasis

• Dysregulation frequently seen in NSCLC

Tyrosine kinase Tyrosine kinase inhibitioninhibition

• Initially developed as second line therapy– BR 21– Increase in the objective response rate (9% <1 %)– Increase in overall survival (6.7 versus 4.7 months)– Improvement in symptoms & physical function

• Early indication of selection– Women– Never/light smoker– Adenocarcinoma

• First line therapy– Platinum doublet

• RR 30%• 65% of patients would be suitable

• Second line chemotherapy– 30% of patients would be suitable

• Single agent docetaxel/gemcitabine/vinorelbine• RR < 10%

• Phase II studies: objective response rates of 55 to 90%

• IPASS study

• Phase III studies were in Far East– IPASS – WJTOG3405

IRESSA

(250 mg daily)

Carboplatin (AUC 5 or 6) /

paclitaxel (200 mg / m2)

3 weekly#

1:1 randomisation

* Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped 15 years ago and smoked 10 pack years; # limited to a maximum of 6 cycles Carboplatin / paclitaxel was offered to IRESSA patients at progressionPS, performance status; EGFR, epidermal growth factor receptor

Patients•Chemonaïve

•Age ≥18 years

•Adenocarcinoma histology

•Never or lightex-smokers*

•Life expectancy≥12 weeks

•PS 0-2

•Measurable stage IIIB / IV disease

Primary• Progression-free survival (non-inferiority)

Secondary• Objective response rate• Overall survival • Quality of life• Disease-related symptoms • Safety and tolerability

Exploratory• Biomarkers

• EGFR mutation• EGFR-gene-copy number• EGFR protein expression

Endpoints

Mok et al 2009, Fukuoka 2009

• IPASS exceeded it’s primary endpoint and demonstrated superiority for IRESSA in PFS compared to doublet chemotherapy

• PFS effect was not consistent over time

609453 (74.4%)

608497 (81.7%)

NEvents

HR (95% CI) = 0.741 (0.651, 0.845) p<0.0001

IRESSACarboplatin /

paclitaxel

Carboplatin / paclitaxel

IRESSA

Median PFS (months)4 months progression-free6 months progression-free12 months progression-free

5.761%48%25%

5.874%48%7%

609

212 76

24

5 0608

118

22

3 1 0363412

0 4 8 12

16

20 24 Months0.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ilit

y o

f P

FS

At risk :

IPA

SS

: P

rog

res

sio

n F

ree

Su

rviv

al (

ITT

)

Mok T, Wu TL, Thongprasert S et al. N Engl J Med 2009; 361:947-995

43

32

05

101520253035404550

IR E S S A C arboplatin/P ac litaxel

Ov

era

ll R

es

po

ns

e R

ate

%(I

TT

Po

pu

lati

on

)

Overall Response Rate, ITT population

IPA

SS

: O

ver

all

Res

po

ns

e R

ate

(IT

T)

IRESSA produced a greater ORR than doublet chemotherapy in a clinically selected group of patients

Odds ratio = 1.59 (95% CI 1.25, 2.01) p=0.0001

Mok T, Wu TL, Thongprasert S et al. N Engl J Med 2009; 361:947-995

• IRESSA halved the relative risk of progression compared with carboplatin/ paclitaxel in EGFR M+ patients1

• Median PFS was over 3 months longer with IRESSA in EGFR M+ patients than carboplatin/paclitaxel (9.5 vs 6.3 months)2

IPA

SS

: P

rog

res

sio

n F

ree

Su

rviv

al (

EG

FR

M+

)PFS in the EGFR M+ population

EGFR M+HR=0.48, 95% CI 0.36, 0.64, p<0.0001

EGFR M-

HR=2.85, 95% CI 2.05, 3.98, p<0.0001

0 4 8 12 16 20 24Time from randomisation (months)

0.0

0.2

0.4

0.6

0.8

1.0IRESSA EGFR M+ (n=132)IRESSA EGFR M- (n=91)

Carboplatin / paclitaxel EGFR M+ (n=129)Carboplatin / paclitaxel EGFR M- (n=85)

Treatment by subgroup interaction test, p<0.0001

Pro

bab

ilit

y o

f P

FS

Mok T, Wu TL, Thongprasert S et al. N Engl J Med 2009; 361:947-995. Iressa SmPC

71

1.1

47

23.5

0

10

20

30

40

50

60

70

80

E G F R M+ E G F R M-

Ove

rall

Res

pons

e R

ate

%

IRESSA Carboplatin / paclitaxel

EGFR M+ odds ratio (95% CI) = 2.75(1.65, 4.60), p=0.0001

EGFR M- odds ratio (95% CI) = 0.04(0.01, 0.27), p=0.0013

(n=132) (n=129) (n=91)(n=85)

IPA

SS

: O

ver

all

Res

po

ns

e R

ate

(E

GF

R M

+)

Superior ORR in the EGFR M+ population

Mok T, Wu TL, Thongprasert S et al. N Engl J Med 2009; 361:947-995Iressa SmPC

The NEJ002 and WJTOG3405 studies

Months since randomization

0

20

40

60

80

100Progression-free survival (%)

0 3 6 9 12 15 18 21 24 27

Carboplatin/

paclitaxel(n=110)

IRESSA(n=114)

Maemondo et al 2010

HR=0.30, 95% CI 0.22 - 0.41, p<0.001Median PFS : 10.8 vs 5.4 months

Months since randomization

0

20

40

60

80

100Proportion without progression (%)

0 10 20 30 40

p<0.0001

8686

2211

43

20

00

6349

117

30

20

Number at riskIRESSA

Cisplatin and docetaxel

Mitsudomi et al 2010

86

9.2 months (8.0-13.0)

86

6.3 months (5.8-7.8)

n

Median PFS (95% CI)

IRESSA Cisplatin and

docetaxel

PFS: progression-free survival

HR=0.49, 95% CI 0.34-0.71; p<0.0001

STUDY Line of Treatme

nt

EGFR M+ (n)

ORR (%) Median PFS

(months)

Median OS

(months)

Sequist et al 2008Journal of Clinical Oncology 2008;

26(15): 2442-2449

1st 31 55% 9.2m 17.5m

Cortes-Funes et al 2005

Annals of Oncology 2005; 16: 1081-1086

Pre-treated

10 60% 12.3m 13m

Cappuzzo et al 2007Journal of Clinical Oncology 2007;

25(16): 2248-55

Mixed 24 62% - -

Yang et al 2008Journal of Clinical Oncology 2008;

26(16): 2745-53

1st 55 69% 8m -

Tamura et al 2008British Journal of Cancer 2008;

98(5): 907-14

1st 28 75% 11.5m -

Sone et al 2007Cancer 2007; 109(9): 1836-44

Mixed 17 59% 7.3m 18.9m

Oshita et al 2006British Journal of Cancer 2006;

95(8): 1070-5

Mixed 11 91% - -

Costa et al 2007Lung Cancer 2007; 58(1): 95-103

Meta-analysis

99 81% 7.7 to 12.9m

Over 15.4m

IRE

SS

A:

Eff

ica

cy

Ind

ep

en

de

nt

of

Eth

nic

ity

AS

IA

NO

N-A

SIA

• Understanding biology and biomarkers is key to improve the management of lung cancer

• Targeting the EGFR pathway represents a major advance in the management of NSCLC

• Mutation rates are low in the Western world (local population is ~ 5%)

KRAS genetics service 6th May 2010 – 2nd Dec 2010

Andrew Purvis, Clinical Scientist

Cheshire and Merseyside Regional Molecular Genetics Laboratory

Liverpool Women’s Hospital

KRAS• KRAS – small GTPase

• Signal transducer downstream of EGFR (RAS/RAF/MAPK pathway)

• Regulator of cell proliferation and survival

• Somatic mutations in KRAS abolish GTPase activity = uncontrolled proliferation

• Pathway isolated from EGFR• Anti-EGFR therapy ineffective

• ~40% of mCRC have a somatic mutation in KRAS (e.g. CO.17)

PP

RAF

MEK

MAPK

EGF

EGFR

KRAS

Cell proliferation and survival

cell membrane

KRAS – sequence and mutations

1 ATGACTGAATATAAACTTGTGGTAGTTGGAGCTGGTGGCGTAGGCAAGAGTGCCTTGAC .-M--T--E--Y--K--L--V--V--V--G--A--G--G--V--G--K--S--A--L--T 60 GATACAGCTAATTCAGAATCATTTTGTGGACGAATATGATCCAACAATAGAGGATTCCTA 20 --I--Q--L--I--Q--N--H--F--V--D--E--Y--D--P--T--I--E--D--S--Y 120 CAGGAAGCAAGTAGTAATTGATGGAGAAACCTGTCTCTTGGATATTCTCGACACAGCAGG 40 --R--K--Q--V--V--I--D--G--E--T--C--L--L--D--I--L--D--T--A--G 180 TCAAGAGGAGTACAGTGCAATGAGGGACCAGTACATGAGGACTGGGGAGGGCTTTCTTTG 60 --Q--E--E--Y--S--A--M--R--D--Q--Y--M--R--T--G--E--G--F--L--C 240 TGTATTTGCCATAAATAATACTAAATCATTTGAAGATATTCACCATTATAGAGAACAAAT 80 --V--F--A--I--N--N--T--K--S--F--E--D--I--H--H--Y--R--E--Q--I

>90% of mutations in mCRC found in codons 12 and 13~5% of mutations found in codon 61

Pyrosequencing assay for detection of KRAS mutations at

LWH• Why Pyrosequencing?

• Unambiguous detection of ALL possible mutations in codons 12, 13 and 61

• Sensitive• Detects 5%-10% mutant depending on the mutation

• Results obtainable from DNA isolated from PETs• DNA of poor quality• DNA of low quantity

• Proven technology• Qualitative and quantitative analysis

Example KRAS Pyrosequencing results

Gene sequence (codons 12 and 13)

Vis

ible

ligh

t

Non-mutated patient (normal sequence)

KRAS mutation +ve and –ve results

c.34G>T, p.Gly12Cys

No mutation

c.38G>A, p.Gly13Asp

KRAS testing 6th May 2010 to 2nd Dec 2010

• 28 referrals (cut sections or tissue blocks) from 5 pathology laboratories:• Arrowe Park 6• Chester 7• Royal Liverpool 3• Southport 8• Whiston 4

• KRAS results obtained for 28/28 referrals

KRAS testing 6th May 2010 to 2nd Dec 2010

• Reporting times of 28 referrals• Mean reporting time 5.5 working days• 18 (64%) reported within 5 working days

KRAS reporting times

0

2

4

6

8

2 3 4 5 6 7 9 10Working days taken to report results

Nu

mb

er o

f re

ferr

als

KRAS testing 6th May 2010 to 2nd Dec 2010

• 16/28 - no detectable KRAS mutation• 12/28 (43%) - detectable KRAS mutation

• 10 in codon 12• 2 in codon 13• 0 in codon 61

34G>T (Gly12Cys), 2

35G>T (Gly12Val), 6

35G>A (Gly12Asp), 2

38G>A (Gly13Asp) , 2

Normal, 16

Proportion of KRAS mutations detected

Sensitivity / UKNEQAS (quality assessment scheme)

• Mutations can be present at low level• Tumour heterogeneity• Accompanying normal tissue

• Pyrosequencing detects mutations down to 5-10% depending on mutation

• Current mutation detection rate is 43% • Agrees with published data• Suggests we have not missed any mutations

• Full marks in recent UKNEQAS scheme• Not all participating labs received full marks• ? include % neoplastic cells on KRAS reports

De Roock et al., JAMA. 2010;304(16):1812-1820

Do all KRAS mutations in codons 12, 13 and 61 have the same effect

on anti-EGFR therapy?

BRAF V600E ?• A proportion of tumours with no KRAS

mutation will not respond to anti-EGFR therapy• Other biomarkers? • BRAF V600E detected in 5-12% of mCRC

• Same pathway as KRAS• V600E increases BRAF activity ~10 fold

• Predicts resistance to anti-EGFR therapy34G>T (Gly12Cys), 2

35G>T (Gly12Val), 6

35G>A (Gly12Asp), 2

38G>A (Gly13Asp) , 2

Normal, 16

Colorectal Cancer

Place of K-ras testing

Colorectal Cancer

Stage Incidence 5yr survival

Dukes A 10% 90+%

Dukes B 22% 60-80%

Dukes C 39% 30-60%

Metastatic 29% <5%

65% of patients with CRC will eventually die from advanced disease

19,000pts annually in UK

Systemic therapy for CRC

Best supportive care5FU

IrinotecanCapecitabine

Oxaliplatin

Cetuximab

Bevacizumab

1957 1994 2005

302520151050 Median survival - months

Cetuximab - 2003

• Chimeric mouse monoclonal ab

• Targeted against EGFR receptor

• Entry point to signal transduction pathway

– cell proliferation

– cell migration

– cell adhesion

– cell survival

EGFR signaling

Baselga. Eur J Cancer 2001;37 Suppl 4:S16-S22.

Cetuximab

• active in CTX resistant colorectal xenografts

• synergistic with

– Irinotecan

– radiotherapy

NCI of Canada ph III Cet vs BSC CO.17

572 pts, egfr expression +veNon responders to Ctx

Cetuximab BSCMS 6.1m 4.6mPR 8% 0%

0

20

40

60

80

100

0 2 4 6 8 10 12

BOND studyTime to progression

Patients free of progression (%)

Time to progression (months)

Cunningham et al. N Engl J Med 2004; 351:337-345.

p<0.001

ERBITUX + irinotecan ERBITUX

Cetuximab - Toxicity

• Acneiform rash

– Gd >1 76%

– Gd 3/4 12%

– maximal at wk3 then improves

– ? Rash associated with improved survival

http://theoncologist.alphamedpress.org/content/vol10/issue5/images/large/345_fig1A-C.jpeg

CRYSTAL – Ph III Ist line

• 1198 pts

• FOLFIRI +/- cetuximab

Pfs 8.9m 8m

RR 47% 39%

OS 23.5m 20m ns

COIN – first line 3 arm trial

• FOLFOX/XELOX + cet continuous

• FOLFOX/XELOX continuous

• FOLFOX/XELOX + cet intermittent

• 1630pts randomised

• No difference in OS or PFS

EGFR expression

• Not a useful predictive factor– Heterogeneity of EGFR expression– Variable affinity of EGFR for cetuximab– Inconsistency in measurement

K-ras oncogene

• Encode proteins downstream from EGFR

• Essential component of EGFR signalling

• Can acquire activating mutations in exon 2

• Does mutation status of K-ras affect response to anti-EGFR monoclonals?

CO.17

394/572 samples available for K-ras analysis

K-ras mutation detected in 40%

CO.17

Cetuximab BSC

Mutated ms 4.5m 4.6m1yr 13% 19%RR 1% 0%

Wild Type ms 9.5m 4.8m1yr 28% 20%RR 12% 0%

CO.17 - Survival

EGFR signaling

Baselga. Eur J Cancer 2001;37 Suppl 4:S16-S22.

CRYSTAL K-ras WT pts

• Post hoc analysis for NICE (TA176)

• 348pts FOLFIRI + cetuximab

WT Mutant

PFS 9.9 8.7m p=0.0167

MS 24.9m 21 m ns

RR 66% 43% p=0.0028

Surgery 7% 3.7%

COIN – WT analysis

• 729 WT pts OXFp +/- cetuximab

• PFS ns

• OS ns

• RR 64% vs 57% p=0.049

OPUS – first line Ph II

• 336pts 134 K-ras WT

• FOLFOX +/- cetuximab

WT Mutant

PFS 7.7 m 7.2 m p=0.01

RR 60% 37% p = 0.011

Surgery 11% 4.1% sig not reported

CELIM – first line

• Randomised ph II

• 114 pts

• Initially unresectable liver metastases

• folfiri + cetuximab vs folfox + cetuximab

• RR 68% vs 57%

• Subsequent resection 43 vs 40%

1st line cetuximab + Ctx

• Variable effect on survival

• ? Consistently higher response rates

Liver metastases - down sizing

• Systemic therapy may render tumours operable • 95/701 (13.5%) rendered resectable

– Reason unresectable• 60% (too large),

• 49% (ill located),

• 34% (multinodular),

• 18% (extrahepatic)

Inoperableliver metastasis

5yr survival< 5%

Chemotherapy

Operableliver metastasis

5yr survival 30-40%

Adam Ann Surg Oncol 2001

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5 6 7 8 9 10

Survival after chemotherapy-facilitated resection of metastases is the same as that for initially resectable metastases

Adam R. Ann Oncol 2003;14:ii13-ii16.

Proportion surviving

Survival time (years)

Resectable (n = 425) Initially unresectable (n = 95)

54%

50% 34%

34%

27%

29%19%

Resection rate correlates with tumor response rate in both selected and non-selected patients

Studies including all patients with mCRC (solid line) (r=0.74, p<0.001)

Studies including selected patients(liver metastases only, no extrahepatic disease)(r=0.96, p=0.002)

Phase III studies including all patients in mCRC (dashed line)(r=0.67, p=0.024)

Folprecht et al. Ann Oncol 2005;16:1311-1319.

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.3 0.4 0.5 0.6 0.7 0.8 0.9

Resection rate

Response rate

NICE guidance TA176

• Recommended Cetuximab + Chemotherapy for patients

– With inoperable CRC metastases confined to the liver– Who were fit for surgery– Who might be downsized to surgery following systemic therapy

CCO – Survival from I-CET

44ptsMS 10m (6 – 13)

CCO – Survival from 1st line CTX

44pts MS 36m (32 – 39)

Xelox x 12 weeks

Nov 08

Feb 09

May 09

Irinotecan x 12 wks

Oct 09

Jan 10

I-Cetux

Adjuvant Cetuximab

• FOLFOX +/- cetuximab

• NCCTG Intergroup phase III trial NO147

• 1760pts st III colon cancer wild type K-ras

Folfox Fotfox + cet

3yr dfs 74% 73%

3yr os 87% 82%

Cetuximab 2010

• Downsizing liver metastases to resection In combination with oxaliplatin/5FU/Irinotecan

• Third line treatment in pts previously responding to chemotherapy In combination with Irinotecan

Adjuvant cetuximab not of value

The National Cancer Dataset Project

- especially pathology!Di Riley

Director for Clinical Outcomes

.....Better information on cancer services and outcomes will enhance patient choice, drive up service quality and underpin stronger commissioning;

.....Collection of defined datasets on all cancer patients will be mandated through the national model contract. PCTs will be responsible for ensuring that this information is collected by MDTs and sent to cancer registries

CRS, December 2007

.....We particularly need to collect anduse high quality data on:

.....Clinical outcomes, including survival, with adjustments for co-morbidity and stage of disease.

CRS, December 2007

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Five-year relative survival for colorectal cancer patients (diagnosed 1996-2002) by stage at diagnosis, England

Number of cases (1996-2006) and five-year relative survival of colorectal cancer patients (diagnosed 1996-2002) by stage at diagnosis, England

Project Purpose

• To redevelop the National Cancer Dataset for use as a full operational standard in England

• To review the current business needs for the collections and make sure that the output is fit for purpose

NCIN ‘Data Views’

Patient Pathway

Dat

aset

s/S

ou

rces

  Refer-ral

Diag Stage Rx Rec/Mets Rx Pall. Care

Death

Diagnostics

CWT              

MDT

RTDS              

HES              

NCASP              

Ca. Reg              

SSCRG progress

• Approved mandated datasets– Cancer registration – additional review– GFoCW– Radiotherapy– CDS

• 12 SSCRGs identified ‘site specific’ items– Link to ‘output’ requirements– Based on existing datasets e.g. NCASP, BAUS– Period of definitional testing

• Mandated for NHS from October 2012

Challenges....

• Clinical data from MDTs?• Transport via standard NHS data flows

– SUS, Open Exeter (Cancer Waits)– Direct Cancer Registries & Nat. Repository– Direct to NCASP

• Linking activity and ‘care record’ data– OPCDS + radiotherapy– CWT + ‘registration’– NHS number linked data views

• Coded data from path/radiology/etc

Pathology Data

• Patient care & management– MDT– Staging– Ongoing care

• Cancer Outcomes/Registration– Staging– Morphology, topography, grade– Risk adjusted analysis

NCRD – pathology items -1

DiagnosisDIAGNOSIS DATE (CANCER) PRIMARY DIAGNOSIS (ICD) TUMOUR LATERALITY BASIS OF DIAGNOSIS (CANCER) HISTOLOGY (SNOMED) 

GRADE OF DIFFERENTIATION (AT DIAGNOSIS) 

Staging

T CATEGORY (FINAL PRETREATMENT) 

STAGING CERTAINTY FACTOR (T CATEGORY) 

N CATEGORY (FINAL PRETREATMENT) 

STAGING CERTAINTY FACTOR (N CATEGORY) 

M CATEGORY (FINAL PRETREATMENT) 

STAGING CERTAINTY FACTOR (M CATEGORY) 

TNM CATEGORY (FINAL PRETREATMENT) 

STAGING CERTAINTY FACTOR (TNM CATEGORY) 

SITE SPECIFIC STAGING CLASSIFICATION 

TNM CATEGORY (INTEGRATED) 

T CATEGORY (INTEGRATED STAGE) 

N CATEGORY (INTEGRATED STAGE) 

M CATEGORY (INTEGRATED STAGE) 

Pathology DetailsPATHOLOGY INVESTIGATION TYPE SAMPLE RECEIPT DATE INVESTIGATION RESULT DATE CONSULTANT CODE (PATHOLOGIST) ORGANISATION CODE (OF REPORTING PATHOLOGY) PRIMARY DIAGNOSIS (ICD) TUMOUR LATERALITY INVASIVE LESION SIZE SYNCHRONOUS TUMOUR INDICATOR HISTOLOGY (SNOMED) GRADE OF DIFFERENTIATION CANCER VASCULAR OR LYMPHATIC INVASION EXCISION MARGIN NODES EXAMINED NUMBER NODES POSITIVE NUMBER T CATEGORY (PATHOLOGICAL) N CATEGORY (PATHOLOGICAL) M CATEGORY (PATHOLOGICAL) TNM CATEGORY (PATHOLOGICAL) SERVICE REPORT IDENTIFIER SERVICE REPORT STATUS SPECIMEN NATURE ORGANISATION CODE (REQUESTED BY) CARE PROFESSIONAL CODE (REQUESTED BY) T CATEGORY EXTENDED (PATHOLOGICAL) M CATEGORY EXTENDED (PATHOLOGICAL) 

NCRD – pathology items -2

RCPath Datasets

• Guidelines for good clinical reporting– Specific for different cancer sites

• What proportion of pathologists use proforma-based reporting tools?

• How to or should we progress to encoded data?• Cancer registration & outcomes analysis would

benefit from it?• Would MDTs also benefit - MDT dataset?

NCIN/RCPath Pathology Project

• Structured or proforma reporting• Codify & mandate ‘Core’ items• Direction of travel too great

– Systems not available– Change in clinical practice– Patient management v outcomes analysis

• What is the solution?– Professional & Clinical Record Standards

• Clarification of content to be provided within free text reports (RCPAth Core Items)

• Or the use of the RC Path proforma.

• Communication to Pathologists of content specification and mechanism for transmission to Registries.

• Both of these aspects covered by RC Path guidance

Professional Standard -Stage 1

• Professional Standard version 2– stipulation of proforma to be used for

reporting– introduction of structured/coded items

• Patient Record Standard version 1– identification of items which can be

structured and have SNOMED CT codes

Standards - Stage 2

• Professional Standard version 3 – structured data items

• Patient Record Standard version 2 – all items structured with SNOMED CT

coding– identification of the linkage standards to

allow record to Registry transmission and use.

Standards - Stage 3

Timescales & Process

• Working Group– RCPath / NCIN / CfH /DH– National Clinical Content & Requirements Board (NCCRB)– Role of RCPath for governance key– Align with other related initiatives

• Estimated time – 5 years (2015)– Content Proposal – approved November 2010– Requirements Statement– Assurance Statement– Then the Information Standards Board

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