408453 149530 1 8001-17 HER2 ASCP presentation 1 .ppt · 2017. 9. 2. · lymph node specimens: •Her2 overexpression in 33% of primary and 39% of metastatic lymph nodes •81 Primary

8001-17Update on Published

CAP/ASCP/ASCO HER2 Testing and Clinical Decision Making

in Gastroesophageal Adenocarcinoma

Kay Washington, MD, PhD

Vanderbilt University Medical Center

DISCLOSURE

In the past 12 months, I have not had any significant financial interest or other relationship with the manufacturers of the products or providers of the services that will be discussed in my presentation.

Objectives

3

• Present the Guideline for HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma

• Review guidance to oncologists to:

• Help identify appropriate patients for HER2-targeted therapy

• Help identify which patients to test for HER2-targeted therapy

Objectives

4

• Provide guidance to pathologists on:

• Choosing the appropriate specimens to test for HER2

• How to test for HER2 expression/amplification

• How to interpret and report the test results to clinicians and patients

Objectives

5

• Introduction to ERBB2 (HER2), background and history in GEA and breast

• Methodology of Guideline process

• Clinical background on HER2 in GEA

• HER2 as a prognostic indicator

• Specimen selection for HER2 testing

• Immunohistochemistry (IHC) and in-situ hybridization (ISH) testing and interpretation

Objectives

6

• Brief discussion on HER2 genomic testing

• Reporting HER2 results and turnaround time (TAT)

• Summary of the Guideline and new directions with mention of ongoing clinical trials

Gastroesophageal Adenocarcinoma (GEA)

• Esophageal: 8th

• Stomach: 5th

• Most common cancers worldwide

• Often diagnosed at an advanced stage

• Therapies are limited

7

http://www.cancernetwork.com

8

HER2 (ERBB2)

9www.intechopen.com

HER2 expression by IHC

10

Trastuzumab (Herceptin)

11

http://trialx.com/

Bang et al, Lancet, 2010

HER2 as a therapeutic target for gastroesophageal adenocarcinoma (GEA)

12

Source: Junttila TT, Akita RW, Parsons K, et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively

inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. 2009;15(5):429-40.

Background

• 2007- expert panel with members from American Society of Clinical Oncology (ASCO) and the College of American Pathology (CAP)

oGuidelines for when and how to test for the HER2 gene in breast cancer

oRecommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: the American Society of Clinical Oncology/College of American Pathologists Clinical Practice Update

14

Source: Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American

Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997-4013.

Methodology and Guideline Process

• Partner Organizations:

• CAP

• ASCP

• ASCO

• Pathologists, oncologists, gastroenterologist, patient advocate

• Physician methodologist experienced in systematic review and guideline development

• Medical librarian

15

HER2 Testing in GEA Project Team

16

Co-Chairs

Angela N. Bartley, MD – CAP

M. Kay Washington, MD – ASCP

Jaffer Ajani, MD - ASCO

Expert Panel

Al Benson, III, MD

Alfredo Carrato, MD, PhD

Margaret Gulley, MD

Dhanpat Jain, MD

Sanjay Kakar, MD

Srinadh Komanduri, MD

Helen Mackay, MD

Catherine Streutker, MD

Laura Tang, MD, PhD

Megan Troxell, MD, PhD

Advisory Panel

Andrew Bellizzi, MD

Katherine Geiersbach, MD

Syma Iqbal, MD

Rahul Jawale, MD

Alyssa Krasinskas, MD

Shiwen Song, MD

William Sukov, MD

Hanlin Wang, MD, PhD

Christopher Willett, MD

Christa Whitney-Miller, MD

Staff

Christina Ventura, MT(ASCP)

Carol Colasacco, MLIS, SCT(ASCP)

Jennifer Clark, BS, SCT(ASCP)

Nofisat Ismaila, MD (ASCO)

Conflict of Interest Review

• Potential panel members completed disclosure process reporting any actual or potential conflict

• Potential conflicts were reviewed by co-chairs

• Members were required to disclose conflicts continuously throughout the timeline

• No industry funding was involved in any aspect of the guideline development

• Panel members were volunteers

17

Key Questions – Overarching Questions

• Clinical question 1: What is the optimal testing algorithm for the assessment of HER2 status in patients with gastroesophageal adenocarcinoma?

oKey questions 1-6

• Clinical question 2: What strategies can help ensure optimal performance, interpretation and reporting of established assays in patients with gastroesophageal adenocarcinoma?

oKey questions 7-16

18

Systematic Review

• Title Abstract Review – 969 abstracts

• Full Text Review – dual review of 280 full text articles

• Data Extraction – 116 articles

o 1 Systematic review

o 2 Meta-analysis

o 2 Randomized control trials

o 27 Prospective studies

o 69 Prospective-retrospective studies

o 15 Retrospective studies

19

Strength of RecommendationsCAP Designation GLIDES

Designation

Recommendation Rationale

Strong

Recommendation

Strong Recommend For or Against a particular practice

(Can include must or should)

Supported by high (convincing) or

intermediate (adequate) quality of

evidence and clear benefit that outweighs

any harms

Recommendation Moderate Recommend For or Against a particular practice

(Can include should or may)

Some limitations in quality of evidence

(intermediate [adequate] or low

[inadequate]), balance of benefits and

harms, values, or costs but panel

concludes that there is sufficient evidence

and/or benefit to inform a

recommendation.

Expert Consensus

Opinion

Weak Recommend For or Against a particular practice

(Can include should or may)

Serious limitations in quality of evidence

(low [inadequate] or insufficient), balance

of benefits and harms, values or costs,

but panel consensus is that a statement is

necessary.

No Recommendation N/A No recommendation for or against a particular

practice

Insufficient evidence or agreement of the

balance of benefits and harms, values, or

costs to provide a recommendation

20Source: Guyatt GH, Oxman AD, Vist GE, et al; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of

recommendation. BJM. 2008;336(7650):924-926.

Open Comment Period

• Open December 2015 and closed January 11th 2016.

• 294 responses were posted, with high agreement from open comment participants.

• Based on the open comment period,

• One draft recommendation was modified

• Four draft recommendations were combined

21

Recommendation 1

• Strong Recommendation: In patients with GEA who are potential candidates for HER2 targeted therapy, the treating clinician should request HER2 testing on tumor tissue.

• (Quality of evidence: High; Strength of recommendation: Strong)

22

Recommendation 3

• Recommendation: Treating clinicians or pathologist should request HER2 testing on tumor tissue in the biopsy or resection specimens (primary or metastasis) preferably prior to the initiation of trastuzumab therapy if such specimens are available and adequate. HER2 testing on FNA specimens (cell blocks) is an acceptable alternative.

• (Quality of evidence: Moderate/Intermediate; Strength of recommendation: Strong)

23

24

25

In patients with advanced GEA

Request in all patients who seem to qualify for trastuzumab (and chemotherapy)

26

Should you ever repeat HER2 testing?

No (no data but some BC docs do)

Should you continue trastuzumab beyond progression?

No (no data but many BC docs do)

Should you wait for HER2 results to start therapy?

NO (Most patients are symptomatic and can add trastuzumab later if HER2 is positive)

Source: Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687-697.

27

Updated Trastuzumab Survival Benefit

28

Trastuzumab: The FDA Update

29

Source: U.S. Food and Drug Administration.Herceptin (trastuzumab) final labeling text.

http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/103792s5250lbl.pdf. Accessed: March 28, 2016.

Other attempts to improve outcome of HER2 + tumor patients

30

• Both lapatinib trials (first line [Logic] and second line [Tytan]) were negative

• T-DM-1 trial was negative

• Pertuzumab trial (Jacob) results are pending. [dual blockade of HER2 and HER3 using trastuzumab and pertuzumab]

• Many interesting molecules are progressing in the clinic.

• e. g., margetuximab (Fc-modified chimeric monoclonal antibody in Phase 1)

Nature Reviews Cancer August 2012 31

Nature Reviews Cancer August 2012

Conclusions

32

• No need to wait for HER2 status to start treatment with chemotherapy.

• Novel strategies (such adding a checkpoint inhibitor, bispecific antibodies, or adding immunogenic sequences to antibodies) may improve outcome even when HER2 is “negative”

Recommendation 2

• Recommendation: Treating clinicians or pathologist should request HER2 testing on tumor tissue in the biopsy or resection specimens (primary or metastasis) preferably prior to the initiation of trastuzumab therapy if such specimens are available and adequate. HER2 testing on FNA specimens (cell blocks) is an acceptable alternative.

• (Quality of evidence: Moderate/Intermediate; Strength of recommendation: Strong).

33

Tumor Specimens from the Primary GEA

• MAGIC trial: 93% concordance between biopsy and resection specimens

• ToGA trial: overall positive rate 23.2 % for biopsy and 19.7% for surgical specimens

34

Source: Okines AF, Thompson LC, Cunningham D, et al. Effect of

HER2 on prognosis and benefit from peri-operative chemotherapy

in early oesophago-gastric adenocarcinoma in the MAGIC trial.

Ann Oncol. 2013;24(5):1253-1261.

Tumor Specimens from the Primary GEA

• 381 advanced GEA patients:• No difference in HER2 positivity between

resections and biopsies (21% vs 19%) of primary of metastatic disease

• 207 advanced GEA patients:• 207 surgical resection specimens with paired

biopsies

• HER2 gene amplification in 31% of surgical resections and 32% of biopsy specimens

• Concordance between IHC and FISH: 90.9% and 90.2% in resections and biopsy specimens, respectively.

35

Source: Janjigian YY, Werner D, Pauligk C, et al. Prognosis of

metastatic gastric and gastroesophageal junction cancer by

HER2 status: a European and USA international collaborative

analysis. Ann Oncol. 2012;23(10):2656-2662.

Tumor Specimens from Resected GEA

• 61 consecutive pairs of biopsy and surgical specimens:

• Concordance of 92%

• Limited number of paired biopsy and resection specimens suggests a fair degree of concordance for HER2 expression/amplification.

36

Source: Pirrelli M, Caruso ML, Di Maggio M,

Armentano R, Valentini AM. Are biopsy specimens

predictive of HER2 status in gastric cancer

patients? Dig Dis Sci. 2013;58(2):397-404.

How many biopsy fragments are needed?

• A minimum of five, but optimally 6-8 biopsy fragments

• If there is concern of adequacy:

• Test additional specimen when available

• Communicate to clinician any question of adequacy

37

Source: Gullo I, Grillo F, Molinaro L, et al. Minimum biopsy set for HER2

evaluation in gastric and gastro-esophageal junction cancer. Endosc Int Open.

2015;3(2):E165-170.

38

Tumor Specimens from Metastatic GEA

• 100 primary gastric and metastatic lymph node specimens:

• Her2 overexpression in 33% of primary and 39% of metastatic lymph nodes

• 81 Primary versus metastatic lymph node specimens:

• 92.5% concordance of HER2 amplification by SISH

39

Source: Qiu Z, Sun W, Zhou C, Zhang J. HER2

expression variability between primary gastric

cancers and corresponding lymph node metastases.

Hepatogastroenterology. 2015;62(137):231-233.

Tumor Specimens from Metastatic GEA

• 68 paired GEA samples:

• 98.5% concordance of FISH and 95% concordance of IHC

• Only one case discordant; being negative in the primary and positive in the metastasis

• Given overall high degree of concordance, HER2 testing on neoplastic tissue from the primary or metastatic tumor is appropriate

40

Source: Bozzetti C, Negri FV, Lagrasta CA, et al.

Comparison of HER2 status in primary and

paired metastatic sites of gastric carcinoma. . Br

J Cancer. 2011;104(9):1372-1376.

Fine needle aspiration (FNA) or cytology specimen from primary or metastatic tumor

41

HER2 as a Prognostic Marker?

• Data are somewhat conflicting, but larger studies show no correlation with outcome

• Japanese cohort of 1006 patients • 836 HER2 negative, 112 HER2 positive

(defined as IHC 3+, FISH amplified) [948 undergoing curative resection]

• HER2 status correlated with older age, male gender, lower grade, and nodal status

• HR for recurrence was 1.109 (0.685-1.796), for cancer-related death 0.565 (0.262-1.219)

42

Source: Aizawa M, Nagatsuma AK, Kitada K, et al. Evaluation of

HER2-based biology in 1,006 cases of gastric cancer in a

Japanese population. Gastric Cancer. 2014;17(1):34-42.

HER2 as a Prognostic Marker?

43

Source: Grabsch H, Sivakumar S, Gray S, Gabbert HE, Muller W.

HER2 expression in gastric cancer: rare, heterogeneous and of no

prognostic value - conclusions from 924 cases of two independent

series. Cell Oncol. 2010;32(1-2):57-65.

Overall Survival in a Chinese Cohort (1562 cases)

Shen GC, et al. World J Gastroenterol 22(23):5406, 2016.

Recommendation 5

• Strong Recommendation: When GEA HER2 status is being evaluated, laboratories/pathologists should perform/order IHC testing first followed by ISH when IHC result is 2+ (equivocal). Positive (3+) or negative (0 or 1+) HER2 IHC results do not require further ISH testing.

• (Quality of evidence: High; Strength of recommendation: Strong)

45

46

Basis for Recommendation of IHC

• Patients with amplification by ISH without overexpression by IHC did not benefit from trastuzumab in ToGA

• Benefit of therapy appears to correlate with protein overexpression

• No need to test 0 and 1+ IHC with ISH (amplification rate is low (14-24%))

• IHC 3+ and ISH positivity concordance is high (>90%)

47

IHC 2+ cases should be tested with ISH

• 30-50% of IHC 2+ cases will show amplification (considered eligible for treatment)

• If there is uncertainty over whether score is 1+ or 2+, consider ISH

48

HER2 Status in ToGA ParticipantsTrastuzumab +

chemotherapy

(n=294)

Chemotherapy

alone (n=290)

FISH+/IHC 0 23 (8%) 38 (13%)

FISH+/IHC 1+ 38 (13%) 32 (11%)

FISH+/IHC 2+ 80 (27%) 79 (27%)

FISH+/IHC 3+ 131 (45%) 125 (43%)

FISH -/IHC 3+ 9 (3%) 6 (2%)

FISH +/IHC no result 5 (2%) 2 (1%)

FISH no result/IHC 3+ 8 (3%) 8 (3%)

49

Source: Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687-697.

50

Recommendation 7

• Recommendation: Pathologists should select the tissue block with the areas of lowest grade tumor morphology in biopsy and resection specimens. More than one tissue block may be selected if different morphologic patterns are present.

• (Quality of evidence: Moderate/Intermediate; Strength of recommendation: Recommendation/Moderate)

51

HER2 and Histologic Subtype

Site % HER2 +

Esophagus/GEJ 32%

Stomach 21%

52

Histologic Type % HER2 +

Intestinal ~ 25%

Diffuse 0-6%

Mixed 0-20%

Rare subtypes Limited data

HER2 and Grade

Grade % HER2 +

Low grade 15%-45%

High grade 6% to 28%

53

• Most studies do not specify grading criteria

• Select better differentiated tumor areas, or if highly

heterogeneous, consider testing more than one block

Recommendation 4

• Strong recommendation: Laboratories/pathologists must specify the antibodies and probes used for the test and ensure that assays are appropriately validated for HER2 IHC and ISH on GEA specimens.


54

Antibody Options

• Multiple antibodies available

• ToGA trial used HercepTest

• Many studies have used Ventana 4B5 or Thermo Fisher Scientific CB11

• Others are available

• Generally moderate to good concordance among antibodies

• No specific recommendation

55

56

Source: Abrahao-Machado

LF, Jacome AA, Wohnrath

DR, et al. HER2 in gastric

cancer: comparative

analysis of three different

antibodies using whole-

tissue sections and tissue

microarrays. World J

Gastroenterol.

2013;19(38):6438-6446.

Score HercepTest 4B5 SP3

0 or 1+ 94.5% 78.3% 73.7%

2+ 0.5% 10.1% 17.2%

3+ 5.1% 11.6% 9.1%

DAKO

CISH SISH

FISH

57

Validation of IHC and ISH

• Cases used for validation should predominantly be GEA cases

• CAP or CLSI guidelines for assay validation

• Method of sampling and fixative should be the same for validation and future use

• Use 20 positive and 20 negative specimens for FDA approved test and 40 of each for LDT

• Records of validation must be maintained per CAP

58

Recommendation 6

• Strong Recommendation: The pathologist should use the Ruschoff/Hofmann method in scoring HER2 IHC and ISH results for GEA.


59

Source: Hofmann M, Stoss O, Shi D, et al.

Assessment of a HER2 scoring system for

gastric cancer: results from a validation

study. Histopathology. 2008;52(7):797-805.

HER2 IHC

Score

HER2 IHC Pattern in

Surgical Specimen

HER2 IHC Pattern in Biopsy

Specimen

HER2 Expression

Assessment

0 No reactivity or membranous

reactivity in <10% of cancer cells

No reactivity or no membranous

reactivity in any cancer cell

Negative by IHC

1+ Faint or barely perceptible

membranous reactivity in ≥10%

of cancer cells; cells are reactive

only in part of their membrane

Cancer cell cluster* with a faint or

barely perceptible membranous

reactivity irrespective of

percentage of cancer cells positive

Negative by IHC

2+ Weak to moderate complete,

basolateral or lateral

membranous reactivity in >10%

of tumor cells

Cancer cell cluster* with a weak to

moderate complete, basolateral, or

lateral membranous reactivity

irrespective of percentage of cancer

cells positive

Equivocal by IHC

3+ Strong complete, basolateral or

lateral membranous reactivity in

≥10% of cancer cells

Cancer cell cluster* with a strong

complete basolateral, or lateral

membranous reactivity irrespective

of percentage of cancer cells

positive

Positive by IHC

* Cancer cell cluster consisting of ≥5 neoplastic cells

Source: Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology.

2008;52(7):797-805. 60

61

Source: Ruschoff J, Dietel M, Baretton G, et al. HER2 diagnostics in

gastric cancer-guideline validation and development of standardized

immunohistochemical testing. Virchows Arch. 2010;457(3):299-307.

62

Source: Ruschoff J, Dietel M, Baretton G, et al. HER2

diagnostics in gastric cancer-guideline validation and

development of standardized immunohistochemical testing.

Virchows Arch. 2010;457(3):299-307.

63

64

2+: moderate + in

>10% tumor cells

65

66

67

68

1+ or 2+?

69

1+: Faint

membranous + in

>10% of tumor

cells

70

71

Pitfalls in IHC Assessment

• Gastric intestinal metaplasia and epithelium next to ulcers

• Edge effect

• Non-specific granular and pericellular staining

• Diffuse cytoplasmic and/or nuclear staining

• Non-specific staining in marginated cytoplasm in signet ring cells

72

Non-Specific IHC

73

Intestinal Metaplasia with cytoplasmic and nuclear staining

74

Tumor Heterogeneity and Non-specific Nuclear staining

75

Extreme degree of heterogeneity

76

Tips to Increase Interobserver Agreement

• 3+: May be visible to naked eye; strong membrane + at low magnification using up to 5x objective

• 2+: Membrane expression first apparent using 10x objective

• 1+: Membrane expression at 40x objective

Membrane expression: distinct linear complete, basolateral, or lateral (not granular) expression at cell-cell contact sites

77

Source: Ruschoff J, Dietel M, Baretton G, et al. HER2 diagnostics in gastric

cancer-guideline validation and development of standardized

immunohistochemical testing. Virchows Arch. 2010;457(3):299-307.

Comparison of HER2 Scoring in GEA and Breast Carcinoma

Esophagogastric Breast

IHC Extent Biopsy > 5 cells; resection >10% > 30%

Circumferential Mostly missing Required for

IHC2+/3+

ISH Cell number 20 cohesive tumor cells showing

highest gene count

Same

Amplification HER2/CEP17 ≥ 2.0 is positive Same

HER2 + Tumor type ~ 30% intestinal type, 15% mixed

type, 5% diffuse type

15-25% G2/G3

ductal type;

special types

rarely +

Tumor location ~ 30% of GEJ, 15% gastric No correlation

78

Fluorescence In Situ Hybridization (FISH)

79

www.abbot

tmolecular.

com

Fluorescence In Situ Hybridization (FISH)

• HER2/CEP17 ratio <2.0 is considered not amplified (negative)

• HER2/CEP17 ratio ≥2.0 is considered amplified (positive)

80

81

http://www.intellmed.eu/www.spandidos-publications.com

Polysomy CEP 17

82

Sapino, A et. al. Front Onc, 2013

<2.0

<2.0

<2.0

<2.0

Polysomy scoring in ISH

• >6 copies of HER2 = positive

• <4 copies of HER2 = negative

• 4 to ≤6 copies of HER2 = count an additional 20 cells

• May use ancillary techniques:

• Multiplex ligation-dependent probe amplification

84

Additional Options For Indeterminate Scoring

• Consultation between scorer and pathologist

• Using an alternate probe for chromosome 17

• Select a different tumor block

• Use genomics or alternate method

85

Quality Assurance

• Assure adequate staining without:

• Background interference

• Overdigestion

• Other artifacts

Failure to detect probe signals in non-malignant cells can indicate poor quality hybridization

86

Technical issues = indeterminate

87

Recommendation 9

• Strong recommendation: Pathologists should identify areas of invasive adenocarcinoma and also mark areas with strongest intensity of HER2 expression by IHC in GEA specimen for subsequent scoring when ISH is required.


88

ISH Interpretation Pearls• Accurate ISH results scoring

depends on localizing:

• Areas of invasive tumor

• Areas of intense HER2 overexpression by IHC

• Morphology of the malignancy to select cells

89

ISH Interpretation Pearls

• Morphologic evaluation of ISH stains helps resolve problematic interpretations due to:

• Over or under fixation

• Delayed fixation

• Inadequate deparaffinization

• Protease digestion

90

Examples of Real Cases:IHC and FISH Correlation

91

Case 195

92

93

Case 195 IHC 2+

94

Case 102

Case 102: IHC 3+

Case 99

Case 99- IHC score 0;

trace in invasive tumor

Case 185 (Mixed diffuse and intestinal adenocarcinoma)

185 IHC 1+

Case # 278- only 2 biopsy fragments of tumor

Case 278- 2+ IHC

Recommendation 10

• Strong Recommendation: Laboratories must incorporate GEA HER2 testing methods into their overall laboratory quality improvement program, establishing appropriate quality improvement monitors as needed to assure consistent performance in all steps of the testing and reporting process. In particular, laboratories performing GEA HER2 testing must participate in a formal proficiency testing program, if available, or an alternative proficiency assurance activity.


107

Recommendation 11

• No Recommendation: There is insufficient evidence to recommend for or against genomic testing in GEA patients at this time.

108

• Polymerase chain reaction (PCR)

• Single nucleotide polymorphism (SNP) chip

• Comparative genomic hybridization (CGH) array

• Gene expression profiling by RNAseq or microarray

• Targeted/exome/whole genome sequencing

• Recent data showing 98% concordance of NGSwith HER2 IHC/FISH

(Ross DS, et al. J Mol Diagnostics 12(2):244-54, 2017)

• Quantitative proteomic analysis

109

Other techniques used to determine HER2 status

Recommendation 8

• Strong Recommendation: Laboratories should report HER2 testing results in GEA specimens in accordance with the CAP biomarker “Template for Reporting Results of HER2 (ERBB2) Biomarker Testing of Specimens From Patients With Adenocarcinoma of the Stomach or Esophagogastric Junction”.


110

Source: Bartley AN, Christ J, Fitzgibbons PL, et al. Template for reporting results of HER2 (ERBB2) biomarker testing of specimens from patients with

adenocarcinoma of the stomach or esophagogastric junction. Arch Pathol Lab Med. 2015;139(5):618-620.111

Turnaround Time

112

Turnaround Time

• Report HER2 results as promptly as possible

• Benchmark: 90% of reports within 10 working days from the date of procedure or specimen acquisition

• Send out testing: 90% of specimens sent to the reference laboratory within 3 working days of tissue processing

113

114

© 2016 College of American Pathologists. Materials are used with the permission of the faculty.

Summary

115


Summary

Future Directions

• Guideline will be reviewed every 4 years, or earlier as warranted as new data become available

116

Future Directions

117

• The JACOB (trastuzumab/pertuzumab) Study results are anticipated soon and it may change the paradigm

• Vaccine strategy using Her2 extracellular domain as the docking molecule for highly immunogenic sequences

• Bi-specific antibodies that may reduce secondary resistance and immune stimulation (including the innate immunity)


Future Directions

118

• More potent conjugates to include Her2 neu negative population (Her2 2+ but not amplified)

• Dual pathway inhibition by anticipating emerging resistance (other oncogenes like Her3, EGFR, IGF, c-MET to be targeted early on to prevent secondary resistance)


Pearls of Pathology

• HER2 testing is appropriate for advanced or metastatic GEA

• Guideline recommends use of IHC first, followed by ISH for 2+ cases

• Use the Ruschoff/Hoffman scoring system

• Scoring systems for HER2 in breast cancer are not appropriate for GEA

119© 2016 College of American Pathologists. Materials are used with the permission of the faculty.

References• Abrahao-Machado LF, Jacome AA, Wohnrath DR, et al. HER2 in gastric cancer: comparative analysis of three different

antibodies using whole-tissue sections and tissue microarrays. World J Gastroenterol. 2013;19(38):6438-6446.

• Aizawa M, Nagatsuma AK, Kitada K, et al. Evaluation of HER2-based biology in 1,006 cases of gastric cancer in a Japanese population. Gastric Cancer. 2014;17(1):34-42.

• Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687-697.

• Bartley AN, Christ J, Fitzgibbons PL, et al. Template for reporting results of HER2 (ERBB2) biomarker testing of specimens from patients with adenocarcinoma of the stomach or esophagogastric junction. Arch Pathol Lab Med. 2015;139(5):618-620.

• Bozzetti C, Negri FV, Lagrasta CA, et al. Comparison of HER2 status in primary and paired metastatic sites of gastric carcinoma. . Br J Cancer. 2011;104(9):1372-1376.

• Corso S, Giordano S. How can gastric cancer molecular profiling guide future therapies? Trends Mol Med. 2016;22(7):534-544.

• Grabsch H, Sivakumar S, Gray S, Gabbert HE, Muller W. HER2 expression in gastric cancer: rare, heterogeneous and of no prognostic value - conclusions from 924 cases of two independent series. Cell Oncol. 2010;32(1-2):57-65.

• Gullo I, Grillo F, Molinaro L, et al. Minimum biopsy set for HER2 evaluation in gastric and gastro-esophageal junction cancer. Endosc Int Open. 2015;3(2):E165-170.

• Guyatt GH, Oxman AD, Vist GE, et al; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendation. BJM. 2008;336(7650):924-926.

120


References• Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation

study. Histopathology. 2008;52(7):797-805.

• Inoue K, Fry EA. Aberrant splicing of estrogen receptor, HER2, and CD44 genes in breast cancer. Genet Epigenet. 2015;7:19-32.

• Janjigian YY, Werner D, Pauligk C, et al. Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA international collaborative analysis. Ann Oncol. 2012;23(10):2656-2662.

• Jiang H, Bai X, Zhao T, Zhang C, Zhang X. Fluorescence in situ hybridization of chromosome 17 polysomy in breast cancer using thin tissue sections causes the loss of CEP17 and HER2 signals. Oncol Rep. 2014;32(5):1889-1896.

• Junttila TT, Akita RW, Parsons K, et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. 2009;15(5):429-40.

• Okines AF, Thompson LC, Cunningham D, et al. Effect of HER2 on prognosis and benefit from peri-operative chemotherapy in early oesophago-gastric adenocarcinoma in the MAGIC trial. Ann Oncol. 2013;24(5):1253-1261.

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