What is HER2 positive breast cancer in 2018? Updated ASCO-CAP guidelines. Giuseppe Viale University of Milan European Institute of Oncology

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1 What is HER2 positive breast cancer in 2018? Updated ASCO-CAP guidelines Giuseppe Viale University of Milan European Institute of Oncology

2 Mission accomplished!

3 First alarming results Breast Intergroup (N9831) trial 1699 patients enrolled (IHC 3+) by local testing 355 (20.9%) not confirmed by central testing 813 cases enrolled as FISH-positive by local testing 97 (11.9%) cases were FISH-negative at central testing HERA trial 10,890 Patients screened at central lab 3132 (28.8%) not confirmed HER2 positive (Perez E, et al: JCO 24:3032, 2006) (Ruschoff J, personal comm)

4 The main causes? Technicalities Pre-analytical conditions Specificity and sensitivity of the assays Human factors Who is reading? Knowledge and consciousness

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6 ASCO/CAP 2007: Le fil rouge To avoid false-positive assessment of HER2 status By giving recommendations on the preanalytical and analytical steps of the assay By rising the thresholds for a positive assay IHC: >30% ISH: ratio >2.2

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8 ASCO/CAP 2013: Le fil rouge To avoid false-negative assessments of HER2 status Not to deny any patient a therapy that could eventually be effective and has a favorable safety profile we elected to err on the side of sensitivity rather than specificity, given the enormous benefit and low level of toxicities of anti-her2 therapy, especially trastuzumab

9 HER2 discordance rate ALTTO ( ) APHINITY ( ) BERENICE ( ) Screened 10,829 5, HER2 neg 1, % negative 14,6% 9,4% 10,6% NEOTRIP (2016- ) Screened 222 HER2 positive 5 (2.3%)

10 e-published May 30, 2018

11 ASCO/CAP 2018: Le fil rouge

12 Clinical Question 1

13 Clinical Question 1

14 Unusual staining patterns of HER2 by IHC can be encountered that are not covered by these definitions. In practice, these patterns are rare and if encountered should be considered IHC 2+ equivocal. As one example, some rare breast cancers (eg, micropapillary carcinomas) show IHC staining that is moderate to intense but incomplete (basolateral or lateral) and can be found to be HER2 amplified. Another example describes circumferential membrane IHC staining that is intense but within 10% of tumor cells.

15 Tumour cells with incomplete (basolateral) membrane staining

16 Complete membrane staining within 10% of tumor cells

17 What to do with <10% positive cells? Assess HER2 status by IHC and ISH in all the available blocks of the primary tumor And in the lymph node metastases (if any) If still <10%, then report on the actual % of HER2-positive tumor cells These patients could benefit most from rebiopsy in case of metastasis

18 In my clinical practice Repeat IHC on another block of the primary tumour Repeat IHC on lymph node metastasis (if any) Reflex ISH on the block with <10% positive cells

19 Clinical question 2: core vs surgery (In the absence of neo-adjuvant therapy) HER2 status may be assessed either on the core biopsy or the surgical specimen It is not recommended to order the test on both samples, with a few exceptions Conversion of HER2 status from core biopsy to surgical specimen Uncommon False-positive results Intratumoral heterogeneity

20 Intratumoral heterogeneity

21 Clinical Question 2: «must» or «may»?

22 Core positive/surgery negative: What to do? Very uncommon Tell your pathologist you are in troubles Candidate for a targeted treatment? Double check HER2 status Confirm with ISH on the core biopsy Re-stain simultaneously both the core and the surgical specimen in the same run Stain all available material (including lymph nodes)

23 If discordance is confirmed The patient would have been eligible for neoadjuvant anti-her2 therapy Adjuvant therapy is «precautionary» and tailored to the worst possible case scenario Favorable safety profile of anti-her2 therapy She is candidate for targeted therapy

24 Clinical Question 3

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26 Clinical Question 3

27 Clinical Question 4

28 Clinical Question 4

29 Clinical Question 4

30 Clinical Question 5

31 The double equivocal results If the HER2 test result is ultimately deemed to be equivocal, the oncologist may consider HER2-targeted therapy. A clinical decision to ultimately consider HER2-targeted therapy in such cases should be individualized on the basis of patient status (comorbidities, prognosis, and so on) and patient preferences after discussing available clinical evidence. ASCO/CAP 2013

32 NSABP Clinical Trials Overview Protocol B-47 (NCT ) A Randomized Phase III Trial of Adjuvant Therapy Comparing Chemotherapy Alone (Six Cycles of Docetaxel Plus Cyclophosphamide or Four Cycles of Doxorubicin Plus Cyclophosphamide Followed by Weekly Paclitaxel) to Chemotherapy Plus Trastuzumab in Women with Node patients: HR 0.98; p= 0.90 Positive or High-Risk Node-Negative HER2-Low Invasive Breast Cancer IHC must be 1+ or 2+ and the ratio of HER2 to chromosome enumeration probe 17 (CEP17) must be <2.0 or, if a ratio was not performed, the HER2 gene copy number must be <4 per nucleus

33 Clinical Question 5

34 In my clinical practice Count additional cells Have another reader to count Repeat ISH on another block of the primary tumour Repeat ISH on lymph node metastasis (if any) Do not use alternative chromosome 17 probes

35 Take home Targeted therapies fro HER2-positive breast cancer have dramatically changed the prognosis of the disease The accurate identification of candidate patients for targeted therapy is a primary goal of the multidisciplinary team Unveiling the mechanisms and the markers of response or resistance to the treatment is our next compelling goal