HER 2 Low Breast Cancer- Kalyan Kusum Mukherjee, Dattatreya Mukherjee Presented in Virtual Breast Cancer Congress 2020

1. EVOLVING CONCEPTS IN HER2 EVALUATION
IN BREAST CANCER: HETEROGENEITY,HER2-
LOW CARCINOMAS AND BEYOND
Dr Kalyan Kusum Mukherjee, MBBS, MD,FCCM,ECMO
Associate Prof and Head of dept of Medical Oncology
Head of the department clinical and translational research
Chittaranjan National Cancer Institute, India

2. ABOUT BREAST CANCER
 Conventional Histopathology is the dissesive factor for
treatment in breast cancer (BC).
 BC is divided into 4 sub groups: Luminal A, Luminal B,
Her 2 enriched and Triple negative (TNBC)
 This has predictive and prognostic importance

7. HER 2 TARGETED AGENTS

11. OUTLINES
 Documents the changes that have contributed to a
better evaluation of the HER 2 status in clinical
practice.
 Discuss the different scenarios encompasing HER
2 heterogeneity
 Complexity of HER 2 equivocal results
 HER 2 low BC
 HER 2 mutation.

12. MEASUREMENT OF HER 2: LATEST CLINICAL
GUIDELINES

15. HER 2 GUIDELINES
 When to test: Primary, recurrent and metastatic cancer, if
tissue sample available
 Acceptable methods: IHC, ISH (FISH and CISH)
 Other methods: PCR, ELISA, Southern blot, mRNA
assay and DNA microarray.(Used for research only)
 Which specimen: Core biopsy or surgical specimen

16. IHC RULES:

19. EVALUATION OF HER 2 AMPLIFICATION ASSAY

23. HETEROGENEITY

24. HETEROGENEITY AND ANTI-HER2
THERAPIES

25. HETROGENEITY (CONTD..)
 3 distinct type of HER 2 status described
1. Clastard 2. Mosaic 3. Scattered
HER 2 generic heterogeneity in BC is more common in
equivocal status in IHC, ISC
 Most probably HER 2 heterogeneity is a cause of equivocal
HER 2 results.
 Increased frequency of chromosome 17 polysomi is seen.
 Is associated with worst patient outcome in terms of DFS
and OS.
 Less response to anti HER 2 therapy. And this group should
be different therapeutic approach.

26. OPTIMIZATION OF HER2 TESTING TO
GUIDE TREATMENT DECISIONS

27. SUMMARY OF HER2 FISH RESULTS IN 1044
HER2 IHC EQUIVOCAL CASES ACCORDING TO THE
ASCO®/CAP 2007, 2013, AND 2018 GUIDELINES

28. SUMMERY FOR HER2 ASCO/CAP NEW GUIDELINES

29. HER 2 LOW BREAST CARCINOMA- A NEW ENTITY IN
THE FIELD

30. HER 2 LOW CONTD…..
 2018 ASCO CUP update shows tumor driven by
HER 2 oncogene addiction benefit from the
addition of Trastuzumab to chemotherapy

31. WHAT IS HER 2 LOW

32. HER 2 NEG. BC

34. BENEFIT OF ANTI HER 2 THERAPY

35. NSABP B-31: QUESTIONED POTENTIAL
BENEFIT OF TRASTUZUMAB IN HER2-
NEGATIVE POPULATION

36. NSABP B-47: ADJUVANT
TRASTUZUMAB FOR HER2-LOW BC

37. CONTD…

38.  About 55% of BCs express low levels of HER2 in
the absence of gene amplification
 HER2-low are either ER+ or ER– (less frequent)
 NSABP B-47 demonstrated that adjuvant
trastuzumab is not effective in these tumours, likely
due to their low or absent addiction to HER2
signalling. Similarly, other agents disrupting the
HER2 pathway have shown modest activity in
HER2-low tumours

39. A paradigm shift in the definition of HER2 status in breast cancer

41. HER 2 MUTATION:

42. CONT
 Through NGS it has come to light that breast carcinoma
can harbor HER 2 activating mutations along with gene
amplification.
 HER 2 somatic mutation (Less prevalent) frequently
occur on HER 2 neg. or Her 2 low BC.
 Majority of cases, Her 2 mutation affect actions 19-20
coding TK domain and remaining relate to axon 8 extra
cellular domain.
 The most common mutation are L755S, V777L and
D79H/Y. These are misscence mutation of the kinase
domain of the protein. PI3KC is the most common co
mutated gene in HER 2 mutation. L755S mutation is
resistance to Lapatinib. Irreversible HER 2 EGFR TKI
Niratinib inhibit the proliferation of cell bearing all
mutations.

43. PREVALENCE, DISTRIBUTION AND SIGNIFICANCE OF
HER 2 SOMATIC MUTATION
 HER 2 mutation also causes resistance to anti Her
2 therapeutic compound.

44. CONCLUSION:
 Assessment of Her 2 is key to treatment decision
making for BC patients
 Heterogeneity of HER 2 may hamper the correct
identification of two responders to anti HER 2
agents.
 Transcriptomic analysis may identify HER 2
enriched Carcinoma that is highly sensative to anti
HER 2 therapy
 HER 2 mutation are emerging as important
molecular alterations

45. CONTD..
 The dichotomous def of Her 2 pos vs Her 2 neg
disease is currently experiencing in wave of
changes by identifying HER 2 low category.
 New therapeutic compound in the form of antibody
drug conjugates may be effected

46. ACKNOWLEDGEMENT
 Dattatreya Mukherjee, MBBS student and
Undergraduate Medical Researcher of Jinan
University helps in scientific writing
 ESMO pro e learning and ASCO e learning
materials

47.  THANK YOU