Breast

Other carcinoma subtypes, not WHO classified

HER2 low breast cancer



Last author update: 6 February 2024
Last staff update: 6 February 2024

Copyright: 2022-2024, PathologyOutlines.com, Inc.

PubMed search: HER2 low breast cancer

Doaa Atwi, M.D.
Lewis A. Hassell, M.D.
Page views in 2023: 493
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Cite this page: Annan AC, Atwi D, Hassell LA. HER2 low breast cancer. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/breastHER2lowbreastcancer.html. Accessed April 14th, 2024.
Definition / general
  • HER2 low breast cancer is defined as either HER2 IHC score of 1+ or 2+ / ISH not amplified
Essential features
  • HER2 low breast cancer is defined as either HER2 IHC score of 1+ or 2+ / ISH not amplified
  • Heterogenous group that includes hormone receptor positive and triple negative breast cancers
  • Per 2023 American Society of Clinical Oncology (ASCO) / College of American Pathologists (CAP) guidelines, interpretation for HER2 low is not recommended in the final pathology report at this time
Terminology
  • HER2 negative by IHC (score 1+)
  • HER2 equivocal by IHC (score 2+) and HER2 ISH not amplified
Clinical features
  • Nearly half (~55 - 60%) of breast cancer patients will fit in HER2 low category
  • Heterogenous group that includes hormone receptor positive and triple negative breast cancers
  • Reference: Nat Med 2022 Jun 16 [Epub ahead of print]
Interpretation
  • 2023 ASCO / CAP update on HER2 IHC and FISH interpretation still follows the 2018 ASCO / CAP guidelines (J Clin Oncol 2023;41:3867)
  • HER2 IHC with a score of 0 or 1+ is still interpreted as negative, while score of 2+ is reported as equivocal with a reflex FISH test (please see also HER2 stain topic)
  • However, the 2023 ASCO / CAP update recommends addition of a footnote to HER2 IHC interpretation report to address HER2 low results and the potential eligibility / benefit for these patients with the new class of ADC drugs (see Sample pathology report below for ASCO / CAP recommended footnote)
  • See 2023 ASCO / CAP update on HER2 testing in breast cancer (Arch Pathol Lab Med 2023;147:993)
  • See 2018 ASCO / CAP update on HER2 testing in breast cancer (J Clin Oncol 2018;36:2105)
Uses by pathologists
  • HER2 IHC positive (score 3+)
  • HER2 IHC equivocal (score 2+) with reflex to HER2 ISH
  • HER2 IHC negative (score 0 or 1+)
  • Per 2023 ASCO / CAP guidelines, interpretation for HER2 low is not recommended at this time
  • Reference: Nat Med 2022 Jun 16 [Epub ahead of print]
Prognostic factors
Treatment
  • HER2 targeted monoclonal antibodies have not shown benefit in HER2 low breast cancer
  • New class of HER2 monoclonal antibodies conjugated with a chemotherapy drug has been developed recently (antibody drug complex, ADC)
  • Bystander effect / killing of ADC: HER2 antibodies target the covalently linked cytotoxic drugs to HER2 expressing cancer cells and kills them; these cytotoxic drugs are then released into extracellular space that are then uptaken by surrounding non-HER2 expressing cancer cells
  • ADCs have shown benefit in HER2 low breast cancer in phase I / II clinical trials (Nat Med 2023;29:2110, J Clin Oncol 2020;38:1887)
  • Phase 3 DESTINY-Breast04 trial shows increased median progression free survival (PFS) in patients receiving trastuzumab deruxtecan with advanced breast cancer (either unresectable or in a metastatic disease setting) (N Engl J Med 2022;387:9)
  • DESTINY-Breast04 trial also shows the risk of disease progression / death is 50% lower in treatment group compared to control arm
Microscopic (histologic) images

Contributed by Anand C. Annan, M.D., Ph.D., Doaa Atwi, M.D. and Lewis A. Hassell, M.D.
Invasive ductal carcinoma, Nottingham grade 2

Invasive ductal carcinoma, Nottingham grade 2

HER2 score 2+

HER2 score 2+

Invasive ductal carcinoma, grade 2

Invasive ductal carcinoma, grade 2

HER2 score 2+

HER2 score 2+

HER2 IHC score 1+ HER2 IHC score 1+

HER2 IHC score 1+


Invasive ductal carcinoma with cord and tubule formation Invasive ductal carcinoma with cord and tubule formation

Invasive ductal carcinoma with cord and tubule formation

HER2 IHC score 1+ HER2 IHC score 1+ HER2 IHC score 1+

HER2 IHC score 1+

Molecular / cytogenetics images

Contributed by Terry Dunn, Ph.D.
Nonamplified HER2 FISH

Nonamplified HER2 FISH

Sample pathology report
  • Breast, left, ultrasound guided core needle biopsy:
    • Invasive breast carcinoma of no special type (ductal), grade 2
      • Estrogen receptor: positive (90%, strong intensity)
      • Progesterone receptor: positive (70%, intermediate intensity)
      • HER2 by IHC: negative (score 1+) (see comment)
    • Comment: Patients with breast cancers that are HER2 IHC 3+ or IHC 2+ / ISH amplified may be eligible for several therapies that disrupt HER2 signaling pathways. Invasive breast cancers that test HER2 negative (IHC 0, 1+ or 2+ / ISH not amplified) are more specifically considered HER2 negative for protein overexpression / gene amplification despite having some level of protein expression. Patients with breast cancers that are HER2 IHC 1+ or IHC 2+ / ISH not amplified may be eligible for treatment with a cytotoxic drug regimen that targets nonamplified / nonoverexpressed levels of HER2 (IHC 0 results do not currently result in eligibility).
Board review style question #1

According to the current 2023 update of American Society of Clinical Oncology (ASCO) / College of American Pathologists (CAP) guidelines for HER2 interpretation in breast cancer, how should the IHC result (see image above) be interpreted in a pathology report?

  1. HER2 negative (score 0)
  2. HER2 negative (score 1+)
  3. HER2 low positive (score 1+)
  4. HER2 positive (score 3+)
Board review style answer #1
B. HER2 negative (score 1+). The above IHC for HER2 shows faint / incomplete staining for HER2 in > 10% of tumor cells and is therefore interpreted with a score of 1+. Answer D is incorrect because as per the 2023 ASCO / CAP update, this IHC result should still be HER2 negative. Answer A is incorrect because tumors demonstrating HER2 IHC score 0 expression show no staining or ≤ 10% incomplete, faint / barely perceptible staining. Answer C is incorrect because although this is considered HER2 low positive, ASCO / CAP guidelines do not recommend using this terminology in the pathology report at this time. See 2023 ASCO / CAP update on HER2 interpretation (J Clin Oncol 2023;41:3867).

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Reference: HER2 low breast cancer
Board review style question #2
What is the current understanding of the prognostic implication of HER2 low positive breast cancer patients?

  1. HER2 low breast cancer patients with an IHC score of 2+ have a better prognosis that those with an IHC score of 1+
  2. There is no definite evidence of distinct prognostic implications
  3. They have a better prognosis than HER2 negative (score 0) patients
  4. They have a poorer prognosis than HER2 negative (score 0) patients
Board review style answer #2
B. There is no definite evidence of distinct prognostic implications. Answers A, C and D are incorrect because although there is some evidence in the literature that shows poorer prognoses for HER2 low patients compared to HER2 negative (score 0) patients, there is no distinct prognostic or predictive implications for HER2 low status.

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Reference: HER2 low breast cancer
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