Adam M. Brufsky, MD, PhD, FACP
University of Pittsburgh School of Medicine

Key Takeaways

  • Approximately one-half of breast cancers classified as human epidermal growth factor receptor 2 (HER2)-negative show low HER2 expression (immunohistochemistry 1+ [IHC 1+] or IHC 2+ and in situ hybridization [ISH]-negative).
  • Early data suggest that new antibody-drug conjugates may be effective in targeting tumors with low HER2 expression; clinical trials are ongoing.
  • Trastuzumab does not benefit women without IHC 3+ or ISH-amplified breast cancer and therefore should not be added to treatment regimens for women with low HER2 expression.
  • Low HER2 expression appears to occur more frequently in hormone receptor-positive (HR+)/HER2-negative tumors than in triple-negative tumors.

Adam M. Brufsky, MD, PhD, FACP, is a professor of medicine at the University of Pittsburgh School of Medicine in Pennsylvania and the associate division chief of the Division of Hematology/Oncology in the Department of Medicine at the University of Pittsburgh School of Medicine. Dr Brufsky is the medical director of the Magee-Womens Cancer Program, associate director for clinical investigations, and codirector of the Comprehensive Breast Cancer Center at UPMC Hillman Cancer Center.

Under current treatment guidelines, breast cancer is categorized as HER2-positie or HER2-negative. However, some investigators now use the term HER2-low expression breast cancer in clinical trials and research.  What parameters define HER2-low breast cancer?

It is difficult to know exactly what HER2-low expression is. HER2-positivity is defined as a 3+ score by IHC and/or a positive ISH result; all other patients are considered to be HER2-negative.1 There is a “gray zone” between HER2-positive and HER2-negative disease: HER2-low. The standard definition for HER2-negative breast cancer per guidelines from the 2018 American Society of Clinical Oncology and College of American Pathologists is breast tumors with low expression of HER2, defined as IHC 1+ or IHC 2+, without amplification by ISH.1 Specifically, HER2-positive status is designated when there is evidence of protein overexpression or gene amplification in an area of the tumor comprises more than 10% of contiguous and homogeneous tumor cells.

Most published data and ongoing clinical trials have defined HER2-low expression as breast cancer with a HER2 IHC score of 1+ or 2+ with a negative ISH assay, according to currently used scoring systems.2 The clinical definition of HER2-low is largely dependent on the type of testing used and can only be applied with the standard IHC or ISH approach. Any parameters using other types of assays have not been formally established. Overall, approximately 70% of breast cancer cases are hormone receptor-positive (HR+) and HER2-negative.3 With the approaches currently used, up to 55% of breast cancers express low levels of HER2 in the absence of gene amplification.2

Are HER2-low tumors now considered a distinct subgroup of breast cancer?

HER2-low tumors arereally a gray area right now and more of a continuous variable. I do not think HER2-low should be considered a distinct subgroup or clinical entity per se, as it is more defined by testing. Investigations are ongoing to evaluate whether HER2-low has distinct characteristics that distinguish it from HER2-zero or HER2-enriched breast cancer. The reason for defining HER2-low is that multiple trials underway are assessing responses to breast cancer treatment based on HER2 status. We do know that specific types of HER2-enriched breast cancer respond very well to trastuzumab, for example, but that has not been the case for HER2-low tumors. So this is where we are in time — investigating why HER2-low status may be important when making treatment decisions.

Over the past decade, multiple retrospective analyses have investigated the prognostic significance of low HER2 expression and some have found low/moderate HER2 expression to be associated with worse outcomes.4-7 Overall, there is no solid evidence to date supporting low HER2 expression as an independent prognostic factor in breast cancer. Additional standardization is needed before low HER2 expression can be used as a routine biomarker for selecting therapy.

A recent pooled analysis of data from 4 clinical trials of women with breast cancer found that among 2310 tumors, 1098 (47.5%) were HER2-low and 1212 (52.5%) were HER2-zero. Of the HER2-low tumors, 64.0% were HR+ and 36.7% were HER2-zero tumors.8 These findings suggest that HER2-low breast cancer is significantly different from HER2-zero breast cancer with regard to HR status. In terms of considering HER2-low as a predictive factor and integral biomarker for trial eligibility, we know that patients with HER2-low tumors gained no benefit from adjuvant trastuzumab in the phase 3 NSABP-B47 trial ( Identifier: NCT01275677) that tested the addition of trastuzumab to standard adjuvant chemotherapy in early breast cancer.9

Trastuzumab deruxtecan adverse effects
Adverse effects commonly reported with trastuzumab deruxtecan include nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, and diarrhea.

Since the concept of HER2-low expression is relatively new, should HER2-negative women be retested? A study presented at the European Society for Medical Oncology (ESMO) Breast Cancer Virtual Congress 2021 assessed how tumor characteristics change between primary and recurrent tumors. Investigators found that 29% of recurrent breast cancer biopsies converted either from or to HER2-low expression.10 In primary tumors vs relapsed tumors, HER2-low expression was seen in 34% and 38% of tumors, respectively, while 15% of HER2-negative tumors switched to HER2-low status and 14% of HER2-low tumors switched to the HER2-negative designation. Specifically, the study found that 14% of triple-negative breast cancers with HER2-negative expression in the primary tumor converted to HER2-low expression?

The HER2-lowconcept is relatively new, and I do not believe in routine retesting. That said, an indication for retesting would be if a woman experiences a relapse and then has a biopsy.  We would retest the HER2 and HR status of recurrent breast cancer given that these can change from negative to positive and vice versa between the time of diagnosis of the primary tumor and the appearance of metastases. Currently, we are not going to retest patients just to re-evaluate HER2 status. At this point, testing for low HER2 would also not change therapy decisions, because we do not yet have targeted treatments for those patients.

As far as treatment is concerned, where does low HER2 expression fit into decision-making? Is a woman treated as if she is HER2-positive or HER2-negative?

If a patient has HER2-low expression, we treat her as if she is HER2-negative. In the NSABP-B47 trial, we found that adding trastuzumab to standard adjuvant chemotherapy did not improve invasive disease-free survival (IDFS) in patients with early-stage breast cancer and low HER2 levels.9 The study included patients with invasive primary breast cancer who had low HER2 expression, defined as a HER2 level of 1+ or 2+ on ISH or an IHC ratio of less than 2.0. These women were randomly assigned to receive standard adjuvant chemotherapy with or without the addition of 1 year of trastuzumab. At 5 years, the rate of IDFS was 89.8% in the trastuzumab group vs 89.2% for women treated with adjuvant chemotherapy alone. There was no significant difference in IDFS between the 2 groups, even after stratifying by IHC score 1+ vs 2+, number of positive lymph nodes, HR status, or chemotherapy regimen.

Have any other trials evaluated alternative treatment regimens in the HER2-low population?

As discussed, trastuzumab was evaluated in women with HER2-low, and the regimen did not improve outcomes. Trastuzumab deruxtecan, an antibody-drug conjugate, is being investigated in HER2-low, but the data are not yet available. It’s important to bear in mind that while the trastuzumab study was negative, patients may actually benefit from antibody-drug conjugates.
Results of a phase 1b trial of trastuzumab deruxtecan have shown promising antitumor activity in heavily pretreated patients with HER2-low advanced or metastatic breast cancer.11

Approximately one-half of the patients had IHC 2+ expression, one-half had IHC 1+ expression, and 87% of patients were HR+. The objective response rate was 37% and the median duration of response was 10.4 months.

For a more definitive answer, we await the results of a randomized phase 3 trial ( Identifier: NCT04494425) evaluating the efficacy, safety, and tolerability of trastuzumab deruxtecan vs investigator’s-choice chemotherapy in patients with HER2-low/HR+ breast cancer who have experienced disease progression on endocrine therapy in the metastatic setting. The estimated primary completion date is late 2022.

In addition, a phase 2 trial ( Identifier: NCT04553770) is currently investigating trastuzumab deruxtecan as monotherapy or in combination with anastrozole in patients with HER2-low/HR+ breast cancer. The trial is now recruiting patients.

This Q&A was edited for clarity and length.


  1. Wolff AC, Hammond MEH, 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. doi:10.1200/JCO.2013.50.9984
  2. Tarantino P, Hamilton E, Tolaney SM, et al. HER2-low breast cancer: pathological and clinical landscape. J Clin Oncol. 2020;38:1951-1962. doi:10.1200/JCO.19.02488
  3. Li C, Li X. Advances in therapy for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer patients who have experienced progression after treatment with CDK4/6 inhibitors. Onco Targets Ther. 2021;14:2929-2939. doi:10.2147/OTT.S298720
  4. Eggemann H, Ignatov T, Burger E, et al. Moderate HER2 expression as a prognostic factor in hormone receptor positive breast cancer. Endocr Relat Cancer. 2015;22(5):725-733. doi:10.1530/ERC-15-0335
  5. Gilcrease MZ, Woodward WA, Nicolas MM, et al. Even low-level HER2 expression may be associated with worse outcome in node-positive breast cancer. Am J Surg Pathol. 2009;33:759-767. doi:10.1097/PAS.0b013e31819437f9
  6. Birner P, Oberhuber G, Stani J, et al; for the Austrian Breast & Colorectal Cancer Study Group. Evaluation of the United States Food and Drug Administration–approved scoring and test system of HER-2 protein expression in breast cancer. Clin Cancer Res. 2001;7(6):1669-1675.
  7. Camp RL, Dolled-Filhart M, King BL, Rimm DL. Quantitative analysis of breast cancer tissue microarrays shows that both high and normal levels of HER2 expression are associated with poor outcome. Cancer Res. 2003;63(7):1445-1448.
  8. Denkert C, Seither F, Schneeweiss A, et al. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol. 2021;22(8):1151-1161. doi:10.1016/S1470-2045(21)00301-6
  9. Fehrenbacher L, Cecchini RS, Geyer CE Jr, et al. NSABP B-47/NRG oncology phase III randomized trial comparing adjuvant chemotherapy with or without trastuzumab in high-risk invasive breast cancer negative for HER2 by FISH and with IHC 1+ or 2. J Clin Oncol. 2020;38(5):444-453. doi:10.1200/JCO.19.01455
  10. Miglietta F, Griguolo G, Bottosso M, et al. HER2-low breast cancer: evolution from primary breast cancer to relapse. Ann Oncol. 2021;32(suppl 2):S21-S36. doi:10.1016/j.annonc.2021.03.018
  11. Modi S, Park H, Murthy RK, et al. Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ib study. J Clin Oncol. 2020;38(17):1887-1896. doi:10.1200/JCO.19.02318

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Reviewed December 2021