Author: Cornflower
This article is published with the author’s permission by Yiliao Tong. Please do not reproduce without authorization.
Human epidermal growth factor receptor 2 (HER2) positive breast cancer is a highly aggressive molecular subtype with poor prognosis. The advent of anti-HER2 targeted therapies has significantly improved its prognosis.
Currently, international standards generally consider that only patients with immunohistochemistry (IHC) testing of 3+, indicating HER2 protein overexpression, or those with IHC testing of 2+ who are found to have HER2 gene amplification positive via in situ hybridization (ISH) are classified as “HER2 positive breast cancer.” If the IHC test is 2+ but ISH is negative, or if the IHC test is 1+, these breast cancers, despite having HER2, are classified as “HER2 negative breast cancer.”
In terms of proportions, breast cancers that truly do not detect HER2 account for only about 30-40% of all breast cancers. Currently recognized HER2 positive breast cancers account for about 15-20%, while the remaining approximately 50% are referred to as “HER2 low-expressing breast cancers”[1].
Previously, for various reasons, the medical community did not classify “HER2 low-expressing breast cancer” as a distinct subtype of breast cancer. However, with the rapid advancements in drug development in recent years, HER2 targeted therapies are expected to break through bottlenecks, allowing low-expressing HER2 to become a treatment target, thus providing these patients with hope of escaping the dilemma of having no available treatments. Recently, a study published in The Lancet showed that through IHC testing, HER2 low-positive tumors can be identified as a new subtype of breast cancer distinct from HER2 zero-expressing tumors, improving treatment options for patients with treatment resistance and hormone receptor negative (HR-) tumors[2].
In this study, experts hypothesized that HER2 low-expressing tumors (IHC1+ or IHC2+/ISH negative) have different biological and clinical prognostic characteristics compared to completely HER2 negative tumors (HER2 IHC0). They combined biological parameters from patients receiving neoadjuvant treatment in four prospective clinical trials (GeparSepto, NCT01583426; GeparOcto, NCT02125344; GeparX, NCT02682693; Gain-2, NCT01690702), including hormone receptor status, tumor proliferation, tumor-infiltrating lymphocytes (TIL), and clinically relevant somatic and germline mutations to explore potential other subtypes of HER2 low-expressing tumor patients.
In this pooled analysis of individual patient data, experts analyzed 2310 patients with primary breast cancer without HER2 gene amplification from the aforementioned four studies. All enrolled patients had previously received traditional or dose-dense anthracycline-taxane chemotherapy and had no history of anti-HER2 treatment. HER2 testing was conducted at a central laboratory before patient enrollment. According to the guidelines of the American Society of Clinical Oncology/American Society of Pathology, patients with HER2 low-positive status were defined as IHC1+ or IHC2+/ISH negative, while HER2 (0) was defined as IHC 0. Additionally, the laboratory assessed patients’ estrogen receptor, progesterone receptor, Ki-67, and TIL.
The results showed that compared to HER2 zero-expressing tumor patients, HER2 low-positive tumor patients had a significantly lower pathological complete response rate (pCR) (29.2% vs. 39.0%, P=0.0002); in the hormone receptor positive subgroup, the pCR rate of HER2 low-positive patients was significantly lower than that of HER2 zero-expressing tumor patients (17.5% vs. 23.6%, P=0.024); there was no difference in the hormone receptor negative subgroup (50.1% vs. 48.0%, P=0.21).
HER2 low-positive tumor patients had a significantly longer survival than HER2 zero-expressing tumor patients (3-year disease-free survival rate: 83.4% vs 76.1%, 3-year overall survival rate: 91.6% vs 85.8%). Similar survival differences were observed in hormone receptor negative tumor patients (3-year disease-free survival rate: 84.5% vs 74.4%, 3-year overall survival rate: 90.2% vs. 84.3%). No significant differences were shown in the hormone receptor positive subgroup.
The results indicate that HER2 low-positive tumors can be identified as a new subgroup of breast cancer through standardized IHC, distinct from HER2 zero tumors. HER2 low-positive tumors exhibit specific biological characteristics and show differences in response to treatment and prognosis, particularly related to treatment resistance and hormone receptor negativity. Currently, the use of anti-HER2 drugs is limited to patients with HER2 positive tumors; however, this experiment suggests that antibody-drug conjugates can effectively treat more breast cancer patients, such as those with HER2 low expression.
Other Potential Treatment Options for HER2 Low-Expressing Breast Cancer
1. DS-8201a
DS-8201a is an antibody-drug conjugate (ADC). In the phase II DESTINY-Breast 01 trial, DS-8201a showed significant survival benefits in treating HER2 positive advanced breast cancer[3]. Therefore, there is great anticipation for its efficacy in the HER2 low-expressing breast cancer population.
In February 2020, the Journal of Clinical Oncology published results from a phase Ib clinical trial of DS-8201a in HER2 low-expressing populations. This study included 54 HER2 low-expressing breast cancer patients confirmed by central laboratory who had undergone multiple lines of treatment (the median number of previous cancer regimens was 7.5 lines), and these patients received at least one dose of DS-8201a (at doses of 5.4 or 6.4 mg/kg). The results showed that the objective response rate (ORR) of DS-8201a reached 37%, the disease control rate (DCR) was as high as 87%, the duration of response (DOR) was 10.4 months, and the median progression-free survival (PFS) was 11.1 months, with tumors continuing to shrink. The main adverse reactions were gastrointestinal and hematological toxicities, with a 1.9% incidence of grade 5 interstitial pneumonia adverse events[4].
With nearly 37% efficacy in patients who were resistant after a median of 7.5 lines of treatment, this indicates that DS-8201a has outstanding anti-tumor effects for HER2 low-expressing breast cancer patients, providing a new treatment avenue for this population beyond conventional chemotherapy and endocrine therapy. A multicenter, randomized, open-label phase III trial comparing DS-8201a to chemotherapy for HER2 low-expressing advanced breast cancer, DESTINY-Breast 04, is currently underway, expected to complete in early 2023[5].
2. SYD985
SYD985 is another ADC drug under investigation. In 2018, early study data was reported for treating advanced HER2 low-expressing breast cancer patients. The overall ORR for 50 treated patients was 33%, with a median PFS of 9.4 months, where the ORR for hormone receptor positive patients was 27%, and for hormone receptor negative breast cancer patients, the ORR was 40%[6]. SYD985 is currently being explored for its efficacy in early HER2 low-expressing breast cancer patients for neoadjuvant treatment.
3. Tumor Vaccines
Entering the era of immunotherapy, tumor vaccines are also a hot frontier concept. Unlike preventive cancer HPV vaccines, therapeutic tumor vaccines introduce signals from cancer cell surface antigens, such as parts of the HER2 protein, into the patient’s body to activate immune cells to produce a strong anti-tumor immune response, thereby eliminating HER2-expressing cancer cells. Currently, various vaccines for HER2 breast cancer patients are under investigation, including some studies targeting low-expressing patients.
For example, a phase II clinical study of the antigen peptide E75, combined with trastuzumab and granulocyte colony-stimulating factor (G-CSF) as postoperative adjuvant therapy for early breast cancer patients with HER2 low expression and high-risk factors, was able to reduce the postoperative recurrence risk in hormone receptor negative patients, with a 2-year disease-free survival rate of 92.6% in the treatment group, higher than the control group’s 70.2%[7].
For a long time, traditional breast cancer classification has been based on hormone receptor positive, HER2 negative, HER2 positive, and triple-negative classifications. This study supports the view that there are other clinically relevant subtypes of breast cancer. Now, these new subtypes can be distinguished through standardized pathological assessments of hormone receptors and HER2, especially bringing new treatment strategies for HER2 low-expressing patients. This research delineates a more complex biological classification of breast cancer but also provides more precise targets for breast cancer targeted therapy, laying a solid foundation for improving future diagnosis and treatment strategies.
References:
1. Tarantino P, Hamilton E, Tolaney S M, et al. HER2-Low Breast Cancer: Pathological and Clinical Landscape[J]. Journal of Clinical Oncology, 2020, 38(17): 1951-1962.
2. 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 Aug;22(8):1151-1161. doi: 10.1016/S1470-2045(21)00301-6. Epub 2021 Jul 9. PMID: 34252375.
3. Modi S et al. N Engl J Med. 2020 Feb 13;382(7): 610-621.
4. Modi S et al. J Clin Oncol. 2020 Jun 10;38(17):1887-1896.
5. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03734029.
6. Saura C, Thistlethwaite F, Banerji U, et al. A phase I expansion cohorts study of SYD985 in heavily pretreated patients with HER2-positive or HER2-low metastatic breast cancer[J]. Journal of Clinical Oncology, 2018, 36(15_suppl): 1014.
7. Final analysis of nelipepimut-S plus GM-CSF with trastuzumab versus trastuzumab alone to prevent recurrences in high-risk, HER2 low-expressing breast cancer: A prospective, randomized, blinded, multicenter phase IIb trial[J]. Journal of Clinical Oncology, 2019, 37(8_suppl): 1.
