The emergence of new ADC drugs has broken the traditional perception that only HER2-positive breast cancer patients can benefit from anti-HER2-targeted treatment in the past 20 years.

Figure 1. Exploration of monoclonal antibody and TKI in HER2-low-expressing breast cancer

Figure 2. Retrospective analysis showed that T-DM1 has limited efficacy in HER2-negative breast cancer

Because previous HER2-low-expressing breast cancer lacks targeted treatment methods, it is often referred to the treatment strategies of HR+/HER2- and triple-negative breast cancer (TNBC), but the overall ≥2-line treatment benefits were limited ^[1,2]. For most HR+/HER2-breast cancer patients, the first and second lines are endocrine or endocrine combined with CDK4/6 inhibitors as the standard treatment option. There are fewer treatment options after endocrine therapy resistance, mostly mainly chemotherapy, and the median progression-free survival (PFS) is only 4-4.2 months. For patients with advanced TNBC, median PFS with first-line single-agent chemotherapy or combined chemotherapy is not ideal (4-11 months). Although immunotherapy for has improved the treatment benefits of patients with advanced TNBC to a certain extent, it is only effective for patients with positive PD-L1 expression. Although PARP1 inhibitors can be selected in patients with BRCA1/2 germline mutations, the BRCA1/2 mutation rate in TNBC is not high (about 12%), which suggests that immunotherapy and targeted therapy benefit in TNBC is relatively limited.

At present, chemotherapy still occupies an important position in the field of TNBC treatment, but the median PFS for second- and third-line chemotherapy is about 4-4.2 months, and the median PFS for the promising Trop-2 targeted ADC drug≥2 line treatment was only 5.6 months. From this point of view, whether it is the HR+/HER2- or TNBC population, new treatment strategies need to be explored to further improve the treatment benefits of patients. In fact, more than half of HER2-negative breast cancers have HER2-low expression patients ^[4]. In the above context, patients with low HER2 expression of breast cancer can benefit from anti-HER2 treatment, which will greatly improve the unmet treatment needs of HER2-negative populations.

Figure 3. Classic treatment strategies in HR+/HER2- or TNBC

The new generation of ADC drugs -

The breakthrough in achieving HER2 low expression Individualized treatment

The new ADC drug T-DXd is still effective in heterogeneous tumors based on high active drug loading, high drug antibody ratio (DAR) and strong bystander effects. Early data show great therapeutic potential. In the DS8201-A-J101 study ^[5], 54 patients with low HER2 expression of breast cancer were included, with a median treatment line of up to 7.5 lines. Despite this, the centrally evaluated ORR and median PFS were still observed at 37.0% and 11.1 months, respectively. This study data has made a major breakthrough in the treatment of breast cancer with low expression of HER2.

Figure 4. Early data show that the effectiveness of T-DXd in patients with HER2 low-expression advanced breast cancer

multiline treatment

based on the good treatment benefits of T-DXd in the DS8201-A-J101 study. The investigator designed the DB04 clinical trial ^[6]. This study aims to evaluate the efficacy and safety of T-DXd in patients with low HER2 expression (IHC 1+ or IHC 2+/ISH-), unresectable and/or metastatic breast cancer (HR-positive patients must be resistant to endocrine therapy or are not suitable for endocrine therapy) compared with physician-selected chemotherapy (TPC). The results showed that in terms of PFS of HR-positive patients at the primary endpoint, the T-DXd group had a significant benefit compared with the TPC group. The median PFS in the two groups were 10.1 months and 5.4 months, respectively, reducing the risk of disease progression by 49% (HR=0.51, 95% CI, 0.40-0.64, P0.0001). The median OS of the two groups was 23.9 months and 17.5 months, respectively, and there were also significant statistical differences (HR=0.64, 95% CI, 0.48-0.86, P=0.0028).

Figure 5. PFS and OS benefits of HR+/HER2 low patients in DB04 study

In terms of exploratory endpoints, the median PFS in the T-DXd group was 8.5 months, which was significantly longer than 2.9 months in the chemotherapy group (HR=0.46, 95% CI, 0.24-0.89). Median OS also showed the same benefit trend, with the two groups being 18.2 months and 8.3 months (HR=0.48, 95% CI, 0.24-0.95).

Figure 6. PFS and OS benefits of HR-/HER2 low patients in DB04 study

DB04 is the first phase III clinical study conducted in HER2 low-expression breast cancer. Based on this result, as early as April 27, 2022, the FDA awarded T-DXd breakthrough therapy certification for the treatment of unresectable or metastatic breast cancer with low-expression (IHC 1+ or IHC 2+/ISH negative). The major results of DB04 research were officially announced at the 2022 ASCO Plenary Conference, and were published simultaneously in the "New England Journal of Medicine". Subsequently, the 2022 NCCN V4 Breast Cancer Guidelines ^[1] is rapidly updated, and T-DXd is recommended for HER2 IHC 1+ or 2+/ISH-, patients with tumors who have received at least first-line chemotherapy due to metastatic disease, and patients with HR-positive and resistant to endocrine therapy (Class 1 evidence). On July 5, 2022, ASCO's official website released an update instructions on the HER2-negative breast cancer guidelines, suggesting that patients with low HER2 breast cancer should be given T-DXd treatment. The rapid update of authoritative guidelines suggests that T-DXd has become the standard treatment option for HER2-low-expressing advanced breast cancer.

Figure 7. DB04 was published simultaneously in ASCO and NEJM, obtained the FDA breakthrough therapy certification, and NCCN and ASCO guidelines recommended for HER2 low-expression breast cancer

. Based on existing research, the development direction of HER2 low-expression breast cancer clinical treatment

01 HER2 breast cancer dichotomy has entered the era of third-partition

Previous HER2 positive standards According to the definition of the therapeutic efficacy of trastuzumab, patients who cannot benefit from trastuzumab are defined as HER2 negative. Under this traditional conceptual understanding, although HER2 low expression accounts for about 45%-55% of total breast cancer ^[7], due to the lack of targeted treatment methods and the unclear significance of clinical and biological , HER2 low expression is not clinically considered as a special subtype. In fact, the concept of low expression of HER2 has been proposed very early. Based on the original HER2 negative definition, patients with IHC 1+ or IHC 2+ and ISH negative are defined as low expression of HER2, while IHC result is 0, which is defined as zero expression of HER2 [8].

Based on HER2 low expression patients, patients with low HER2 expression have shown that they can benefit from the treatment of novel ADC drugs in early studies, and low HER2 expression has gradually received attention. The success of the DB04 study has fully confirmed the status of low HER2 expression as clinical treatment classification. After more than 20 years of exploration, it has finally had individualized targeted therapy, which shows that HER2-expressed breast cancer, which is oriented towards clinical treatment, will officially move from dichotomy to a new era of trigrams. Individualized treatments with low expression of HER2 will also be conducted in more in-depth exploration, including new drugs and deployment and joint applications with endocrine therapy, immunotherapy, chemotherapy and other targeted therapies.

02 Pathological detection requires accurate distinction between HER2 low expression and HER2 zero expression

In current pathological practice, HER2 detection is still based on dichotomy detection and scoring system, so most pathologists pay more attention to HER2 IHC 2+ or 3+, and there is a lack of precise identification of IHC 0 and 1+. In a study using the current standard HER2 test ^[9], using data from the American Academy of Pathology (CAP) from more than 1,400 laboratories around the world, the results showed that the current standard HER2 test had poor evaluation consistency for 0 and 1+ cases, at only 26%. And the study found that the inconsistency between 0 and 1+ is significantly greater than between 2+ and 3+.

Although the film reading experts have only 58% consistency of 2+ and 3+, their clinical impact is not great, because 2+ cases need to pass ISH testing before treatment to guide the formulation of treatment decisions, while 0 and 1+ cases do not have such a interpretation verification process. This result shows that the accurate distinction between 0 and 1+ cases needs to be taken seriously. As the treatment benefits of T-DXd in patients with low HER2 expression of breast cancer have been fully verified, it is becoming increasingly important to distinguish between IHC 0 and 1+. Under this trend, to achieve accurate detection of low expression of HER2, new requirements have been put forward for sample sampling, detection process, detection methods and film reading.

03 HER2 is a continuous variable . The cut-off value of HER2 low expression needs to be clarified

Not only that, the expression of HER2 is increasingly considered a continuous variable, and further exploration is still needed on the cut-off value of HER2 low expression.

DAISY study published by SABCS in 2021 ^[10] shows that T-DXd not only has significant efficacy against HER2-positive and HER2-low-expressing breast cancer, but also shows good therapeutic activity in IHC 0 patients. The median PFS was 4.2 months and the optimal response rate (BOR) was 29.7%. It should be noted that from the definition of IHC 0 (no staining or ≤10% of infiltrated cancer cells presenting incomplete and weak cell membrane staining), this type of patients is not that HER2 is not expressed at all, but that a considerable number of patients are expressed at lower levels of HER2. The research results show that even such patients can benefit from the treatment of T-DXd. Therefore, it is necessary to explore cut-off values ​​of low HER2 expression, providing more patients with opportunities to benefit from the treatment of novel ADC drugs.

In addition, further exploring the therapeutic activity of T-DXd in breast cancer patients with extremely low expression of HER2 (IHC 0 to 1+) is underway. Relevant research results may indicate an important direction for clarifying the cut-off value of HER2 low expression, and are expected to further promote the precise stratification of T-DXd beneficiaries.

novel ADC drug has shown unprecedented therapeutic benefits in HER2-low-expressing breast cancer and has broad application prospects. However, this also means that the current clinical typing treatment strategies and HER2 detection models need to be adjusted to a greater extent, which requires clinical experts and pathologist to collaborate with each other to achieve the benefit of more precise treatment of breast cancer patients in the new era of treatment typing.

Expert Profile

Hu Xichun Professor

Director of the Department of Oncology, Executive Deputy Director of the Clinical Trial Institution, Doctoral Supervisor

ESMO Breast Cancer Faculty Member

ABC5 panelist

China Anti-cancer Association Multiple primary and unknown primary tumor committee Chairman of the Chinese Medical Association Tumor Branch Vice Chairman of the Oncology Medical Committee

Shanghai Chemotherapy Quality Control Center

China Research Hospital Society Breast Committee Deputy Chairman of the Breast Committee

China Anti-cancer Association Breast Cancer Committee Standing Committee and Secretary-General

Shanghai Anti-cancer Association Cancer Rehabilitation and Palliative Care Committee Chairman

National Food and Drug Administration Review Center Review Expert

National Food and Drug Administration Review Center Review Expert

References:

[1]NCCN Clinical Practice Guidelines in Oncology:Breast Cancer(Version 4.2022)

[2] Guidelines and Specifications for Breast Cancer Diagnosis and Treatment of Chinese Anti-Cancer Association (2021 Edition)

[3] Expert Consensus on BRCA1/2 Gene Detection and Clinical Application of Chinese Breast Cancer Patients (2018 Edition)

[4]Tarantino P, Jin Q, Tayob N, et al. Prognostic and Biologic Significance of ERBB2-Low Expression in Early-Stage Breast Cancer. JAMA Oncol. 2022 Jun 23.

[5]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 Jun 10;38(17):1887-1896.

[6]S. Modi, W. Jacot, T. Yamashita, et al.Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer.NEJM. DOI: 10.1056/NEJMoa2203690

[7]Tarantino P, Hamilton E, Tolaney SM, et al. HER2-Low Breast Cancer: Pathological and Clinical Landscape. J Clin Oncol. 2020 Jun 10;38(17):1951-1962.

[8] 2022 CSCO Breast Cancer Guide

[9]Fernandez AI, Liu M, Bellizzi A, et al. Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue. JAMA Oncol. 2022 Feb 3:e217239.

[10]Diéras V, Deluche E, Lusque A, et al. Trastuzumab deruxtecan (T-DXd) for advanced breast cancer patients (ABC), regardless of HER2 status: A phase II study with biomarkers analysis (DAISY) . 2021 SABCS. PD8-02.

[11]Home - ClinicalTrials.gov

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