Therapeutic strategies and key issues for HER2-low expression breast cancer

*For medical professionals only

After the release of the DB04 study, where will the path of individualized treatment of HER2 low expression lead
?

The advent of new ADC drugs breaks the traditional wisdom
that for more than 20 years only patients with HER2-positive breast cancer can benefit from anti-HER2-targeted therapy.
The release of DESTINY-Breast04 (DB04) research results confirmed the significant efficacy of T-DXd in HER2-low expression breast cancer, which led to a major shift in the classification of breast cancer clinical treatment and became a major milestone in the history of breast cancer treatment
.
While HER2 low-expression breast cancer patients usher in the era of individualized anti-HER2 therapy, the treatment and pathological detection of related patient populations will face corresponding treatment strategy adjustments
.
ADC Academy is honored to invite Professor Hu Xichun from Fudan University Cancer Hospital to analyze related issues
.

There is a lack of targeted treatment for HER2 low expression advanced breast cancer

Conventional anti-HER2 therapy is ineffective

The advent of anti-HER2 therapy has significantly improved the prognosis of patients with HER2-positive breast cancer, but treatments such as trastuzumab, pertuzumab, lapatinib, and T-DM1 have shown therapeutic activity only in patients with HER2-positive (IHC3+ or IHC2+/ISH+) breast cancer, while therapeutic explorations in HER2-low breast cancer have failed
.

Figure 1.
Exploration of monoclonal antibodies and TKIs in HER2-low expression breast cancer

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

Because of the lack of targeted treatment for previous HER2-low expression breast cancers, the treatment strategies for HR+/HER2- and triple-negative breast cancer (TNBC) are often referred to, but overall ≥ the 2nd line has limited benefits ^[1,2].

For most patients with HR+/HER2-breast cancer, endocrine or endocrine combined with CDK4/6 inhibitors are used as the standard treatment option in the first and second lines, and the treatment options after endocrine therapy resistance are few, mostly chemotherapy, and the median progression-free survival (PFS) is only 4-4.
2 months
.
The median PFS of first-line single-agent chemotherapy or combination chemotherapy is not ideal (4 to 11 months) for patients with advanced TNBC, and although immunotherapy has improved the therapeutic benefit of patients with advanced TNBC to some extent, it is only effective
in patients with positive PD-L1 expression.
Although PARP1 inhibitors are an option for patients with BRCA1/2 germline mutations, the BRCA1/2 mutation rate of TNBC is not high (approximately 12 percent) ^[3], suggesting that immunotherapy and targeted therapy have a limited
group of benefits in TNBC.

At present, chemotherapy still plays an important role in the field of TNBC treatment, but the median PFS of second-line and third-line chemotherapy is about 4-4.
2 months, and the median PFS of promising Trop-2-targeted ADC drugs ≥ second-line therapy is only 5.
6 months
.
From this point of view, both HR+/HER2- and TNBC people need to explore new treatment strategies to further improve the treatment benefits
of patients.
In fact, more than half of patients with low HER2 expression are present in traditional HER2-negative breast cancer ^[4].

In this context, patients with HER2-low expression breast cancer who benefit from anti-HER2 therapy will greatly improve the unmet treatment needs
of HER2-negative people.

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

Next Generation ADC Drugs –

A breakthrough in individualized therapy for HER2 low expression

The novel ADC drug T-DXd is still effective against heterogeneous tumors based on high active drug loading, high drug-antibody ratio (DAR) and potent bystander effect, and early data show great therapeutic potential
.
In the DS8201-A-J101 ^{study [5]}, 54 patients with HER2-low expression breast cancer were included with a median treatment line of up to 7.
5 lines, although center-assessed ORR and median PFS were observed to be 37.
0% and 11.
1 months
, respectively.
The data from this study are a breakthrough
in the therapeutic benefits of previous HER2-low expression breast cancer.

Figure 4.
Early data showed that T-DXd was low in HER2 expression in advanced breast cancer

Efficacy in multi-line therapy

Based on the good therapeutic benefit of T-DXd in the DS8201-A-J101 study, the investigators designed the DB04 clinical trial ^[6] to evaluate the low expression of HER2 (IHC1+ or IHC2+/ISH-), unresectable and/or metastatic breast cancer with T-DXd compared with physician-selected chemotherapy (TPC), Efficacy and safety in
patients who have previously received 1- to 2 lines of advanced chemotherapy (HR-positive patients must be endocrine resistant or not candidates for endocrine therapy).
The results showed that the T-DXd group had a significant benefit over the TPC group in terms of PFS in HR-positive patients with the primary endpoint, with median PFS of 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, P<0.
0001
).
The median OS of the two groups was 23.
9 months and 17.
5 months, respectively, which also showed significant statistical differences (HR=0.
64, 95% CI, 0.
48-0.
86, P=0.
0028).

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

In terms of PFS and OS in patients with exploratory endpoints HR-negative or triple-negative breast cancer, the median PFS in the T-DXd group was 8.
5 months, significantly longer than the 2.
9 months in the chemotherapy group (HR = 0.
46, 95% CI, 0.
24 to 0.
89).

Median OS had the same trend of benefit, at 18.
2 months and 8.
3 months, respectively (HR = 0.
48, 95% CI, 0.
24 to 0.
95).

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

DB04 is the first Phase III clinical study to be conducted in HER2-low breast cancer, and as a result, as early as April 27, 2022, the FDA granted T-DXd breakthrough therapy certification for the treatment of HER2-low expression (IHC 1+ or IHC 2+/ISH negative) unresectable or metastatic breast cancer
.
The blockbuster results of the DB04 study were officially announced at the 2022 ASCO General Assembly and simultaneously published in the New England Journal of Medicine
.
The subsequent rapid update of the 2022 NCCN V4 Breast Cancer Guidelines ^[1] recommended that T-DXd be used in patients with tumors who have received at least first-line chemotherapy for metastatic disease, and HR-positive patients resistant to endocrine therapy (type 1 evidence).

And on July 5, 2022, ASCO official website released an update of the HER2-negative breast cancer guidelines, suggesting that patients with HER2-low expression breast cancer should be treated with T-DXd
.
The rapid update of authoritative guidelines suggests that T-DXd has become the standard of care for
advanced breast cancer with low HER2 expression.

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

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

01

The HER2 breast cancer dichotomy has entered the era of trichotomy

Previous HER2-positive criteria are defined by the therapeutic efficacy of trastuzumab, and patients who do not benefit from trastuzumab are defined as HER2-negative
.
Although HER2 low expression accounts for approximately 45 to 55 percent of total breast cancers [^7], low HER2 expression is not considered a specific subtype
due to lack of targeted treatment and unclear clinical and biological significance.
In fact, the concept of HER2 low expression has been proposed for a long time, and on the basis of the original HER2 negative definition, patients with HER2 IHC 1+ or IHC 2+ and ISH negative are defined as HER2 low expression, and IHC result of 0 is defined as HER2 zero expression ^[8].

HER2 low expression is gaining attention based on the fact that HER2 low expression patients have shown that they can benefit from new ADC drug treatment in early studies
.
The success of DB04 research has fully confirmed the status of HER2 low expression as a clinical treatment classification, and after more than 20 years of exploration, it finally has individualized targeted therapy, which indicates that clinically oriented HER2 expression breast cancer will officially enter a new era
from dichotomy to trichotomy.
More in-depth exploration will also be carried out on individualized therapies with low HER2 expression, including new drugs and the arrangement and combination of endocrine therapy, immunotherapy, chemotherapy and other targeted therapies
.

02

Pathological testing should accurately distinguish between low HER2 expression and zero HER2 expression

At present, HER2 detection in pathology practice is still based on the dichotomy of detection and scoring system, so most pathologists pay more attention to HER2 IHC 2+ or 3+, and the accurate identification of IHC 0 and 1+ is lacking
.
In a study using the current standard HER2 test ^[9], using data from the American Pathological Society (CAP) survey from more than 1400 laboratories around the world, the results showed that the current standard HER2 test had poor agreement in the evaluation of 0 and 1+ cases, only 26%.

And the study found that the inconsistency between 0+ and 1+ was significantly greater than between
2+ and 3+.

Although the agreement between 2+ and 3+ was only 58% among reading experts, its clinical impact was small, because 2+ cases needed to pass ISH testing before treatment to guide treatment decision-making, while cases 0+ and 1+ did not have such an interpretation verification process
.
This result suggests that the accurate distinction between 0 and 1+ cases needs to be taken seriously
.
As the therapeutic benefit of T-DXd in patients with HER2-low breast cancer is fully validated, it is increasingly important
to distinguish between IHC 0 and 1+.
Under this trend, in order to achieve accurate detection of HER2 low expression, new requirements
are put forward for specimen sampling, detection process, detection method and film reading.

03

HER2 is a continuous variable, and the low expression cut-off value of HER2 needs to be clarified

Moreover, HER2 expression is increasingly considered to be a continuous variable, and the cut-off value of HER2 low expression still needs to be further explored
.

The DAISY study published by SABCS in 2021 ^[10] showed that T-DXd not only showed significant efficacy against HER2-positive and HER2-low expression breast cancer, but also showed good therapeutic activity in IHC 0 patients, with a median PFS of 4.
2 months and an optimal response rate (BOR) of 29.
7%.

。 It should be noted that from the definition of IHC 0 (no staining or ≤ 10% of infiltrating cancer cells exhibit incomplete, weak cell membrane staining), it can be seen that such patients are not completely unexpressed HER2, but a significant number of patients have lower levels of HER2 expression, and the results show that even such patients can benefit
from the treatment of T-DXd.
Therefore, it is necessary to explore the cut-off value of HER2 expression to provide more patients with the opportunity
to benefit from the new ADC drug treatment.

In addition, the DESTINY-Breast06 study [¹¹] to further explore the therapeutic activity of T-DXd in patients with HER2 very low expression (IHC 0 to 1+) breast cancer is being carried out, and the relevant research results may indicate an important direction for clarifying the low expression cut-off value of HER2, and is expected to further promote the precise stratification
of T-DXd-benefiting population.

summary

The novel ADC drugs have shown unprecedented therapeutic benefits in HER2-expressing breast cancer, and have broad application prospects
.
However, this also means that the current clinical classification treatment strategy and HER2 detection mode need to be adjusted to a large extent, which requires clinical experts and pathologists to collaborate to achieve more precision treatment benefits for breast cancer patients in the new era of therapeutic classification
.

Expert profiles

Professor Xichun Hu

Director of the Department of Medical Oncology, Fudan University Cancer Hospital, Executive Deputy Director of Clinical Trial Institution, Doctoral Supervisor

ESMO Breast Cancer Faculty Member

ABC5 panelist

Chairman of the Multi-primary and Unknown Primary Tumor Special Committee of the Chinese Anti-Cancer Association, and Vice Chairman of the Medical Oncology Special Committee of the Chinese Medical Association Oncology Branch

Director of Shanghai Chemotherapy Quality Control Center

Vice Chairman of the Breast Committee of the Chinese Association of Research Hospitals

Member of the Standing Committee and Secretary-General of the Breast Cancer Special Committee of the Chinese Anti-Cancer Association

Chairman of the Cancer Rehabilitation and Palliative Care Committee of the Shanghai Anti-Cancer Association

Evaluation expert of the Evaluation Center of the State Food and Drug Administration

References:

[1] NCCN Clinical Practice Guidelines in Oncology:Breast Cancer(Version 4.
2022)

[2] Guidelines and norms for the diagnosis and treatment of breast cancer of the Chinese Anti-Cancer Association (2021 edition)

[3] Expert consensus on BRCA1/2 gene detection and clinical application in 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 Guidelines

[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 HER2 status: A phase II study with biomarkers analysis (DAISY) .
2021 SABCS.
PD8-02.

[11] Home - ClinicalTrials.
gov