Professor Liu Jian: New ADC drugs have created a new situation, and HER2 low thinking is in the ascendant

Can HER2 low expression be used as an independent subtype, and what are the current research progress and diagnostic difficulties?

Low HER2 expression accounts for approximately 45 to 55 percent of total breast ^{cancers [1]}, and has historically been classified as HER2-negative breast cancer due to lack of targeted treatment
.
Until the advent of the new ADC drug T-DXd, with its potent anti-tumor activity, an unprecedented therapeutic breakthrough
has been made in the field of HER2 low-expression breast cancer treatment.
In particular, the release of the DESTINY-Breast04 study ^[2] not only confirmed that T-DXd can bring statistically significant and clinically improved median progression-free survival (PFS) and overall survival (OS) benefits to patients with HER2-low expression breast cancer, but also broke the traditional understanding that previous anti-HER2 therapy was only effective for HER2-positive breast cancer, and officially opened the HER2-positive, HER2-low expression and A new era of HER2-negative triclass, and T-DXd may become the first standard of care option
for people with low HER2 expression.
At present, HER2 low expression has become a hot direction in the field of breast cancer diagnosis and treatment, and the relevant explorations around HER2 low expression are also increasingly rich, based on the above background, Professor Liu Jian of Fujian Cancer Hospital was specially invited to give insights in order to transmit new knowledge in the field and enlighten clinical thinking
.

Professor Liu Jian: Traditionally, HER2 status is clinically classified as positive (IHC 3+ or 2+/ISH+) or negative (IHC 2+/ISH-, IHC 1+ or IHC 0), and this classification pattern is mainly based on whether trastuzumab is effective
in treatment.
Based on the breakthrough treatment benefits of novel ADC drugs in HER2-low expression breast cancer, IHC2+/ISH- and IHC1+ were separated from the category of HER2-negative breast cancer, and the definition of HER2 low expression was formalized
.

Epidemiological data show that in HER2-low expression breast cancer, stratification is based on HR status, of which 80% are Luminal type and 15%-20% TNBC ^[3].

Among them, there is no essential understanding
of whether the biological characteristics of Luminal HER2 low-expression breast cancer are driven by ER or HER2 signaling pathway-related genes.
And whether low HER2 expression affects the prognosis of patients, the results are mixed
.
Overall, there is still controversy
about whether HER2 low expression can be used as a separate subtype.
At this year's SABCS conference, Professor Sara M.
Tolaney from Dana-Farber Cancer Institute and Professor Giuseppe Curigliano from the European Oncology Institute debated the issue
.

Professor Sara M.
Tolaney has a negative view, mainly in the following aspects:

(1) No unique clinicopathological features

A study published in Lancet Oncol in 2021 combined patient data from four prospective neoadjuvant therapy clinical trials (including a total of 3512 patients, of which 2310 were included in the analysis) ^[4], aiming to compare the clinical and pathological features of HER2-low expression and HER2 0 breast cancer, found that HER2-low breast cancer included more HR-positive patients and fewer G3 patients.
And Ki67 expression was lower
than HER2 0.
The 2022 SABCS Congress presented analytical data from the National Cancer Database (HER2-11) reported by Peiffer D et al.
^[5], and the same observations were made
.

Figure 1.
The clinical and pathological features of HER2-low expression tumors differ

In addition, data from studies at Dana-Farber Cancer Institute, KHC Leuven and the National Cancer Database all indicate that low HER2 expression levels increase
with increased ER.
The SABCS conference also presented the results of a global, multicenter, retrospective study (HER2-15) by Viale G et al.
to evaluate HER2-negative metastatic breast cancer ^[6], which found no significant difference
in the demographic or clinical characteristics of patients with low HER2 expression compared with HER2 0 in the metastatic setting.

Figure 2.
Low HER2 expression levels increase with increasing ER

There are also related studies that show that differences in clinical and pathological characteristics between HER2 low expression and HER2 0 tumors are driven by differences in ER expression, not by HER2 low expression status, and are therefore insufficient to support HER2 low expression as a separate subtype
.

(2) Not associated with different prognosis

In this retrospective cohort study of Peiffer D (HER2-11) ^[5], which included 1,191,389 patients, including 394,937 HER2 0 and 796,452 cases with low HER2 expression, survival analysis of HR-positive tumor populations showed that HER2-low breast cancer was only associated with OS improvement in stage 4 disease (HR=0.
96, 95% CI 0.
92-0.
99).

。 In 62,667 patients receiving neoadjuvant chemotherapy, low HER2 status was associated with a lower pCR rate (OR=0.
88, 95% CI 0.
84–0.
92).

Figure 3.
Low HER2 expression benefits OS over HER2 0

A retrospective study of Viale G (HER2-15) showed ^{that there} was no statistically significant difference in median OS and time to first follow-up treatment between HER2 low expression and HER2 IHC 0 groups, regardless of HR status, with median time to HER2 low expression and HER2 IHC 0 to first follow-up treatment in the HR-positive metastatic breast cancer subgroup, respectively, 9.
8 months and 8 months
, respectively.

Figure 4.
Hierarchical by HR status, there was no difference in prognosis between low HER2 expression and HER2 0

In addition, multiple previous retrospective studies have analyzed the prognostic significance of HER2 low expression, and when stratified according to different HR status, most studies have found no OS difference
between HER2 low expression and HER2 0 breast cancer.
Overall, there is currently no conclusive evidence to support low HER2 status as an independent prognostic factor
.

(3) Not associated with different treatment benefits

In terms of the effect of HER2 low expression status on the efficacy of neoadjuvant therapy, in the pooled analysis of four prospective neoadjuvant therapy studies ^[4], it was observed that the pCR rate of HER2 low expression tumor patients was significantly lower than that of HER2 0 tumor patients
.
In HR-positive tumors, it was also observed that the pCR rate of HER2 low expression was significantly lower than that of the HER2 0 group
.
However, in HR-negative tumors, no difference in
pCR rates between different HER2 expression status groups was observed.
The study also did not observe any difference in
pCR rates between HER2 IHC1+ and HER2 IHC2+ tumors.

A study by Tarantino P et al.
, published in JAMA Oncol evaluating the prognosis and biological significance of low HER2 expression in early-stage breast cancer ^[7], found that among 675 patients receiving neoadjuvant chemotherapy, the pCR rate was higher in patients with HER2 0 tumors (26.
8% vs.
16.
6%; P =0.
002）
。 However, when the patients with HR-positive, low-ER, and non-ER-low HR-positive or TNBC tumors were analyzed separately, there was no statistically significant difference
in pCR rates between HER2-low expression and HER2-0 tumors.

Figure 5.
Effect of low HER2 expression on efficacy of neoadjuvant therapy

The RxPONDER study ^[8] evaluated the efficacy and safety of endocrine therapy alone (ET) or endocrine combination chemotherapy (CET) in stage II-III HR+/HER2- breast cancer and showed that CET resulted in low HER2 expression (HR=0.
67) and HER2 0 subgroup (HR=0.
57) in premenopausal women with relapse score (RS) adjusted Noninvasive disease survival (IDFS) was numerically improved (interaction p=0.
55); In postmenopausal women, there was no difference in the benefit of IDFS in the subgroup with ET (HR=0.
98) and HER2 0 (HR=1.
12) (interaction p=0.
57).

And overall, there was no difference
in treatment benefit between HER2 low expression and HER2 0 patients in the two trial groups.

According to the research report presented at this SABCS conference, in HR+/HER2-metastatic breast cancer patients who received CDK4/6 inhibitor + ET in the advanced first-line, the correlation between HER2 low expression and PFS and OS benefits was not consistent
.

In addition, although anti-HER2 drugs were not specifically developed to treat HER2-low breast cancer, monoclonal antibodies, ADC drugs, and other novel drugs are actively exploring in the field of HER2-low expression breast cancer treatment, but their therapeutic benefits are very different, such as the NSABP B-47 study ^[9].
Breast cancer patients with IHC 1+, IHC 2+/ISH- or IHC 2+/HER2 copy number < 4.
0 were included, and the results showed that adding trastuzumab to adjuvant chemotherapy did not improve IDFS (5-year IDFS rate: 89.
8% in the chemotherapy plus trastuzumab group versus 89.
2% in the chemotherapy alone; P=0.
85）
。 And no difference in IDFS benefit was
observed between the two groups in different HER2 expression subgroups.
The DESTINY-Breast04 study fully verifies that the new ADC drug T-DXd can bring unprecedented therapeutic breakthroughs for HER2-low expression breast cancer, regardless of HR status
.
The difference between the two findings may be due to the fact that the antitumor activity of T-DXd depends mainly on the highly active drug load, and its ability to exert a potent bystander effect, with less
reliance on HER2 expression levels.
Therefore, traditional anti-HER2 therapeutic drugs must exert anti-tumor effects by blocking the HER2 signaling pathway
.
This also shows that HER2 low expression is not a new subtype characterized by oncogenic drivers, but a biomarker of HER2-targeted drug treatment benefits of novel ADCs
.

(4) No biological differences (uniqueness)

To elucidate the clinicopathological and molecular biology of HER2-low expression breast cancer, a study collected retrospective clinicopathological and PAM50 data from 3689 patients with HER2-negative breast cancer ^[10].

The results found:

Distribution of PAM50 intrinsic subtypes:

• Compared with HER2 expression (3.
  5%), HER2 enrichment (HER2-E) was more common in the HER2 0 (5.
  9%) group.
  

• Luminal A (51.
  8% for HER2 0, 57.
  9% for HER2 1+, 60.
  6% for HER2+) and Luminal B subtypes (34.
  9% for HER20, 33.
  1% for HER2 1+, and 33.
  8% for HER2 2+), are most common in HR-positive tumors and are not associated with HER2 low expression status;

• Basal cell-like tumors are the main subtype of TNBC (85.
  2% for HER20, 85.
  4% for HER2 1+, and 78.
  4% for HER2+), independent of
  HER2 low expression status.
  

Figure 6.
Intrinsic molecular subtypes stratified by HR and HER2 low expression states

Gene expression profiles based on HER2 expression (HER2 low expression and HER2 0) and HR status:

• HR status is a key determinant of the potential biological characteristics of HER2-low expression breast cancer;

• Proliferation-related genes (e.
  g.
  , CCNE1, MKI67, and EXO1) were found to be more expressed in TNBC than in HR-positive tumors, regardless of HER2 IHC status (i.
  e.
  , low HER2 expression vs.
  HER2 0).
  

• Conversely, Luminal-related genes (such as ESR1, AR and BCL2) and ERBB2 were found to be more expressed in HR-positive tumors than TNBC, again independently
  of HER2 IHC status.
  

Figure 7.
Hierarchical stratification by HR status, low HER2 expression and genomic characteristics of HER20

In addition, multiple studies presented at the 2022 SABCS Congress also showed that the genomic characteristics of HER2-low expression tumors are not unique
.

(5) Not biologically stable or consistent

HER2 low expression is only moderately consistent locally with central laboratory results, such as the DESTINY-Breast04 study, which reported a 78 percent agreement for HER2 low expression at the SABCS conference ^[11].

。 The retrospective study (HER2-15) mentioned above also showed an overall agreement of 81.
3% between rescores and historical HER2 scores for patients with previously HER2 IHC negative metastatic breast cancer, with 87.
5% agreement between HER2 low expression and HER2 IHC 0 samples
, respectively 。 In the TALENT study of T-DXd neoadjuvant therapy for HR-positive, HER2-low-expression early-stage breast cancer reported at the SABCS conference, pathologists had a 57%
agreement between HER2 0 and HER2 1+.
Another study evaluated 18 pathologists from 15 institutions for HER2 IHC evaluation of whole tissue sections from 170 separate biopsy cases collected from Yale University, and observed that 18 pathologists had only 26% agreement rate of IHC 0 and 1+ and 58
% agreement rate of IHC 2+ and 3+.

Figure 8.
Low HER2 expression was only moderately consistent locally with central laboratory results

Several studies have confirmed the instability of the evolution of HER2 low expression from primary to metastasis, such as a study published by Tarantino P et al.
in the European Journal of Cancer in 2022 ^[12].
A total of 232 patients with HER2-low expression breast cancer were included for analysis, and the results showed that the matched biopsy samples collected at the time of recurrence showed that HER2 expression was significantly inconsistent with the primary tumor, 44% of patients with HER2 0 primary tumor showed an increase in HER2 score on recurrent biopsy, and 22% of patients with HER2 low-expression primary tumor switched to HER2 0
when the disease recurred.
In another study comparing HER2 levels between primary and relapsed/metastatic lesions in 547 patients with recurrent breast cancer ^[13], the inconsistency rate between HER2 between primary and metastases before and after neoadjuvant therapy was 38.
0%, mainly manifested by low HER2 0 expression (15%) and HER2 low expression to HER2 0 (14%)
。

Figure 9.
HER2 low expression is unstable

In addition, the PenelopeB study [14] showed that in 1119 cases with residual disease before and after neoadjuvant therapy, neoadjuvant therapy led to HER2 low expression and HER2 0 state conversion in 37% of cases (^14.
4% of patients had HER2 0 to HER2 low expression; 22.
7% of patients had low HER2 expression converted to HER2 0 (HER2-06).

The TALENT ^{study [15]} reported 49% inconsistency in HER2 status before and after neoadjuvant therapy
.

Figure 10.
Effects of neoadjuvant therapy on HER2 low expression status

Based on the above evidence, Professor Sara M.
Tolane believes that HER2 low expression cannot be used as a separate breast cancer subtype
.

Professor Giuseppe Curigliano believes that HER2 low expression can be used as an independent subtype, and he mainly elaborates from the following three perspectives:

(1) Clinical impact: prognosis, unique prognosis of low HER2 expression

Most studies have found no significant difference in OS between low HER2 expression and HER2 0 breast cancer
, regardless of HR expression status.
In a pooled analysis of four prospective neoadjuvant therapy studies conducted by Denkert C et al^.
[4], a total of 2310 patients with HER2-negative (including HER2 0 and HER2 low expression) breast cancer were included, of which HR-positive (1148) and HR-negative (1162) accounted for half
each 。 Among HR+/HER2- patients, 703 (61.
2%) patients with low HER2 expression and 445 (38.
8%) HER2 0 patients were included; Among TNBC patients, 395 (34%) patients with low HER2 expression and 767 (66%) HER2 0 patients
were included.
Patients with HER2 low expression had a lower proportion of grade 3 tumors and lower proliferative (lower Ki67 levels)
than HER2 0 patients.
In terms of prognosis, DFS and OS of HER2-low expression tumors showed an improvement trend, especially in the HR-negative subgroup
.
DFS and OS were also improved
in the HR-negative, HER2 low expression (traditional TNBC) subgroup of non-pCR patients.
Overall, in this large national cohort study, low HER2 expression was associated with a slight improvement in patient survival benefit, particularly in advanced TNBC (although the 5-year OS difference ≤2%)
.
A small decrease in pCR (approximately 3%
in absence) was observed in patients with low HER2 expression receiving neoadjuvant chemotherapy.

Figure 11.
Four prospective neoadjuvant therapy studies were pooled and analyzed

The HER2 low expression status of early-stage invasive lobular carcinoma (ILC) is also unique (HER2-14) ^[16]:

1.
Compared with HER2-negative ILC patients, HER2-low ILC patients have worse DFS;

2.
Patients with ILC with HER2 low expression are more likely to undergo total mastectomy than lumpectomy;

3.
Patients with HER2 low expression ILC are more likely to develop PR-positive tumors
.

(2) Clinical impact: treatment, a unique treatment strategy with low HER2 expression

In the DESTINY-Breast04 study, T-DXd significantly improved the PFS and OS benefits of patients with HER2-low expression breast cancer, and may become the first standard treatment option for HER2 low expression breast cancer, based on which this study also established HER2 low expression as a new anti-HER2 targeted therapy classification
.
This shows that HER2 low expression is a clinically relevant disease, and for such patients, there are currently special treatment options
for both PFS and OS.

The study described above by Denkert C et al.
also showed ^[4] that the pCR rate in patients with HER2-low expression breast cancer was reduced compared to HER2 0, especially in HR-positive patients
.
Zattarin E et al.
conducted a retrospective-prospective study (HER2-02) by collecting patient data from 6 Italian cancer centers ^[17] to assess HER2 status (low vs.
0) Effect
on survival benefit in patients receiving CDK4/6 inhibitor + ET (aromatase inhibitor or fulvestrant) first-line therapy with HR+/HER2- advanced breast cancer.
The results showed that low HER2 expression was associated with
PFS and OS worse than HER20.

Figure 12.
HER2-low tumors had lower rates of pCR, especially in the HR-positive subgroup

Several previous studies have demonstrated changes in HER2 status before and after neoadjuvant therapy
.
And studies have shown ^[18] that switching from low HER2 expression to HER2 0 is not
associated with a significant survival benefit.
Conversely, changes in HER2 low expression after switching from HER2 0 before neoadjuvant therapy to neoadjuvant therapy were significantly associated with a decrease in IDFS compared with the persistent HER2 low expression group (p=0.
04).

Correlation analysis of AIMS (Absolute Intrinsic Molecular Subtyping) subtypes of HER2-low expression breast cancer before and after neoadjuvant therapy and survival benefit showed that different AIMS subtypes (lumB/basal/HER2-E vs.
lumA/normL; There was a significant difference
in IDFS for the overall p-value <0.
0001).
Survival was improved in patients with tumors with low expression of the aggressive AIMS subtype (lumB/basal/HER2E) after neoadjuvant therapy, but not in the less aggressive AIMS subtype (lumA/normL) (PD4-02) ^[18].

Figure 13.
Correlation between AIMS subtypes and survival benefit of HER2-low expression breast cancer before and after neoadjuvant therapy

Since traditional anti-HER2-targeted drugs are only effective for HER2-positive breast cancer treatment, in the past, HER2 low expression was considered HER2-negative breast cancer
due to the lack of targeted therapies.
Not only that, but around 2013, HER2-activating mutations were found in breast cancer, which were also interpreted as HER2 negative according to IHC/ISH test ^{results [19].}

。 Similar HER2 mutations (about 2%-4%) were found in non-small cell lung cancer (NSCLC) in 2004, and in August 2022, the FDA approved the indication of a new ADC drug T-DXd for the treatment of HER2-mutant NSCLC, which means that the field of lung cancer ushered in the first ADC drug and anti-HER2 therapy
.
Studies have shown that HER2 mutations can improve their anti-tumor effects
by increasing the internalization of T-DXd.
The presence of HER2 mutations in 2%-5% of ER-positive and HER2-negative metastatic breast cancer has also caused researchers to think ^[19], and whether HER2-mutant breast cancer patients can benefit from new ADC drugs may become a future exploration direction
.

(3) Classification: Unique biology and reliable and robust detection methods to define HER2 low-expression isoforms

Analysis of molecular characterization of HER2 low-expressing TNBC showed ^[20]:

• In stage I-III TNBC, low HER2 expression was associated with increased AR expression and genes associated with fatty acid and steroid hormone metabolism;

• Gene expression analysis showed that HER2 low expression and HER2 0 tumors had different drivers of drug resistance to neoadjuvant therapy.
  

• This difference in gene expression can be further explored to refine neoadjuvant therapy strategies
  in patients with stage I-III TNBC.
  

In the study of Bansal R et al.
(HER2-12) ^[21], mutations were detected by DNA next-generation sequencing (NextSeq 592 genome or NovaSeq whole exome panel), including 3403 HR-positive, HER2-low-expression and 946-HR-negative, HER2-low breast cancers
。 Compared with TNBC, differences in PIK3CA mutation rate (33.
5% vs 16.
7%) and TP53 mutation rate (74% vs 86%) were observed between HER2-low expression tumors and TNBC
.

Figure 14.
Genome and transcriptome mapping of HER2-low expression breast cancer

In a study published by Denkert C et al.
at the 2022 SABCS Congress (PD4-02) ^[18] evaluating the spatial and temporal heterogeneity of TNBC prediction and prognosis features in neoadjuvant therapy with immunotherapy combined with chemotherapy, the authors used a combination of HTG tumor biomarkers to identify differentially expressed genes before and after neoadjuvant therapy, and found that a total of 52 genes were significantly associated
with HER2 status after neoadjuvant therapy.

In terms of detection methods, whether it is the development of new detection technology or the in-depth exploration of artificial intelligence (AI)-assisted IHC interpretation, encouraging research results have been achieved, such as automatic quantitative analysis technology, targeted mass spectrometry measurement, high-field asymmetric waveform ion mobility spectroscopy (FAIMS) determination, etc.
, all of which show good application prospects
.

Professor Giuseppe Curigliano also pointed out that whether HER2 low expression can be used as a standalone subtype depends largely on the definition of
"subtype".
Because even classical HER2-positive breast cancer does not qualify for a subtype if strictly defined (HER2 amplification can be considered a single additional molecular event), targeted therapies make it a separate subtype
.
Further research is needed to explore the characteristics of
HER2 low expression as a "separate subtype".

In general, although it is not clear whether HER2 low expression can be used as an independent subtype, with the in-depth exploration of research, the establishment of a more rigorous definition system and more accurate interpretation standards has been promoted, and it is the general trend
for HER2 low expression to become an independent subtype in the future.

Professor Liu Jian: Previous drugs including monoclonal antibodies, small molecule TKIs and second-generation ADCs have not improved the survival benefits
of HER2-low breast cancer patients.
However, the relevant studies are only retrospective subgroup analyses, and there are no prospective exploratory studies specifically for HER2 low expression patients, which does not actually exclude the possibility
that such drugs are also effective in the treatment of HER2 low expression breast cancer.
Despite the regret, the advent of the new ADC drug T-DXd has successfully opened up a new situation
in which HER2-low expression breast cancer can benefit from anti-HER2 targeted therapy.
This is mainly due to the upgrading and optimization of its structure and mechanism: stable tetrapeptide cleavage linker, drug-antibody ratio (DAR) up to 8, highly active drug loading with unique mechanism, and potent bystander effect
.
These advantages have made T-DXd a great benefit in patients with HER2-low expression breast cancer, and related research has become a milestone and important progress
in the history of breast cancer treatment.

Research progress of positive HR and low HER2 expression:

DESTINY-Breast04 is the first randomized, phase III clinical study for HER2-low expression metastatic breast cancer ^[2].
A total of 557 patients with HER2-low expression breast cancer were randomly received T-DXd and investigator-selected chemotherapy (TPC) 2:1, including 88.
7% (494/557) of HR-positive, HER2-low expression breast cancer patients, and nearly 70% (348/494) of this patient population were CDK4/6 inhibitor-treated people, and the results showed that in HR-positive and HER2-low expression breast cancer, T-DXd significantly extended the median PFS compared with the TPC group At 4.
7 months (10.
1 versus 5.
4 months), the risk of disease progression or death was reduced by 49% (HR = 0.
51; 95% CI: 0.
40 to 0.
64; p<0.
001
).
The median OS in the two groups was 23.
9 months and 17.
5 months, respectively, and the T-DXd group also had a significant advantage
.
In addition, the objective response rate (ORR) of T-DXd was as high as 52.
6%, which was more than
3 times that of 16.
3% in the TPC group.

Figure 15.
DB04 Study PFS, OS (HR+ and General Population)

The DB04 study subgroup analysis presented at the 2022 SABCS Conference showed ^{that for} patients with HR-positive and HER2-low expression breast cancer treated with CDK4/6 inhibitors, the median PFS was 10.
0 months, which was significantly better than that of the chemotherapy group at 5.
4 months, and the ORRs of the two groups were 50.
6% and 13.
0%, respectively, showing a consistent benefit trend
with the overall HR-positive population.

Due to the cross-benefit population of HR+/HER2-expressing breast cancer and traditional HR+/HER2-breast cancer (of which 55%-65% of patients with low expression) have cross-benefited people [^3], the therapeutic progress of Trop-2-targeted ADC drugs in HR+/HER2-breast cancer has also attracted much attention
。 TROPiCS-02 is a global, multicenter, open-label clinical phase III trial, including a total of 543 patients with HR+/HER2- metastatic breast cancer, randomized to SG group or TPC group in a 1:1 ratio, data released at the 2022 ASCO Congress ^[23], in the ITT population, the median PFS of the SG group was 5.
5 months, significantly better than the TPC group of 4.
0 months, but there was no statistically significant difference in OS
。 The 2022 ESMO Congress released OS data from the second interim analysis of the study ^[24], with median OS of 14.
4 months and 11.
2 months, respectively, and the SG group showed a statistically significant therapeutic advantage
for the first time.
In addition, the ORRs of the two groups were 21% and 14%, respectively (p=0.
035).

Figure 16.
TROPiCS-02 studies PFS and OS

Despite the lack of head-to-head studies, the PFS, OS, and ORR benefits of T-DXd in the treatment of HR-positive and HER2-low expression breast cancer were numerically better
compared with the above study data.
Based on the DB04 research results, NCCN/ASCO guidelines have recommended T-DXd as the preferred treatment
for advanced breast cancer with low HER2 expression.
At present, under the new breast cancer treatment pattern, for patients with advanced breast cancer with positive HR, low HER2 expression and visceral crisis, after receiving CDK4/6 inhibitors combined with endocrine first-line therapy, T-DXd may become a more effective treatment option
when formulating follow-up drug regimens.

Research progress of HR-negative and low HER2 expression:

The DESTINY-Breast04 study included 11.
3 percent of HR-negative, HER2-low breast cancer patients, and T-DXd treated HR-negative, HER2-low expression breast cancer patients who had previously received 1 to 2 lines of chemotherapy, with a median PFS of 8.
5 months, a median OS of 18.
2 months, and a deeper disease response and an ORR of 50 percent ^[2].

Figure 17.
DB04 Research PFS, OS(HR-)

HR-negative, HER2-low breast cancers account for about 35% of TNBC ^[3], and research progress
in the treatment of TNBC by SG has been published before T-DXd.
In a randomized controlled, phase III ASCENT study, SG treated patients with metastatic TNBC who had previously received two to four lines of chemotherapy with a median PFS of 5.
6 months, OS of 12.
1 months, and an ORR of 35 percent ^[25].

Subgroup analysis showed efficacy independent of HER2 low expression status, with a median PFS of 6.
2 months, median OS of 14 months, and an ORR of 32 percent for HER2-low metastatic TNBC ^[26].

Figure 18.
ASCENT studies PFS, OS, ORR

In the past, HR-negative, HER2-expressing advanced breast cancer is often classified as TNBC, and first-line chemotherapy or chemotherapy combined with immunotherapy is preferred, and platinum or PARP inhibitors
can be used in patients with BRCA mutations.
In terms of ≥ 2-line therapy, the overall benefit is very limited, including SG can only bring patients a median PFS benefit of 5.
6 months, median OS is just 1 year, and T-DXd also presents certain advantages in numerical terms, median PFS up to 8.
5 months, median OS more than 1 and a half years, can be used as an important choice
for HR-negative, HER2-low expression breast cancer patients after the progression of first-line therapy.

Professor Liu Jian:

Challenge one: distinguish between IHC 0 and IHC 1+

The clinical definition of HER2 low expression essentially depends on the detection technology, and the current HER2 low expression also uses standard IHC/ISH detection methods, and the initial IHC is mainly to determine HER2 positive status, not HER2 low expression or HER2 0, so there may be some shortcomings in the interpretation of HER2 low expression based on IHC detection (the above study has mentioned that the consistency of interpretation of HER2 low expression needs to be improved).

。 In the past, due to the lack of practical significance of IHC 0 and IHC 1+, both clinical and pathologists paid less attention to it, and as HER2 low expression gradually entered the "mainstream stage" of breast cancer, how to accurately distinguish IHC 0 and IHC 1+ has also become an urgent problem
to be solved.
And in the future, the interpretation of HER2 may not be simply distinguished according to IHC 0, IHC 1+, IHC 2+, IHC 3+, but similar to the interpretation standard of ER, using percentages to indicate the degree of
IHC positivity.

Challenge 2: HER2 low expression is unstable

As mentioned earlier, HER2 low expression is not stable during disease evolution and there is strong heterogeneity
.
This is pathological, due to the dynamic changes in the low expression state of HER2 in the primary lesion and metastasis, the material taken for the primary lesion alone may not truly reflect the actual HER2 expression state, which may cause some patients to miss the opportunity to benefit from the treatment of the new ADC drug (especially patients whose primary lesion is interpreted as HER2 IHC 0).

Although it is also emphasized to re-test HER2 for recurrent metastases or residual lesions after neoadjuvant therapy, metastases may also be encountered in clinical practice
.

Challenge 3: HER2 low expression lower limit

HER2 expression is increasingly considered a continuous lineage, and even in cases of IHC 0, a significant proportion can be present< 10% of infiltrating cancer cells exhibit incomplete, weak membrane staining<b10>.
The efficacy of T-DXd in the treatment of HER2-low breast cancer is unquestionable, and the phase II DAISY study has fully verified the therapeutic benefit of T-DXd in patients with HER2 ultra-low expression breast cancer, which collectively suggests the need to clarify the lower limit of HER2 low expression to comprehensively screen out the population
with T-DXd treatment benefit 。 The DESTINY-Breast06 study was designed to evaluate the efficacy and safety of T-DXd compared with TPC in patients with low HER2 expression (700 patients with HER2 IHC 1+ or IHC 2+/ISH-) and ultra-low expression [150 patients with IHC 0-1+ (defined as weak or barely visible membrane staining in 10% or fewer tumor cells)], and the results may provide an important evidence-based basis for clarifying the lower limit of HER2 expression.
It is also expected to promote the precise stratification
of T-DXd beneficiary populations.
Not only that, once the future HER2 expression status is expressed as a percentage with reference to the ER interpretation standard, the lower limit of HER2 expression will be further clarified
.