Low HER2 expression may increase the risk of breast cancer brain metastases

*For medical professionals only

Low HER2 expression leads to shortened survival in breast cancer patients and a higher risk
of brain metastases.

Although HER2-expressing breast cancers can benefit from novel anti-HER2 therapeutics, the clinical features and prognostic significance of HER2-low expression need to be further clarified, and whether there is clinical similarity
between the metastatic patterns of HER2-positive and HER2-low expression breast cancers has not been evaluated 。 A large cohort study with long-term follow-up showed that the overall incidence of breast cancer brain metastases was 6.
9%, among which the incidence of brain metastases in HER2-negative patients, HER2-low expression patients, and HER2-positive patients was 5.
1%, 8.
5%, and 10.
1%, respectively
。 This study shows for the first time that HER2 low expression is associated with an increased risk of brain metastasis in breast cancer patients, adding new evidence to characterize the prognostic significance of HER2 low expression, and also providing a certain basis
for whether to take measures to prevent brain metastasis in patients with low HER2 expression.

01

Research methods

This retrospective cohort study evaluated data
from 3151 adult breast cancer patients followed at Hacettepe University Cancer Center from 01.
01.
2000 to 30.
12.
2016.
All patients treated within a pre-defined date were included, while patients treated in clinical trials, patients with incomplete clinical and survival data, and patients with metastatic disease at baseline were excluded
.
HER2 status is determined by IHC and HER2 expression levels are graded as negative, 1+, 2+, and 3+
according to relevant ASCO/CAP guidelines at tumor evaluation.
Fluorescence in situ hybridization (FISH)
is also performed in IHC2+ cases.
Patients with HER2 1+ and HER2 2+ and FISH negative were classified as having low HER2 expression
.

Due to local policies, the patients enrolled in this study did not re-evaluate HER2 status
.
Baseline demographics (age, sex, marital status), menopausal status, patient weight and height, tumor T-N-M stage, tumor hormone and HER2 expression status, lymphovascular invasion (LVI), perineural invasion (PNI), history of surgery and radiotherapy, comorbidities and routine medications, and survival data
were recorded.
In addition, whether brain metastases
occurred during follow-up were recorded.
As recommended by the guidelines, the patient was diagnosed with brain metastases during follow-up with imaging tests due to symptoms, and no routine head imaging was performed
.
Comorbidities are classified
according to the Charlson Comorbidities Index (CCI).
Disease-free survival (DFS) events are defined as metastatic or new-onset breast tumors
at follow-up and/or death.
Overall survival (OS) time is defined as time from diagnosis to last follow-up and/or death, and DFS time is defined as time from diagnosis to disease progression and/or death
.

02

Study results

Baseline characteristics

After excluding patients with incomplete data (n=171) and patients with metastatic disease at baseline (n=294), a total of 2686 patients
were followed between pre-specified dates.
The median age of the cohort was 48 years (IQR 41–56), and 49.
3% of patients were premenopausal
at diagnosis.
Most patients had T1 or T2 disease (84%), and more than half had positive lymph nodes (53.
3%) (Table 1).

There were 673 (25.
1%) HER2-positive patients, compared with 1723 (64.
1%) HR-positive patients and 290 (10.
8%)
patients with triple-negative (TN) breast cancer.
Hypertension was the most common comorbid condition (22.
5%), with a median CCI of 1
.
1625 (60.
5%) patients were HER2 0,172 (6.
4%) HER2 1+ patients, 265 (9.
9%) patients were 2+, 624 (23.
2%) patients were HER2 3+
.
In addition, 49 patients were HER2 2+ and FISH positive
.
HER2 1+ and 2+ patients were included in the analysis as HER2 low expression groups (n=388).

Most patients with low HER2 expression were positive for HR (n=347, 89.
6%), while a few patients were patients with low expression of TN-HER2 (n=41, 10.
6%)
.
HER2-low and HER2-positive tumors have higher T and N stages compared to HER2-negative tumors (Table 2).

The median age of the HER2-negative cohort was slightly higher than that of the HER2-positive cohort, and hypertension occurred more frequently in patients with HER2-negative and HER2-low expression than in the HER2-positive cohort (Table 2).

Table 1.
Baseline characteristics of the patient

Table 2.
Baseline characteristics of patients were compared according to different HER2 status

Survival analysis

During a median follow-up of 95.
4 (IQR 72.
6 to 123.
1), 539 (20.
1%) patients died and 710 (26.
4%) patients had DFS events that did not reach median OS and DFS
.
In univariate analysis, T3–T4 primary, node-positive, diabetes, and higher CCI (2 vs.
0–1) were associated with lower OS (all p< 0.
001).

Similarly, in univariate analysis, these factors were associated with lower PFS (p<0.
001 for T3-T4 primary, node-positive, and higher CCI, p=0.
004 for diabetes).

OS and DFS were reduced in patients with LVI or PNI, while survival differences between normal and overweight patients were not statistically significant (p=0.
092 for OS, p=0.
439 for DFS).

There were no significant differences
in OS(p=0.
981) and DFS (p=0.
294) in patients with HER2 low expression compared to the rest of the cohorts, including HER2-negative and HER2-positive patients.
When compared alone with HER2-negative patients, OS was similar in patients with HER2 low expression (p=0.
393).

However, low HER2 expression was associated with a significant decrease in DFS (Figure 1).

The adverse effects of low HER2 expression on HR+/HER2-low breast cancer were statistically significant (p=0.
008), while there was no significant difference in patients with low TN-HER2 expression (p=0.
242).

In univariate OS analysis, a multivariate model
is constructed using statistically significant variables.
In multivariate analysis, all included parameters except diabetes history were significantly negatively correlated
with OS.
DFS analysis is consistent with OS analysis (Table 3).

Figure 1.
DFS and OS in patients with different HER2 expression states

Brain metastases risk assessment

A total of 184 patients (6.
9%)
developed brain metastases during follow-up.
Premenopausal and node-positive patients and patients with T3-T4 tumors are
at increased risk of brain metastases.
In addition, patients with low HER2 expression and HER2-positive had an increased risk of brain metastases (p=0.
001).

Brain metastases occurred in 5.
1% of HER2-negative patients, 8.
5% of HER2-low patients, and 10.
1% of HER2-positive patients (Figure 2).

Multivariate binary logistic regression models demonstrated an increased risk of brain metastases in patients with HER2 low expression (OR: 1.
611, 95% CI 1.
055-2.
460, p=0.
027) and HER2-positive breast cancer (OR: 1.
837, 95% CI 1.
308-2.
580, p < 0.
001) (Table 3).

The increased risk of brain metastases in patients with low HR+/HER2 expression remained significant (OR: 1.
655, 95% CI 1.
041-2.
664, p=0.
033).

The correlation between the risk of brain metastases and low HER2 expression was not statistically significant in patients with low TN-HER2 expression (OR: 1.
590, 95% CI 0.
568–4.
450, p=0.
377).

Table 3.
Multivariate analysis of brain metastasis risk, OS, and DFS

Figure 2.
Incidence of brain metastases in patients with different HER2 expression states

Figure 3.
Risk of brain metastases in patients with different HER2 states

03

Research discussion and summary

Breast cancer is the second most common cause of brain metastases, and the occurrence of brain metastases is associated with
significant mortality.
The risk of breast cancer brain metastases is subtype-dependent, and the risk of HER2-positive tumors is significantly increased
.
The brain tropism of HER2-positive tumors may be related to the interaction of multiple factors in the tumor microenvironment and the blood-brain barrier, and the HER2 oncogene may be the center of
these interactions.
HER2-low breast cancer also has a certain level of HER2 receptor on the cell surface, but whether there is a similar brain metastasis tendency in HER2-low breast cancer is unknown
.

In this study, a 61% increased risk of brain metastases in HER2-low
expression breast cancer was observed compared to HER2-negative patients.
If this correlation is supported by prospective evidence, patients with HER2-low breast cancer may be candidates for adjuvant therapies to prevent new therapeutic strategies for brain metastasis
.
The increased risk of brain metastases in the TN group was not statistically significant, and the small sample size (n=289) and limited number of events (n=26) may be responsible for the lack of correlation, and the association
between HER2 expression and brain metastasis risk should be evaluated in a larger TN breast cancer cohort.
Conversely, patients with low HR+/HER2 expression had a significantly increased risk of brain metastases, independent of
tumor T and N stages.
Although patients with HR-positive tumors generally have a better prognosis and a lower risk of brain metastases, HER2 low expression can define a biologically aggressive subtype, so HR+/HER2 patients with low expression have an increased risk of brain metastasis, possibly due to a biological mechanism
more similar to HER2-positive tumors.

In this study, similar OS was observed in patients with HER2-low expression and HER2-negative tumors, while DFS was significantly reduced in patients with HER2-low expression tumors, especially in the HR+/HER2 low-expression subgroup
.
Several other studies on localized breast cancer have similarly assessed the effect of low HER2 expression on survival, but have yielded conflicting results
.
In previous reports by Camp et al.
, both high and normal expression levels of HER2 were associated with poor prognosis, while intermediate HER2 expression was associated
with better DFS in a cohort of 300 breast cancer patients.
The authors defined HER2 expression using histograms and report that 71.
3% of breast cancer HER2 expression was intermediate [^2].

The latter medium-sized report (n=91) showed that any level of HER2 expression was associated with reduced DFS (p=0.
001) and OS (p=0.
001) in patients with node-positive breast cancer, although HER2-low expression diseases accounted for a significantly lower proportion of their cohort (14% HER2 1+ and 5% HER22+) ^[3], which is similar
to this study.
In the HR+/HER2 positive cohort, the adverse prognostic effect was more pronounced [3], again similar
to this study.
The study conducted by Rossi et al.
, which included a larger cohort of HER2-negative and HER2-low expression patients (n=1150), observed lower DFS in HER2 2+ patients compared to HER2-negative and HER2 1+ patients
.
The proportion of HER2 1+ patients in this study was higher than in the study cohort (39% vs.
6.
4%), while the proportion of HER2 2+ patients was similar (10% vs.
9.
9%)
.
and time-dependent adverse effects have been observed in patients with HER2 2+ ^[4].

Interestingly, in a large sample size study (> 5000 patients), researchers from Germany reported lower DFS (HR: 1.
217, 95% CI 1.
052-1.
408, p=0.
008) in HR-positive patients with moderate HER2 expression, but similar breast cancer-specific survival (HR=1.
045, 95% CI 0.
926-1.
178, p=0.
474).

The difference in DFS among HR-negative patients was not statistically significant ^[5].

These data and observations in HR-positive patients suggest that low HER2 expression may be an additional prognostic factor in HR-positive patients, whereas HR-positive patients traditionally have a better prognosis than patients with TN ^{disease [6].}

Overall, despite some limitations of the study, a significant increased risk of brain metastases was observed in patients with HER2-low breast cancer, and this is the first report
on the association between HER2 expression and the risk of developing breast cancer brain metastases.
In addition, this study also shows that the DFS is shorter in patients with HR+/HER2 low expression breast cancer, which also provides new evidence
for further exploration of the prognostic value of HER2 low expression in breast cancer.

References:

[1].
Guven DC, Kaya MB, Fedai B, et al.
HER2-low breast cancer could be associated with an increased risk of brain metastasis.
Int J Clin Oncol.
2022 Feb; 27(2):332-339.

[2].
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 Apr 1; 63(7):1445-8.

[3].
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 May; 33(5):759-767.

[4].
Rossi V, Sarotto I, Maggiorotto F et al (2012) Moderate immunohistochemical expression of HER-2 (2+) without HER-2 gene amplification is a negative prognostic factor in early breast cancer.
Oncologist 17:1418–1425.

[5].
Eggemann H, Ignatov T, Burger E et al (2015) Moderate HER2 expression as a prognostic factor in hormone receptor positive breast cancer.
Endocr Relat Cancer 22:725–733.

[6].
Howlader N, Cronin KA, Kurian AW et al (2018) Differences in breast cancer survival by molecular subtypes in the United States.
Cancer Epidemiol Biomark Prev 27:619.

* This article is supported by AstraZeneca and is intended for medical professionals only

Approval number: CN-106928 Valid until: 2023-12-6