Prognostic significance of HER2 low expression in patients with HR-positive early-stage breast cancer

*For medical professionals only

Low HER2 expression does not affect the prognosis of HR-positive breast cancer, but there is a tendency
to increase the risk of recurrence in some histological subtypes.

A recently published retrospective study aimed to evaluate the prognostic significance
of low expression of human epidermal growth factor receptor 2 (HER2) in patients with hormone receptor (HR)-positive breast cancer.
A total of 949 patients with HR-positive/HER2-negative breast cancer were enrolled, and the results showed that low expression of HER2 in patients with HR-positive breast cancer did not affect prognosis, but may lead to shortened
recurrence-free survival (DFS) in patients with invasive lobular carcinoma and invasive breast ductal/lobular carcinoma, as well as patients with HER2 2+ and node-positive lymph nodes.
Although the study had limitations such as single-center case origin and retrospective study, the effect of HER2 low expression on the prognosis of different histological subtypes was also observed, further supporting the idea that
HER2 low expression can be used as a new subtype of breast cancer.

background

HER2 is a transmembrane receptor with tyrosine kinase activity, encoded
by the ERBB2 gene.
The amplification of ERBB2 gene can cause HER2 protein overexpression, which is closely related
to the occurrence and development of breast cancer.
Previous studies have shown that HER2 overexpression is associated with poor prognosis in breast cancer and has a clear prognostic value
.
With the emergence of the anti-HER2-targeted drug trastuzumab, HER2 overexpression has also become the main predictor
of anti-HER2 drug treatment.

At present, the detection of HER2 in breast cancer tissues is divided into two types: protein detection (immunohistochemistry, IHC) and genetic diagnosis (in situ hybridization, ISH), and the judgment criterion is the comprehensive analysis
of IHC and ISH results.
IHC test results showing HER2 3+ or HER2 2+ and ISH+, defined as HER2-positive breast cancer; When IHC 0, 1+, or HER2 2+ and ISH-, HER2-negative breast cancer
is defined.
However, there is growing evidence that HER2-low and HER2-0-expressing tumors belong to different biological subtypes with different clinicopathological features
.
Moreover, HR levels also affect the characteristics and prognosis
of HER2-low expression tumors.

With the development of HER2 ADC drugs, the status of HER2 low expression in the field of breast cancer has gradually become obvious
.
The biological and prognostic significance of low HER2 expression in breast cancer still needs to be further explored
.
This study aimed to evaluate the prognostic significance
of low HER2 expression in HR-positive early breast cancer.

method

Patients with breast cancer admitted from 2007 to 2021 were included for retrospective analysis
.
Inclusion criteria: 1) patients diagnosed with breast cancer after pathological examination; 2) HR positive/HER2 negative, HER2 status (0, 1+, 2+/ISH-) determined by ISH; 3) have completed initial treatment (surgery and/or chemotherapy and/or radiotherapy); 4) Hormone therapy
has been started.
The primary endpoint of the study was RFS, defined as the time interval
from completion of initial treatment (surgery, chemotherapy, and radiotherapy) to the first recording of any breast cancer event (local or distant recurrence of breast cancer) or death.
Stratification
was performed by HER2 status (0, 1+, 2+/ISH-) and lymph node status (node-negative, node-positive).

outcome

A total of 949 HR-positive/HER2-negative patients were included, with a median age of 51 years and a median follow-up of 2.
8 years
.
In terms of nodal status, 645 patients were node-negative, 297 were node-positive, and 7 were unknown
.
A total of 125 patients received neoadjuvant therapy, of which 113 received neoadjuvant chemotherapy and 12 received neoadjuvant hormone therapy
.
221 patients received adjuvant chemotherapy
.
944 of the 949 patients received hormone therapy, 408 received aromatase inhibitor (AI), 397 received tamoxifen, 79 received tamoxifen plus gonadotropin-releasing hormone agonist (GnRHa), and 60 received AI plus GnRHa
.

66.
6% of patients (472 IHC 1+ and 160 IHC 2+/ISH-) had low HER2 expression
.
Compared with isolated invasive ductal carcinoma, the incidence of low HER2 expression was significantly reduced in patients with invasive lobular carcinoma and invasive ductal carcinoma with mixed ductal of the invasive breast (53.
1% vs 69.
3%, P=0.
000081, see Table 1).

There were no statistically significant differences in age and genetic characteristics (pathologic germline mutation status, grade, Ki-67 expression, and risk of recurrence) in HER2 status (Table 1).

Table 1.
Patient characteristics summarized by HER2 immunohistochemical status

HER2 status is not a prognostic factor
for RFS.
In terms of lymph node status, HER2 status is not an indicator of prognosis in patients with negative or node-positive lymph nodes (Figures 1A, B); However, in node-positive people, the risk of recurrence in HER2 2+ patients tended to increase compared with HER2 0 expression patients, but there was no statistically significant difference (Figure 1B).

Figure 1.
Kaplan-Meyer was performed according to the RFS of HER2 expression in node-negative patients (A), node-positive patients (B), patients with invasive ductal carcinoma (C), and patients with invasive lobular carcinoma and invasive ductal and/lobular carcinoma (D).

analyse

In patients with invasive lobular carcinoma and invasive ductal and/lobular carcinoma, there was an increased risk of recurrence with low HER2 expression compared with HER2 0 expression, but there was no statistically significant difference (HR = 2.
192, 95% CI 0.
819-5.
912, Figure 1D).

In addition, HER2 status did not have a significant effect on RFS in patients treated with tamoxifen or AI (Figure 2).

Among patients receiving neoadjuvant chemotherapy, 10 patients achieved pathologic complete response (pCR, 8.
93%), but low HER2 expression had no prognostic significance
for response to neoadjuvant chemotherapy.

Figure 2.
Kaplan-Meyer analysis of RFS in patients receiving adjuvant treatment with AI(A) or tamoxifen (B) based on HER2 expression

Summarize and think

Breast cancer with IHC test results showing HER2 1+ or 2+ and ISH- is defined as a low-expression type of HER2
.
Currently, treatment of HR-positive breast cancer does not distinguish between low HER2 expression or HER2 0 expression
.
However, recent studies have found that HER2 low expression and HER2 0 expression breast cancer are very different in terms of clinicopathological characteristics and molecular typing, and it is unreasonable
to classify them as HER2 negative for treatment.

In this retrospective analysis of 949 patients with HR-positive early-stage breast cancer, the results of this study to evaluate the effect of HER2 status on the prognosis of patients with HR-positive early breast cancer showed no significant difference in RFS in patients with different HER2 status
.
Also, no statistically significant differences
were found in either node-negative or node-positive patients.

A large pooled analysis of data from 2310 patients from four prospective studies showed that compared with patients with HER2 0 expression, the pCR rate of breast cancer with HER2 low expression was significantly reduced (29.
3% vs 39.
0%, p=0.
0002), but disease-free survival (DFS) and overall survival (OS) were significantly increased (3-year DFS rate: 83.
4% vs 76.
1%, p=0.
0084; 3-year OS rate: 91.
6% vs 85.
8%, p=).
0.
0016）
。 Moreover, the pCR rate of patients in both groups was also affected
by HR levels.
In HR-positive patients, the pCR rate and median DFS with low HER2 expression were lower than those expressed by HER2 0, but there was no significant difference
between the two in HR-negative patients.

In addition, the molecular characterization analysis of this study showed that HR-positive/HER2 low expression patients had fewer grade 3 tumors, lower Ki-67, and lower TP53 mutation rates, that is, these patients were less
aggressive.
This may also be one of the reasons for the lower pCR rate in patients with low HER2 expression: patients with less aggressiveness have a weaker
response rate to neoadjuvant therapy.
The results suggest that HR-positive/HER2-low tumors should be evaluated
separately from HR-negative/HER2-expressing tumors.
This is consistent with the findings of Eggemann et al.
, which found significantly lower
DFS and breast cancer-specific survival in HR-positive patients compared to those with HER2 0 or 1+.

This study found that there was no significant difference between HER2 low expression of DFS and HER2 0 expression in HR-positive patients, which is inconsistent with the above reports, but similar results
have been obtained.
A retrospective analysis of 804 patients by Agostinetto et al.
showed that there was no significant difference
in DFS and OS in patients with different HR states in patients with low HER2 expression.
Horisawa et al.
also found that in 4918 patients, regardless of HR status, there was no statistically significant difference
in the prognosis of patients with low HER2 expression and HER2 0 expression.
In summary, the prognostic significance of low HER2 expression in breast cancer is controversial, and more clinical studies are needed to confirm it
.

Although these findings are conflicting, different subgroups with low HER2 expression may differ in histological subtypes
.
This study found that the incidence of low HER2 expression in invasive lobular carcinoma and invasive ductal carcinoma/lobular mixed carcinoma (53.
1%) was significantly lower than that in invasive ductal carcinoma alone (69.
3%)
.
The same differences have been reported in other studies, with retrospective analysis of 608 HR-positive/HER2-negative breast cancer patients showing significantly more common invasive lobular carcinoma in patients with HER2 0 expression compared to low HER2 expression
.
The correlation between histological isotypes and low HER2 expression levels needs to be validated
in more prospective studies.
In addition, this study also found that low HER2 expression was associated with an increased risk of recurrence in invasive ductal and/lobular carcinoma, but there was no statistically significant difference
.
Since relatively few patients with invasive lobular carcinoma and invasive ductal and/lobular carcinoma were enrolled, further validation of the prognostic significance
of low HER2 expression in these relatively rare breast cancer patients is needed in larger studies.

References

[1].
Douganiotis G, Kontovinis L, Markopoulou E, et al.
Prognostic Significance of Low HER2 Expression in Patients With Early Hormone Receptor Positive Breast Cancer.
Cancer Diagn Progn.
2022 May 3; 2(3):316-323.

Approval number: CN-105956

Expiration date: 2023-11-22

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