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Abstract

Background:

Heterogeneity of human epidermal growth factor receptor 2 (HER2) expression exists in triple-negative breast cancer (TNBC). The evolution of the HER2 testing algorithm has led to the new classification of the HER2-low category, with unclear clinicopathological and molecular features in Asian women with HER2-low TNBC.

Objectives:

This study aimed to assess the clinicopathological and molecular characteristics of HER2-low TNBC in Asian women.

Design:

Our study prospectively included 3376 patients with TNBC diagnosed from 2009 to 2021 in the Shanghai Jiao Tong University Breast Cancer Database (a multicenter dataset), and 92 patients from The Cancer Genome Atlas (TCGA) cohort were enrolled.

Methods:

Two different independent TNBC cohorts were included, a multicenter cohort (Whole cohort, n = 3376) and the TCGA cohort (n = 92). Genomic profiling covering 32 mutations for Homologous Recombination Repair and other cancer predisposition genes was obtained. Clinicopathological features, genomic status of the above genes, treatment response, and disease prognosis were compared between HER2-low and HER2-zero TNBC patients.

Results:

In Asian females, 1611 (47.72%) TNBC patients were HER2-low. HER2-low was associated with a higher percentage of postmenopausal status (odds ratio (OR) = 1.64, p < 0.001), lymph node positivity (OR = 1.14, p = 0.003), and invasive ductal carcinoma histology (OR = 1.21, p = 0.012). HER2-low group had less BRCA1 mutation (7.02% vs 13.76%, p = 0.038) but was associated with a higher rate of PIK3CA mutation (28.07% vs 12.17%, p < 0.001) compared with HER2-zero TNBC. No significant difference in breast pathologic complete response rate, breast cancer-free interval, or overall survival was observed between HER2-low and HER2-zero TNBC. In the TCGA cohort, lipid metabolism genes were upregulated in the HER2-low TNBC, enriched in alpha-linolenic acid metabolism (normalized enrichment score = 1.51, p = 0.019).

Conclusion:

Our results show that HER2-low TNBC had specific clinicopathological, genomic profiling, and biological features compared with HER2-zero TNBC in Asian women, but without significant differences in treatment response and prognosis, warranting exploring better treatment strategies to improve disease outcomes.

Keywords

clinicopathological features genomic profiling HER2-low prognosis treatment response triple-negative breast cancer

Introduction

Breast cancer is one of the most common cancers and the main cause of cancer-related mortality for females worldwide. Triple-negative breast cancer (TNBC), defined as estrogen receptor (ER) negative, progesterone receptor (PR) negative, and human epidermal growth factor receptor 2 (HER2) negative, accounts for 15%–20% of newly diagnosed cases and has the worst prognosis in breast cancer.^1–3 HER2 status is traditionally recognized as a binary classification of either positive or negative, which also guides anti-HER2 treatment. With the evolution of the HER2 testing algorithm, the nomenclature of the HER2-low category was brought out with relatively low HER2 protein expression, that is, immunohistochemistry (IHC) HER2 1+ or 2+, while non-amplified by fluorescence in situ hybridization (FISH) testing. HER2-low tumors comprise approximately 45%–55% of total breast cancer.^4,5 With such a large proportion, studies exploring its biological behaviors and potential treatment targets are warranted.

Studies have been looking into the differences in clinical and biological behaviors between HER2-low and HER2-zero tumors while achieving conflicting findings. Multiple analyses have demonstrated the prognostic significance of HER2-low status, but without consistent outcomes.^6–9 Recently, Khoury et al.¹⁰ found that a higher proportion of Asian patients had HER2-low tumors compared with other racial groups, indicating the epidemiologic difference between HER2-low and HER2-zero tumors. However, the study comprehensively evaluating the association between HER2-low expression and clinicopathological, biological, and prognostic variables in Asian women, especially in Asian women with TNBC, is still lacking.

Compared with other types of breast cancer, TNBC has limited treatment options, including chemotherapy, immunotherapy with restricted indications, targeting TROP2 antibody–drug conjugate (ADC) therapy, etc. The new classification of HER2-low has raised challenges in treatment strategies of this subtype, and targeting the HER2 ADC agent deruxtecan has been approved for HER2-low breast cancer treatment.^11–13 It is worth mentioning that poly-ADP-ribose-polymerase (PARP) inhibitors are now approved for HER2-negative breast cancer with germline BRCA1/2 mutations, which are also investigated in a wider range of breast cancer in various settings beyond germline BRCA1/2 mutations, such as somatic BRCA1/2 mutations and other homologous recombination repair (HRR) mutations.¹⁴ However, little was understood about the difference in HRR genes between HER2-low and HER2-zero TNBC, which would possibly guide further PARP inhibitor choice in TNBC with different HER2 expression.

In the current study, we enrolled Asian TNBC patients with different HER2 statuses from multiple centers, and then comprehensively analyzed the clinicopathological features, spectrum mutation of HRR-related genes, treatment response, and prognosis of HER2-low TNBC compared with HER2-zero TNBC. TNBC patients from The Cancer Genome Atlas (TCGA) dataset were analyzed for the molecular biology of HER2-low TNBC.

Materials and methods

Patients and tumor samples

Early-stage TNBC female patients receiving surgical treatment from January 2009 to December 2021 were retrospectively included. All data were offered by the Shanghai Jiao Tong University Breast Cancer Database (SJTU-BCDB), in which 40 Chinese medical centers contributed their data. The inclusion criteria were as follows: (1) The diagnosis of enrolled Asian female patients was historically categorized as TNBC; (2) tumor size ⩾1 cm; (3) complete clinicopathological and follow-up profiles; and (4) patients with neoadjuvant treatment (NAT) receiving at least four cycles of neoadjuvant chemotherapy (NAC). In our center, patients were recommended for genetic testing if any one of the conditions is met: (1) Age at diagnosis ⩽50 years; (2) the diagnosis was historically categorized as TNBC; (3) male breast cancer; (4) family history of cancer; and (5) consent of the patients. Tumor samples of all the patients tested should be accessible. All patients with TNBC are eligible for genetic analysis. A subset analysis was performed among the group of patients who underwent tumor 32 gene testing. The protocol was approved by the Ethical Committee/Institutional Review Board and was conducted in accordance with the Declaration of Helsinki.

For the TCGA cohort, clinicopathological data were retrieved from the cBioPortal (http://www.cbioportal.org/). Transcriptomic profiles (RNA-seq) and genomic profiles were downloaded from the TCGA GDC (http://xena.ucsc.edu/). A total of 92 TNBC patients with clinical information were enrolled in our study, of which 91 with RNA-sequencing data, and 79 with somatic mutation profiles.

The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement (Supplemental Material 1).

Pathological and IHC evaluation

Pathologic assessment was conducted by at least two independent expert pathologists in local laboratories, with the implication of IHC to define ER, PR, and Ki-67 expression status. According to the guidelines, less than 1% nuclear staining in tumors was considered ER or PR negative.¹⁵ Due to version updates of the definition of HER2 positivity recommended by ASCO/CAP guidelines, experienced pathologists reviewed cases diagnosed before 2014. HER2 status was tested and defined by IHC and/or ISH and was assessed by at least two experienced pathologists in local medical centers according to the ASCO/CAP guidelines of that time. HER2 IHC can be classified as 0, 1+, 2+, and 3+. HER2 negative was defined as HER2-IHC 0, 1+, or 2+ with negative ISH results. HER2-zero was defined as HER2-IHC 0, and HER2-low was defined as HER2-IHC 1+ or 2+ with negative ISH results.¹⁶ Breast pathologic complete response (pCR) was defined as the absence of invasive tumor in the breast, ypT0/is, regardless of nodal status (ypT0/is). Total pCR was defined as the absence of invasive cancer cells in the breast and axilla (ypT0/is ypN0).

Follow-up and disease outcomes

Patients enrolled were followed up with relevant examination every 3 months for 2 years after surgery and every 6 months for 3–5 years after surgery. Clinical outcomes were analyzed according to the Standardized Definitions for Efficacy End Points criteria Version 2·0.¹⁷ Breast cancer-free interval (BCFI) was defined as the time from the date of surgery to the date of initial breast cancer associated incidence, including invasive ipsilateral breast tumor recurrence, local-regional invasive recurrence, distant recurrence, invasive contralateral breast cancer, ipsilateral ductal carcinoma in situ (DCIS), contralateral DCIS, and death from breast cancer. Overall survival (OS) was defined as the time from the date of surgery to the date of mortality from any cause. The last follow-up was completed by October 2023.

Targeted sequencing and variant classification

Formalin-Fixed Paraffin-Embedded (FFPE) tumor tissues were stained with hematoxylin and eosin and assessed by two experienced pathologists to identify the tumor purity. MagPure FFPE DNA LQ Kit (Magen, Guangzhou, China) was used to extract genomic DNA from FFPE tumor tissues. DNA was sequenced by Illumina MiSeq (Paired-End Reads, 2 × 150 cycles) and analyzed by AmoyDx next-generation sequencing (NGS) data analysis system (ANDAS) (Amoy Diagnostics, Xiamen, China). A targeted NGS panel (AmoyDx HANDLE HRR NGS Panel) covering 32 genes, including 17 HRR-related genes (ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, FANCL, MRE11, NBN, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L) and other cancer predisposition genes (AR, BRAF, CDH1, CDK12, ERBB2, ESR1, HDAC2, HOXB13, KRAS, NRAS, PIK3CA, PPP2R2A, PTEN, STK11, and TP53) was used to clarify somatic mutations. Only pathogenic or likely pathogenic variants were classified as gene mutations according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines.¹⁸

Bioinformatic analyses

The genomic mutation landscape was displayed by the Maftools package in R (version 4·1·2, R Core Team (2024), Vienna, Austria). PAM50 analysis of the HER2-low and HER2-zero groups was performed using the genefu package.¹⁹ The differentially expressed genes (DEGs) between HER2-zero and HER2-low TNBC in the TCGA cohort were identified by the R package DEseq2²⁰ with the cutoff padj value <0·05 and |log2 fold change| > 1. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses were performed in DEGs by the clusterProfiler package.²¹ Gene set enrichment analysis (GSEA) software (version 4·1·0)^22,23 was used to determine whether a priori defined pathways were significantly enriched in different subgroups. Heatmap and volcano plots were generated with R software by ggplot2 and pheatmap packages.

Statistical analysis

All statistical analyses were performed using R software 4·1·2 and SPSS software 26·0 (IBM, Armonk, NY, USA). Two-sided p values <0.05 were considered statistically significant. Categorical variables were compared by Pearson’s Chi-squared (χ²) test or Fisher’s exact test if needed. Multivariable logistic regression models were applied to determine independent factors related to different HER2 statuses. The genomic mutation landscape was displayed by the Maftools package in R. Survival outcomes among different groups were performed by Kaplan–Meier curves and the Cox proportional hazards model in multivariate settings.

Results

Patients’ characteristics among different HER2 status subgroups

The process and results of the current study are presented in Supplemental Figure 1. A total of 3376 Asian female TNBC patients were included in the Whole population cohort. The patient enrolled in our study received surgery from January 2009 to December 2021; the time when breast cancer was diagnosed is represented in Supplemental Table 1. Clinicopathological features of HER2-zero and HER2-low TNBC are listed in Table 1. A total of 1611 patients (47.72%) were classified as HER2-low TNBC. Patients with HER2-low TNBC were more likely to be post-menopausal (61.89% vs 49.35%, p < 0.001) than patients with HER2-zero TNBC. Cases with HER2-low expression exhibited a higher rate of family history of breast or ovarian cancer (5.46% vs 3.97%, p = 0.040), more lymph node involvement (32.84% vs 28.61%, p = 0.008), a higher percentage of invasive ductal carcinoma (IDC) histology (69.34% vs 64.70%, p = 0.004), more lymphovascular invasion (9.75% vs 7.71%, p = 0.035), but a lower proliferation rate (Ki-67 ⩽30%, 32.15% vs 27.37%, p = 0.002) compared with HER2-zero TNBC. Multivariate analysis demonstrated that menopausal status (odds ratio (OR) = 1.64, 95% confidence interval (CI): 1.43–1.89, p < 0.001), family history of breast or ovarian cancer (OR = 1.47, 95% CI: 1.06–2.04, p = 0.021), lymph node involvement (OR = 1.14, 95% CI: 1.05–1.25, p = 0.003), and IDC histology (OR = 1.21, 95% CI: 1.04–1.40, p = 0.012) were independently associated with HER2-low tumors (Supplemental Table 2). In the TCGA cohort, 18 (19.57%) patients with HER2-zero and 74 (80.43%) patients with HER2-low TNBC. More patients with HER2-low TNBC were postmenopausal (67.57% vs 38.88%, p = 0.023) while no differences were observed in any other clinicopathological features between HER2-zero and HER2-low TNBC (Supplemental Table 3).

Table 1.

Baseline clinicopathological characteristics between HER2-low and HER2-zero groups in triple-negative breast cancer (whole population cohort).

Characteristics	Total, N (%)N = 3376	HER2-zero, N (%)N = 1765	HER2-low, N (%)N = 1611	p-Value
Menopausal status				<0.001
Pre/peri-menopausal	1508 (44.67)	894 (50.65)	614 (38.11)
Post-menopausal	1868 (55.33)	871 (49.35)	997 (61.89)
Family history (breast or ovarian cancer)				0.040
No	3218 (95.32)	1695 (96.03)	1523 (94.54)
Yes	158 (4.68)	70 (3.97)	88 (5.46)
Family history (other cancers)				0.117
No	3220 (95.38)	1693 (95.92)	1527 (94.79)
Yes	156 (4.62)	72 (4.08)	84 (5.21)
Tumor size, cm				0.336
⩽2.0	1311 (38.83)	699 (39.60)	612 (37.99)
>2.0	2065 (61.17)	1066 (60.40)	999 (62.01)
Node status				0.008
Negative	2342 (69.37)	1260 (71.39)	1082 (67.16)
Positive	1034 (30.63)	505 (28.61)	529 (32.84)
Histologic type				0.004
IDC	2259 (66.91)	1142 (64.70)	1117 (69.34)
Non-IDC^a	1117 (33.09)	623 (35.30)	494 (30.66)
Grade				0.122
I/II	996 (29.50)	481 (27.25)	515 (31.97)
III	1833 (54.30)	941 (53.31)	892 (55.37)
NA	547 (16.20)	343 (19.43)	204 (12.66)
Ki-67, %				0.002
⩽30	1001 (29.65)	483 (27.37)	518 (32.15)
>30	2375 (70.35)	1282 (72.63)	1093 (67.85)
Lymphovascular invasion				0.035
No	3083 (91.32)	1629 (92.29)	1454 (90.25)
Yes	293 (8.68)	136 (7.71)	157 (9.75)
Adjuvant treatment strategy				0.221
Others	616 (18.25)	336 (19.04)	280 (17.38)
A + T	2216 (65.64)	1147 (64.98)	1069 (66.36)
NA	544 (16.11)	282 (15.98)	262 (16.26)
Adjuvant treatment strategy (carboplatin)				0.121
No	2528 (74.89)	1307 (74.05)	1221 (75.79)
Yes	304 (9.00)	176 (9.97)	128 (7.95)
NA	544 (16.11)	282 (15.98)	262 (16.26)

Other: capecitabine, fluorouracil, vinorelbine, etc.

Non-IDC: invasive lobular carcinoma, metaplastic carcinoma, secretory carcinoma, apocrine carcinoma, etc.

A, anthracyclines; HER2, human epidermal growth factor receptor 2; IDC, invasive ductal carcinoma; NA, not available; T, taxanes.

Gene mutation landscape between HER2-low and HER2-zero tumors in the HRR cohort and the TCGA cohort

All TNBC patients were eligible for the HRR test. Limited by financial burden and accessibility of tumor sample, a total of 360 TNBC patients were finally sequenced for HRR and other cancer predisposition genes (HRR cohort). Clinicopathological features of the HRR cohort and the differences between the whole cohort and the HRR cohort were, respectively, presented (Supplemental Tables 4 and 5). HRR-related genes status was summarized and stratified according to HER2 status (HER2-low vs HER2-zero) in Figure 1. The most frequently mutated gene was BRCA1 (10.56%) in the HRR cohort (Figure 1(a)). The HER2-low group had fewer BRCA1 mutations (7.02% vs 13.76%, p = 0.038) compared with the HER2-zero group. No significant differences were found among other HRR-related gene mutations between patients with HER2-zero and HER2-low TNBC (all p > 0.05).

Figure 1.

The HRR and other cancer-associated genomic landscape of the HRR cohort according to HER2 status. (a) Landscape of HRR and cancer associated genes mutations Altered in 289 (80.28%) of 360 samples. (b) Different frequency of mutations between HER2-low and HER2-zero groups. Integrated diagram of genetic mutation landscape and clinicopathological features of the HRR cohort stratified by HER2-low and HER2-zero status. Types of specific mutation sites were plotted in the lower panel. Regarding HRR-associated genes, the mutation frequency of BRCA1 was highest (11%), followed by BRCA2 (4%). HER2-low tumors harbored less BRCA1 mutations (p = 0.038). Regarding other cancer-associated genes, the mutation frequency of TP53 was highest (62%), followed by PIK3CA (20%) and PTEN (8%). HER2-low tumors harbored more PIK3CA mutations (p < 0.001).

Regarding other cancer-associated gene mutations, the most highly mutated genes were TP53 (62.22%), followed by PIK3CA (19.72%) and PTEN (8.05%) in TNBC patients (Figure 1(b)). HER2-low tumors expressed more PIK3CA mutations compared with HER2-zero tumors (28.07% vs 12.17%, p < 0.001), while no differences were observed with other cancer-associated gene mutations in cases with different HER2 statuses (all p > 0.05).

Comparably, patients with available gene mutation profiles (N = 79) in the TCGA cohort were also analyzed and plotted in Supplemental Figure 2. The most highly mutated genes were TP53 (79.7%), followed by PIK3CA (11.4%) and PTEN (6.3%) in all TNBC patients (Supplemental Figure 2(a)). BRCA2 mutations occurred more frequently in the HER2-zero group compared with the HER2-low group (16.67% vs 1.35%, p = 0.023), so as the HRR mutations (33.33% vs 10.81%, p = 0.017; Supplemental Figure 2(b)). HER2-low TNBC had a numerically higher frequency of PIK3CA (13.51% vs 0.00%) mutations than HER2-zero, though with no statistical significance.

Gene expression level among different HER2 status subgroups

Transcriptomic profiling of TNBC patients in the TCGA cohort was evaluated according to HER2 expression status (HER2-zero vs HER2-low; Figure 2). First, PAM50 intrinsic subtypes are distributed differently between HER2-zero and HER2-low TNBC (Figure 2(a)). HER2-low TNBC tended to have a higher proportion of HER2-enriched (HER2-E) subtype compared with HER2-zero TNBC (17.81% vs 0.00%, p = 0.064, Figure 2(b)). DEGs between HER2-low and HER2-zero TNBC were then analyzed. It turned out that 375 genes were significantly upregulated and 43 genes were downregulated in HER2-low TNBC (Figure 2(c)), and upregulated genes were mainly enriched in the metabolism pathway (p < 0.01) and peroxisome proliferator-activated receptors signaling pathway (p < 0.01; Figure 2(d)). Moreover, GO enrichment analysis based on biological process also suggested a strong association between HER2-low TNBC and metabolism-related terms (including oxidation–reduction process, regulation of hormone levels, etc.; Figure 2(e)). Furthermore, GSEA analysis revealed a significant enrichment in pathways involving transmembrane transport of fatty acid (p = 0.048 and normalized enrichment score (NES) = 1.52), regulation of cholesterol efflux (p = 0.013 and NES = 1.65), and metabolism of α-linolenic (p = 0.019 and NES = 1.51) in HER2-low TNBC compared with HER2-zero TNBC (Figure 2(f)). Specifically, HER2-low TNBC expressed higher levels of ACADL and ACSBG1, indicating an activation of the fatty acid degradation pathway in HER2-low TNBC, compared with HER2-zero TNBC, while higher levels of PLA2G4E and PLA2G2A also revealed an enrichment in α-linolenic acid metabolism pathway (Figure 2(g)).

Figure 2.

Transcriptomic features and upregulated lipid metabolism of HER2-low TNBC in the TCGA cohort. (a) PAM50 intrinsic subtype distribution according to HER2 status. (b) Distribution of PAM50 intrinsic subtype based on HER2-enriched subtype according to HER2 status. (c) Volcano map illustrating DEGs between HER2-low and HER2-zero subgroups. Red dots, upregulated in HER2-low tumors (log₂FC > 1, p < 0.05), N = 375. Blue dots, downregulated in HER2-low tumors (log₂FC < −1, p < 0.05), N = 43. Gray dots, no difference between HER2-low and HER2-zero tumors (p ⩾ 0.05). (d, e) Enrichment assays based on KEGG and GO for 375 DEGs upregulated in the HER2-low group in (b). (f) GSEA plots showing pathways positively enriched in HER2-low tumors. (g) Heatmap showing expression level (z-score) of four representative DEGs annotated in metabolism-related pathways in (e). All significant differences were indicated by p < 0.05.

Correlations between HER2 status and treatment response

In our study, 376 patients received NAC (Supplemental Table 6). Regarding NAT regimens, 269 (71.54%) patients were treated with anthracyclines plus taxanes, while 16.49% (62/376) of patients received NAC with carboplatin. All patients received at least four cycles of NAT. None of them received immune checkpoint inhibitors in the neoadjuvant and adjuvant settings because the immune checkpoint inhibitors were not approved in China before 2021. In patients receiving NAC treatment, breast pCR (ypT0/Tis) and total pCR (ypT0/isN0) were 22.87% and 14.63%, respectively. There were 51 (26.70%) patients with HER2-zero TNBC achieving breast pCR, and 35 (18.32%) achieving total pCR. In patients with HER2-low TNBC, breast pCR and total pCR were 18.92% and 10.81%, respectively (Figure 3). No difference was observed in breast pCR between HER2-zero and HER2-low groups (p = 0.072), but the total pCR rate of HER2-zero TNBC was higher than that of HER2-low TNBC (p = 0.039). The breast pCR and total pCR rates, according to different NAC cycles, are presented in Supplemental Figure 3.

Figure 3.

Breast pCR and total pCR rates of the patients receiving NAC stratified by HER2 status. All significant differences were indicated by p < 0.05.

Univariate and multivariate analyses were used to analyze the factors associated with pCR, including the impact of treatment regimens. Both univariate and multivariate analyses showed that tumor size, node status, grade, and lymphovascular invasion affected the rate of breast pCR in TNBC patients receiving NAC (Supplemental Table 7, all p < 0.05). Carboplatin-based therapy was associated with breast pCR in univariate analysis (p = 0.011), but not in multivariate analysis (p = 0.097). According to total pCR, we found that menopausal status and grade significantly affected the rate of total pCR of TNBC in both univariate and multivariate analyses (all p < 0.05, Supplemental Table 8).

Concerning different NAC regimens, the breast pCR rate was not significantly different between HER2-zero and HER2-low patients regardless of NAC strategy (Supplemental Figure 4, all p > 0.05).

Correlations between HER2 status and survival outcomes

With a median follow-up of 49.4 months, 193 patients died, and 359 BCFI events were observed in the whole population cohort. No differences of BCFI (hazard ratio (HR) = 0.97, 95% CI: 0.79–1.20, p = 0.796) and OS (HR = 1.27, 9% CI: 0.95–1.68, p = 0.104) were observed between patients with HER2-low and HER2-zero TNBC (Figure 4(a) and (b)). Multivariate analysis demonstrated that HER2-low expression did not affect BCFI or OS in TNBC patients (p > 0.05). Univariate and multivariate analyses both found that tumor size >2.0 cm, lymph node metastasis, grade III, lymphovascular invasion, and adjuvant treatment regimens other than anthracycline combined with paclitaxel therapy were independently associated with worse BCFI (all p < 0.05, Table 2). Similar results were observed when we evaluated univariate and multivariate analyses of factors associated with OS (menopausal status: HR = 1.55, p = 0.019; tumor size: HR = 2.28, p < 0.001; node status: HR = 3.50, p < 0.001; lymphovascular: HR = 1.17, p = 0.015, adjuvant treatment strategy (other vs A + T): HR = 1.70, p = 0.001, Table 3).

Figure 4.

Survival outcomes according to HER2 status in the whole population cohort. Kaplan–Meier curves comparing BCFI and OS between HER2-low and HER2-zero tumors in the whole population cohort (a, b). Yellow line: HER2-low; blue line: HER2-zero. The log-rank test was applied to determine significant differences (p < 0.05).

Table 2.

Univariate and multivariate analyses of factors associated with BCFI in triple-negative breast cancer (whole population cohort).

Variables	Univariant analysis			Multivariant analysis
Variables	HR	95% CI	p-Value	HR	95% CI	p-Value
HER2 status (low vs zero)	0.97	0.79–1.20	0.796	0.87	0.69–1.11	0.257
Menopausal status (post vs pre/peri-menopausal)	1.04	0.84–1.28	0.735	NA	NA	NA
Tumor size, cm (>2.0 vs ⩽2.0)	2.61	2.03–3.36	<0.001	2.20	1.65–2.93	<0.001
Node status (positive vs negative)	3.32	2.69–4.09	<0.001	2.43	1.90–3.11	<0.001
Histologic type (IDC vs non-IDC^a)	1.14	0.91–1.43	0.263	NA	NA	NA
Grade (III vs I/II)	1.18	1.01–1.37	0.039	1.21	1.00–1.46	0.042
Ki-67, % (>30 vs ⩽30)	1.11	0.88–1.40	0.364	NA	NA	NA
Lymphovascular invasion (positive vs negative)	2.86	2.20–3.71	<0.001	1.92	1.41–2.61	<0.001
Adjuvant treatment strategy
Other vs A + T	4.07	2.89–5.73	<0.001	1.23	1.00–1.51	0.049
Carboplatin vs without carboplatin	0.80	0.53–1.21	0.289	NA	NA	NA

Other: capecitabine, fluorouracil, vinorelbine, etc.

Non-IDC: invasive lobular carcinoma, metaplastic carcinoma, secretory carcinoma, apocrine carcinoma, etc.

A, anthracyclines; BCFI, breast cancer-free interval; CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; IDC, invasive ductal carcinoma; NA, not available; T, taxanes.

Table 3.

Univariate and multivariate analyses of factors associated with OS in triple-negative breast cancer (whole population cohort).

Variables	Univariant analysis			Multivariant analysis
Variables	HR	95% CI	p-Value	HR	95% CI	p-Value
HER2 status (low vs zero)	1.27	0.95–1.68	0.104	1.05	0.73–1.48	0.806
Menopausal status (post vs pre/peri-menopausal)	1.43	1.06–1.91	0.017	1.55	1.08–2.22	0.019
Tumor size, cm (>2.0 vs ⩽2.0)	2.98	2.08–4.26	<0.001	2.28	1.48–3.50	<0.001
Node status (positive vs negative)	4.31	3.22–5.79	<0.001	3.50	2.42–5.07	<0.001
Histologic type (IDC vs non-IDC^a)	0.98	0.71–1.36	0.906	NA	NA	NA
Grade (III vs I/II)	0.95	0.77–1.17	0.624	NA	NA	NA
Ki-67, % (>30 vs ⩽30)	0.95	0.70–1.28	0.724	NA	NA	NA
Lymphovascular invasion (positive vs negative)	3.02	2.13–4.28	<0.001	1.71	1.11–2.63	0.015
Adjuvant treatment strategy
Other vs A + T	5.76	3.69–9.00	<0.001	1.70	1.23–2.36	0.001
Carboplatin vs without carboplatin	0.65	0.34–1.25	0.197	NA	NA	NA

Other: capecitabine, fluorouracil, vinorelbine, etc.

Non-IDC: invasive lobular carcinoma, metaplastic carcinoma, secretory carcinoma, apocrine carcinoma, etc.

A, anthracyclines; CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; IDC, invasive ductal carcinoma; NA, not available; OS, overall survival; T, taxanes.

Concerning different subgroups, a forest plot was conducted to compare survival outcomes between HER2-zero and HER2-low TNBC patients. In patients diagnosed as non-IDC, HER2-zero was associated with better BCFI (Supplemental Figure 5, HR = 0.57, p = 0.006). No significances of BCFI were observed in other subgroups between HER2-zero and HER2-low TNBC (all p > 0.05). The association between HER2 status and OS was analyzed in different subgroups (Supplemental Figure 6). HER2-zero was an independent risk for worse OS in patients without a family history of breast cancer or ovarian cancer (p = 0.06), diagnosed as IDC (p = 0.02), without lymphovascular invasion (p = 0.09), or who underwent A + T treatment (p = 0.09). In other subgroups, HER2 low expression did not affect OS in TNBC patients (all p > 0.05).

In addition, with previous results showing the high frequency of PIK3CA mutations in HER2-low TNBC, here we reported the specific outcomes in HER2-low tumors according to the status of PIK3CA mutations (Supplemental Figure 7). Among the group with HER2-low TNBC, no significant difference in BCFI (p = 0.622) or OS (p = 0.806) between patients with and without PIK3CA mutations was observed. Likewise, no significant differences in BCFI (p = 0.315) or OS (p = 0.577) were observed according to the different status of PIK3CA mutations in patients with HER2-zero TNBC.

Discussion

In the current study, we integrated multicenter data and the TCGA data to analyze clinicopathological and molecular characteristics of HER2-low TNBC in Asian females. We found that HER2-low TNBC had comparable treatment response and survival outcomes but different clinicopathologic features compared with HER2-zero TNBC patients. Regarding gene mutations, HER2-low tumors had a lower percentage of BRCA1 mutations but with a higher frequency of PIK3CA mutations compared with HER2-zero TNBC. Moreover, HER2-low TNBC was associated with activating lipid metabolism pathways, which may provide specific target therapy strategies for further clinical investigation.

In our study, 47.72% of TNBC patients had HER2-low tumors, consistent with the published report, which showed that the proportion of HER2-low tumors of Asian TNBC patients was 48.3%.²⁴ We also found that HER2-low TNBC patients were more likely to be postmenopausal, lymph node positivity, with IDC histology, and had more family history of breast cancer or ovarian cancer in comparison with HER2-zero patients. In vitro experiments showed that estradiol could decrease HER2 expression in MCF-7 cells possibly due to the presence of cross-talk between ER and HER2, which would partially explain the higher percentage of HER2-low tumors in postmenopausal patients.²⁵ HER2-low TNBC in the whole population cohort had more lymph node involvement, which was consistent with previous reports ranging of 28%–48%,^13,24,26,27 possible explanations including more HER2-E subtype or PI3KCA mutations in HER2-low tumors.

Regarding HRR-related genomic mutation landscapes, Denkert et al.⁹ found that HER2-zero breast cancer harbored more BRCA1 mutations than HER2-low breast cancer, regardless of hormone receptor status, which was similar to our results. Regarding other genes in the HRR pathway, we found these HRR-associated gene mutations distributed without distinction between HER2-low and HER2-zero TNBC patients, indicating similar profiles in terms of DNA damage repair deficiency, and possibly due to the similar proportions of basal-like intrinsic subtypes between these two subtypes. Regarding other cancer predisposition genes, HER2-low TNBC harbored a significantly higher frequency of PIK3CA mutations compared with HER2-zero TNBC. PIK3CA mutations occurred more frequently in HER2-overexpressing breast cancer.^28,29 In addition, the PI3K/AKT/mTOR pathway activated by PIK3CA mutations takes an essential role in the process of cell growth, survival, and differentiation, which is regulated by the HER2 protein.^30,31 Thus, the higher mutation rate of PIK3CA in HER2-low TNBC may be attributed to relatively high HER2 expression levels.

To further investigate the possible distinction of molecular features between HER2-zero and HER2-low TNBC, functional analysis from the TCGA cohort revealed an upregulation of metabolic pathways in HER2-low TNBC, especially the metabolism of unsaturated fatty acids and transmembrane transport of fatty acids. Evidence suggests that several enzymes related to HER2 play important roles in lipid metabolism,³² and lipid biosynthesis was upregulated in HER2 overexpressed BC.³³ Interestingly, PIK3CA mutations could also drive the process of metabolism reprogramming among different cancers.^34,35 Oncogenic PIK3CA mutations could enhance arachidonic acid synthesis and further promote lipid metabolism via Mtorc2-Cpla2 signaling.³⁶ Thus, our study revealed a novel intrinsic phenotype of HER2-low TNBC, with activated lipid metabolism and highly mutated PIK3CA, which would serve as a potential novel target for further drug development.

Our study demonstrated that there was no significant difference in breast pCR rate between HER2-low and HER2-zero TNBC, which was consistent with previous studies.^27,37 However, there are several studies with contrary results, possible explanations including different NAC treatment regimens, different inclusion criteria, or HER2 detection methods.^9,38 In addition, with the advent of new agents, pCR rates in TNBC gradually increased with diagnosis time.²⁷ Notably, in the current cohort, the pCR rate was relatively low (breast pCR rate 22.87%, total pCR 14.63%). There were several potential reasons to consider: 31% of patients with locally advanced breast cancer (LABC) were enrolled in our study. It was reported that patients with a large tumor burden were less likely to achieve pCR. Our study is retrospective research, which may lead to a mixture of NAC regimens unavoidably, including treatment cycles and chemotherapy choice. Since all patients in our study were first treated before 2021. Out of 12, none of them used immune checkpoint inhibitors in neoadjuvant or adjuvant settings, and few of our patients received nab-paclitaxel. All the above points might influence the achievement of pCR.

It has been a controversial topic whether HER2-low status was predictive of patient outcomes. Some authors demonstrated that HER2-low was associated with prolonged survival compared to HER2-zero, but depending on hormone receptor expression status^36,39; others came to the opposite conclusion.^9,36 While HER2-low status failed to predict prognosis in lots of studies, which was consistent with our results.^5,40 These contentious results may be explained by different enrolled populations, treatment strategies, and HER2 testing methods. In addition, many authors argued that hormone receptor status, rather than HER2-low expression, was more relevant to prognosis. In our study, we only included hormone receptor-negative patients and found there was no survival difference between HER2-low and HER2-zero patients, indicating novel agents targeting HER2-low tumors are needed to further improve the prognosis of HER2-low TNBC patients.

The emergence of new ADC agents brought a new option for HER2-low tumors. The DESTINY-Breast 04 study found that trastuzumab deruxtecan halved the risk of disease progression or death of HER2-low metastatic BC regardless of hormone receptor status, but there were only 60 HER2-low TNBC patients enrolled.¹¹ In the DESTINY-Breast 06 trial, patients with hormone receptor+, HER2-low, or HER2-ultralow treated metastatic breast cancer in the trastuzumab deruxtecan group had longer progression-free survival (PFS) than the chemotherapy group.⁴¹ However, TNBC patients were limited in those two studies mentioned above, indicating an urgent need to further explore the efficacy of ADCs in HER2-low TNBC. In addition, the high frequency of PIK3CA mutations in HER2-low TNBC suggests a potential benefit from PI3K-targeted therapy. Following the efficacy of PI3K inhibitors in PIK3CA mutant hormone receptor-positive breast cancer, the clinical research of PI3K inhibitors in TNBC has yielded its first results. A phase I/II trial of alpelisib (α-specific PI3K inhibitor) plus nab-paclitaxel in patients with HER2-negative metastatic breast cancer was published in Clinical Cancer Research.⁴² Forty-three patients were enrolled, including 13 patients with TNBC. Forty percent of patients with PI3KCA mutations had longer PFS than the group without mutations (11.9 vs 7.5 months). However, BELLE4 showed no improvement in PFS with buparlisib (pan-classIPI3K inhibitor) versus placebo in the total or PI3K pathway-activated population.⁴³ Inconsistent findings might be due to different types of PI3K inhibitors. In addition, there are several clinical trials ongoing or recruiting (Supplemental Table 9). Currently, there is no high-level evidence for the use of PI3K inhibitors targeted PIK3CA-mutated TNBC. Research in progress may offer a better prospect on how the therapy targeting PIK3CA mutations affects TNBC patients in the future.

Our study has some limitations, including potential bias from a retrospective study, central revision of HER2 expression of all cases not achieved, and numerical limitation of patients with known genetic mutations due to financial or health insurance reasons. The whole population cohort enrolled patients from a long-range period (2009–2021), while the main defining cutoff value for HER2 IHC remains unchanged.

Conclusion

In conclusion, our study found that HER2-low tumors had specific clinicopathological and genetic features compared with HER2-zero tumors in Asian females with TNBC. However, there were no significant differences in treatment response and prognosis between HER2-low and HER2-zero TNBC patients, warranting exploring novel HER2-low target strategies, therapy, and clinical evaluation.

Supplemental Material

sj-docx-1-tam-10.1177_17588359251353083 – Supplemental material for Clinicopathological and molecular significance of HER2-low expression in Asian women with triple-negative breast cancer

Supplemental material, sj-docx-1-tam-10.1177_17588359251353083 for Clinicopathological and molecular significance of HER2-low expression in Asian women with triple-negative breast cancer by Cuiyan Yang, Haoyu Wang, Yiwei Tong, Zheng Wang, Xi Sun, Anqi Li, Yujie Lu, Mengyuan Han, Siji Zhu, Lei Dong, Kunwei Shen and Xiaosong Chen in Therapeutic Advances in Medical Oncology

Supplemental Material

sj-docx-2-tam-10.1177_17588359251353083 – Supplemental material for Clinicopathological and molecular significance of HER2-low expression in Asian women with triple-negative breast cancer

Supplemental material, sj-docx-2-tam-10.1177_17588359251353083 for Clinicopathological and molecular significance of HER2-low expression in Asian women with triple-negative breast cancer by Cuiyan Yang, Haoyu Wang, Yiwei Tong, Zheng Wang, Xi Sun, Anqi Li, Yujie Lu, Mengyuan Han, Siji Zhu, Lei Dong, Kunwei Shen and Xiaosong Chen in Therapeutic Advances in Medical Oncology

Supplemental Material

sj-eps-3-tam-10.1177_17588359251353083 – Supplemental material for Clinicopathological and molecular significance of HER2-low expression in Asian women with triple-negative breast cancer

Supplemental material, sj-eps-3-tam-10.1177_17588359251353083 for Clinicopathological and molecular significance of HER2-low expression in Asian women with triple-negative breast cancer by Cuiyan Yang, Haoyu Wang, Yiwei Tong, Zheng Wang, Xi Sun, Anqi Li, Yujie Lu, Mengyuan Han, Siji Zhu, Lei Dong, Kunwei Shen and Xiaosong Chen in Therapeutic Advances in Medical Oncology

Supplemental Material

sj-eps-4-tam-10.1177_17588359251353083 – Supplemental material for Clinicopathological and molecular significance of HER2-low expression in Asian women with triple-negative breast cancer

Supplemental material, sj-eps-4-tam-10.1177_17588359251353083 for Clinicopathological and molecular significance of HER2-low expression in Asian women with triple-negative breast cancer by Cuiyan Yang, Haoyu Wang, Yiwei Tong, Zheng Wang, Xi Sun, Anqi Li, Yujie Lu, Mengyuan Han, Siji Zhu, Lei Dong, Kunwei Shen and Xiaosong Chen in Therapeutic Advances in Medical Oncology

Supplemental Material

sj-eps-5-tam-10.1177_17588359251353083 – Supplemental material for Clinicopathological and molecular significance of HER2-low expression in Asian women with triple-negative breast cancer

Supplemental material, sj-eps-5-tam-10.1177_17588359251353083 for Clinicopathological and molecular significance of HER2-low expression in Asian women with triple-negative breast cancer by Cuiyan Yang, Haoyu Wang, Yiwei Tong, Zheng Wang, Xi Sun, Anqi Li, Yujie Lu, Mengyuan Han, Siji Zhu, Lei Dong, Kunwei Shen and Xiaosong Chen in Therapeutic Advances in Medical Oncology

Supplemental Material

sj-eps-6-tam-10.1177_17588359251353083 – Supplemental material for Clinicopathological and molecular significance of HER2-low expression in Asian women with triple-negative breast cancer

Supplemental material, sj-eps-6-tam-10.1177_17588359251353083 for Clinicopathological and molecular significance of HER2-low expression in Asian women with triple-negative breast cancer by Cuiyan Yang, Haoyu Wang, Yiwei Tong, Zheng Wang, Xi Sun, Anqi Li, Yujie Lu, Mengyuan Han, Siji Zhu, Lei Dong, Kunwei Shen and Xiaosong Chen in Therapeutic Advances in Medical Oncology

Supplemental Material

sj-eps-7-tam-10.1177_17588359251353083 – Supplemental material for Clinicopathological and molecular significance of HER2-low expression in Asian women with triple-negative breast cancer

Supplemental material, sj-eps-7-tam-10.1177_17588359251353083 for Clinicopathological and molecular significance of HER2-low expression in Asian women with triple-negative breast cancer by Cuiyan Yang, Haoyu Wang, Yiwei Tong, Zheng Wang, Xi Sun, Anqi Li, Yujie Lu, Mengyuan Han, Siji Zhu, Lei Dong, Kunwei Shen and Xiaosong Chen in Therapeutic Advances in Medical Oncology

Supplemental Material

sj-eps-8-tam-10.1177_17588359251353083 – Supplemental material for Clinicopathological and molecular significance of HER2-low expression in Asian women with triple-negative breast cancer

Supplemental material, sj-eps-8-tam-10.1177_17588359251353083 for Clinicopathological and molecular significance of HER2-low expression in Asian women with triple-negative breast cancer by Cuiyan Yang, Haoyu Wang, Yiwei Tong, Zheng Wang, Xi Sun, Anqi Li, Yujie Lu, Mengyuan Han, Siji Zhu, Lei Dong, Kunwei Shen and Xiaosong Chen in Therapeutic Advances in Medical Oncology

Supplemental Material

sj-eps-9-tam-10.1177_17588359251353083 – Supplemental material for Clinicopathological and molecular significance of HER2-low expression in Asian women with triple-negative breast cancer

Supplemental material, sj-eps-9-tam-10.1177_17588359251353083 for Clinicopathological and molecular significance of HER2-low expression in Asian women with triple-negative breast cancer by Cuiyan Yang, Haoyu Wang, Yiwei Tong, Zheng Wang, Xi Sun, Anqi Li, Yujie Lu, Mengyuan Han, Siji Zhu, Lei Dong, Kunwei Shen and Xiaosong Chen in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

The authors appreciate Yidong Du for maintaining the dataset SJTU-BCDB.

Declarations

ORCID iD

Xiaosong Chen

Supplemental material

Supplemental material for this article is available online.

References

Dent

Trudeau

Pritchard

, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 2007; 13(15): 4429–4434.

Sung

Ferlay

Siegel

, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71(3): 209–249.

Foulkes

Smith

Reis-Filho

JS.

Triple-negative breast cancer. N Engl J Med 2010; 363(20): 1938–1948.

Tarantino

Hamilton

Tolaney

, et al. HER2-low breast cancer: pathological and clinical landscape. J Clin Oncol 2020; 38(17): 1951–1962.

Schettini

Chic

Brasó-Maristany

, et al. Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer. NPJ Breast Cancer 2021; 7(1): 1.

Rossi

Sarotto

Maggiorotto

, et al. Moderate immunohistochemical expression of HER-2 (2+) without HER-2 gene amplification is a negative prognostic factor in early breast cancer. Oncologist 2012; 17(11): 1418–1425.

Eggemann

Ignatov

Burger

, et al. Moderate HER2 expression as a prognostic factor in hormone receptor positive breast cancer. Endocr Relat Cancer 2015; 22(5): 725–733.

Agostinetto

Rediti

Fimereli

, et al. HER2-low breast cancer: molecular characteristics and prognosis. Cancers 2021; 13(11): 2824.

Denkert

Seither

Schneeweiss

, et al. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol 2021; 22(8): 1151–1161.

10.

Khoury

Mendicino

Payne Ondracek

, et al. Clinical, epidemiologic, and pathologic significance of ERBB2-low expression in breast cancer. JAMA Netw Open 2024; 7(3): e243345.

11.

Modi

Jacot

Yamashita

, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med 2022; 387(1): 9–20.

12.

Narayan

Dilawari

Osgood

, et al. US Food and Drug Administration approval summary: Fam-trastuzumab deruxtecan-nxki for human epidermal growth factor receptor 2-low unresectable or metastatic breast cancer. J Clin Oncol 2023; 41(11): 2108–2116.

13.

Gradishar

Moran

Abraham

, et al. NCCN guidelines^® insights: breast cancer, Version 4.2023. J Natl Compr Canc Netw 2023; 21(6): 594–608.

14.

Herzog

Vergote

Gomella

, et al. Testing for homologous recombination repair or homologous recombination deficiency for poly (ADP-ribose) polymerase inhibitors: a current perspective. Eur J Cancer (Oxford, England: 1990) 2023; 179: 136–146.

15.

Hammond

Hayes

Dowsett

, et al.; American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med 2010; 134(7): e48–e72.

16.

Wolff

Hammond

MEH

Allison

, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 2018; 36(20): 2105–2122.

17.

Tolaney

Garrett-Mayer

White

, et al. Updated standardized definitions for efficacy end points (STEEP) in adjuvant breast cancer clinical trials: STEEP version 2.0. J Clin Oncol 2021; 39(24); 2720–2731.

18.

Richards

Aziz

Bale

, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17(5): 405–424.

19.

Gendoo

Ratanasirigulchai

Schröder

, et al. Genefu: an R/Bioconductor package for computation of gene expression-based signatures in breast cancer. Bioinformatics 2016; 32(7): 1097–1099.

20.

Love

Huber

Anders

Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 2014; 15(12): 550.

21.

Wang

Han

, et al. ClusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 2012; 16(5): 284–287.

22.

Subramanian

Tamayo

Mootha

, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 2005; 102(43): 15545–15550.

23.

Mootha

Lindgren

Eriksson

, et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 2003; 34(3): 267–273.

24.

Jiao

Zhang

, et al. HER2-low status was associated with better breast cancer-specific survival in early-stage triple-negative breast cancer. Oncologist 2024; 29(3): e309–e318.

25.

Lattrich

Juhasz-Boess

Ortmann

, et al. Detection of an elevated HER2 expression in MCF-7 breast cancer cells overexpressing estrogen receptor beta1. Oncol Rep 2008; 19(3): 811–817.

26.

, et al. Effect of HER2-low expression on neoadjuvant efficacy in operable breast cancer. Clin Transl Oncol 2024; 26(4): 880–890.

27.

Plichta

, et al. Impact of HER2-low status for patients with early-stage breast cancer and non-pCR after neoadjuvant chemotherapy: a National Cancer Database Analysis. Breast Cancer Res Treat 2024; 204(1): 89–105.

28.

Saal

Holm

Maurer

, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 2005; 65(7): 2554–2559.

29.

Martínez-Sáez

Chic

Pascual

, et al. Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast Cancer Res 2020; 22(1): 45.

30.

Mangiapane

Nicotra

Turdo

, et al. PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells. Gut 2022; 71(1): 119–128.

31.

Gong

Yang

Y-S

, et al. Metabolic-pathway-based subtyping of triple-negative breast cancer reveals potential therapeutic targets. Cell Metab 33(1): 51–64.e9.

32.

Ray

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment. Horm Mol Biol Clin Investig 2017; 32(3): /j/hmbci.2017.32.issue-3/hmbci-2017-0020/hmbci-2017-0020.xml.

33.

Ligorio

Pellegrini

Castagnoli

, et al. Targeting lipid metabolism is an emerging strategy to enhance the efficacy of anti-HER2 therapies in HER2-positive breast cancer. Cancer Lett 2021; 511: 77–87.

34.

Lien

Lyssiotis

Cantley

LC.

Metabolic reprogramming by the PI3K-Akt-mTOR pathway in cancer. Recent Results Cancer Res 2016; 207: 39–72.

35.

Koundouros

Karali

Tripp

, et al. Metabolic fingerprinting links oncogenic PIK3CA with enhanced arachidonic acid-derived eicosanoids. Cell 2020; 181(7): 1596–1611.e27.

36.

Mutai

Barkan

Moore

, et al. Prognostic impact of HER2-low expression in hormone receptor positive early breast cancer. Breast 2021; 60: 62–69.

37.

Miglietta

Griguolo

Bottosso

, et al. HER2-low-positive breast cancer: evolution from primary tumor to residual disease after neoadjuvant treatment. NPJ Breast Cancer 2022; 8(1): 66.

38.

Zhu

Fei

, et al. Pathological complete response, category change, and prognostic significance of HER2-low breast cancer receiving neoadjuvant treatment: a multicenter analysis of 2489 cases. Br J Cancer 2023; 129(8): 1274–1283.

39.

Atallah

Haque

Quinn

, et al. Characterisation of luminal and triple-negative breast cancer with HER2 low protein expression. Eur J Cancer (Oxford, UK: 1990) 2023; 195: 113371.

40.

De Moura Leite

Cesca

Tavares

, et al. HER2-low status and response to neoadjuvant chemotherapy in HER2 negative early breast cancer. Breast Cancer Res Treat 2021; 190(1): 155–163.

41.

Bardia

Dent

, et al. Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. N Engl J Med 2024; 391(22): 2110–2122.

42.

Sharma

Abramson

O’Dea

, et al. Clinical and biomarker results from phase I/II study of PI3K inhibitor alpelisib plus Nab-paclitaxel in HER2-negative metastatic breast cancer. Clin Cancer Res 2021; 27(14): 3896–3904.

43.

Martín

Chan

Dirix

, et al. A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2− advanced breast cancer (BELLE-4). Ann Oncol 2017; 28(2): 313–320.

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