MR and mammographic imaging features of HER2-positive breast cancers according to hormone receptor status: a retrospective comparative study

Abstract

Background

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer has two distinct subtypes according to hormone receptor (HR) status. Survival, pattern of recurrence, and treatment response differ between HR–/HER2+ and HR+/HER2+ cancers.

Purpose

To investigate imaging and clinicopathologic features of HER2+ cancers and their correlation with HR expression.

Material and Methods

Between 2011 and 2013, 252 consecutive patients with 252 surgically confirmed HER2+ cancers (125 HR– and 127 HR+) were included. Two experienced breast radiologists blinded to the clinicopathologic findings reviewed the mammograms and magnetic resonance (MR) images using the BI-RADS lexicon. Tumor kinetic features were acquired by computer-aided detection (CAD). The imaging and clinicopathologic features of 125 HR–/HER2+ cancers were compared with those of 127 HR+/HER2+ cancers. Association between the HR status and each feature was assessed.

Results

Multiple logistic regression analysis showed that circumscribed mass margin (odds ratio [OR], 4.73; P < 0.001), associated non-mass enhancement (NME) on MR images (OR, 3.29; P = 0.001), high histologic grade (OR, 3.89; P = 0.002), high Ki-67 index (OR, 3.06; P = 0.003), and older age (OR, 2.43; P = 0.006) remained independent indicators associated with HR–/HER2+ cancers. Between the two HER2+ subtypes, there were no differences in mammographic imaging presentations and calcification features and MR kinetic features by a CAD.

Conclusion

HER2+ breast cancers have different MR imaging (MRI) phenotypes and clinicopathologic feature according to HR status. MRI features related to HR and HER2 status have the potential to be used for the diagnosis and treatment decisions in HER2+ breast cancer patients.

Keywords

Breast tumors human epidermal growth factor receptor 2 (HER2)hormone receptors mammography magnetic resonance imaging (MRI)

Introduction

Human epidermal growth factor receptor 2 (HER2) overexpression accounts for approximately 20% of invasive breast cancers and is associated with decreased survival (1,2). Data from the cancer genome atlas (TCGA) and results of clinical trials with anti-HER2-targeted therapy suggest that HER2-positive (HER2+) cancers are a heterogeneous group of cancers (3 –5). Hormone receptor (HR) status can define two distinct subtypes among tumors with HER2 overexpression: HR-negative (HR–)/HER2+ and HR-positive (HR+)/HER2+ tumors (6,7). Survival, pattern of recurrence, and treatment response differ between these two subtypes. Compared with HR+/HER2+ tumors, patients with HR–/HER2+ tumors had a higher risk of death within 5 years of initial diagnosis, a higher frequency of brain involvement and a lower frequency of bone metastasis, and better response to neoadjuvant chemotherapy (5,8). In combination with chemotherapy, HER2-targeted agents, including trastuzumab, are recommended as systemic treatments for HR–/HER2+ tumors; endocrine therapy with HER2-targeted agents is recommended for HR+/HER2+ tumors (9).

Previous studies have investigated imaging features of HER2+ cancers and found that the presence of microcalcifications (particularly fine pleomorphic or linear branching morphology) on mammography was characteristics of breast tumors with HER2 overexpression (10,11). On magnetic resonance imaging (MRI), irregular mass margins, multifocality, and washout or fast initial kinetics tended to be associated with HER2+ cancers (12,13). However, circumscribed mass margins have also been reported as characteristics of HER2+ tumors on MRI (14,15). In most imaging studies of breast cancer subtypes, analyses have focused on results in triple-negative breast cancer, and imaging findings in HER2+ tumors have not been delineated and compared with regard to HR status. We hypothesized that HR–/HER2+ and HR+/HER2+ tumors would have distinguishing imaging and clinicopathologic features that reflect biologic differences between the two HER2 subtypes. The identification of these features could not only increase our biologic understanding but also have clinical applications including selecting the most appropriate lesions to biopsy in case of multifocal or multicentric tumors and predicting treatment responses or recurrence in HER2+ tumors (10,13,16).

Therefore, the purpose of our study was to investigate whether HER2+ breast cancers with and without HR expression have distinguishing imaging and clinicopathologic features and to assess if certain features could distinguish HR–/HER2+ tumors from HR+/HER2+ tumors.

Material and Methods

Study population

Between January 2011 and December 2013, a search of the pathology database identified a consecutive series of 386 breast cancer patients who had final pathologic diagnoses of invasive ductal carcinoma confirmed in surgical operations as well as HER2 overexpression. Of these 386 patients, 134 were excluded because of neoadjuvant chemotherapy prior to MRI (n = 49) or previous breast surgery prior to MRI (n = 35), microinvasive carcinomas (n = 24), and no MRI (n = 26). We excluded patients who received neoadjuvant chemotherapy prior to MRI because core needle biopsy and surgical specimens can yield discordant result regarding HR and HER2 status (16). Finally, a total of 252 patients (mean age, 52.4 years; age range, 30–79 years) who had both imaging modalities (mammography and MRI) were included in the analysis.

Image acquisition

Standard two-view mammography was performed with two dedicated units (LORAD Selenia, Hologic, Bedford, MA, USA, and Senographe 2000D, GE Healthcare, Milwaukee, WI, USA).

Breast MR examinations were performed using a 1.5-T scanner (Signa, GE Healthcare, Milwaukee, WI, USA). Sagittal fat-suppressed T2-weighted (T2W) fast spin-echo (FSE) images and dynamic contrast-enhanced (DCE) examinations including one pre-contrast and five post-contrast bilateral sagittal image acquisitions were obtained. A commercially available computer-aided detection (CAD) system (CAD stream; Confirma, Kirkland, WA, USA) was retrospectively applied to all MR examinations to assess the kinetic features.

Image analysis

Two experienced radiologists (SES and WKM with 5 and 22 years of breast imaging experience, respectively) reviewed 252 pairs of mammograms and MR images without knowledge of the clinical or histopathological features and interpreted the images based on the 2013 Breast Imaging Reporting and Data System (BI-RADS), established by the American College of Radiology (17), and the criteria from the TCGA Breast Phenotype Research Group (http://www.cancerimagingarchive.net/). Mammograms and MR images were reviewed independently. Before the results were recorded, both radiologists who analyzed the image had to agree on its interpretation. In those patients with multiple masses, only the lesion with the largest diameter was evaluated in each patient.

On mammography, imaging presentations were described as none, mass only, mass with calcifications, calcifications only, or focal asymmetries. Calcifications were evaluated according to morphology and distribution (17). On MR images, the amount of fibroglandular volume (FGV) and the level of background parenchymal enhancement (BPE) were evaluated in the contralateral normal breast (17). Extents of disease were also recorded as unifocal, multifocal, or multicentric. The lesion type was recorded as mass or non-mass enhancement (NME). For mass observations, shape, margin, and internal enhancement patterns and associated NME were evaluated. The intratumoral signal intensity (SI) and peritumoral edema were evaluated on fat-suppressed T2-weighted (T2W) images. Intratumoral SI were classified as low, iso, or high compared to that of the normal parenchymal glandular tissue and peritumoral edema was defined as high signal intensity around the tumor.

Histopathologic analysis

The histopathologic diagnoses included histologic type, grade (Elston and Ellis method (18)), presence, grade of the associated ductal carcinoma in situ (DCIS), as well as tumor size and axillary lymph nodal status. Routinely formalin-fixed, paraffin-embedded tissue blocks were sectioned to 4 -µm thickness prior to use in immunohistochemistry (IHC). Imaging information was available during the histopathologic examination in all cases. For multifocal lesions, the correlation of pathological findings and imaging features were performed in multimodality conference to make sure that the HR-tested mass was indeed the MRI-assessed mass. The estrogen receptor (ER), progesterone receptor (PR), and Ki-67 were evaluated using the avidin-biotin complex IHC technique. ER and PR positivity were defined as the presence of positive staining in at least 1% of the nuclei in ten high-power fields (19). HR positivity was defined as ER- or PR-positive tumors. HER2 status was assessed using IHC and/or FISH. HER2 positivity was defined as an IHC score of 3+ or 2+ staining with positive HER2 gene amplification on FISH using the PathVysion HER2 DNA probe (Abbott Molecular Inc., Downers Grove, IL, USA). A FISH ratio (HER2 gene signal to chromosome 17 signal) of greater than 2.2 was considered a positive result (20). Ki-67 expression was graded as low (<20%) or high (≥20%) (9).

Statistical analysis

Statistical analyses were performed using SPSS version 19.0 software (SPSS Inc., Chicago, IL, USA). Among the HER2+ cancers, the association between HR status and the clinicopathologic and imaging features was assessed using Fisher’s exact test or the chi-square test. Lesion sizes on MR images of the HR–/HER2+ versus HR+/HER2+ tumors were compared using Student’s t test. On a CAD, the proportions with a rapid component in the initial phase and a washout component in the delayed phase were compared using the Mann–Whitney test. Variables showing a P value of less than 0.05 with Fisher’s exact test or the chi-square test were entered as input variables for univariate analysis and multiple logistic regression analysis with stepwise selection was used to identify independent predictors of HR negativity within HER2+ cancers. Receiver-operating-characteristic (ROC) curve analysis was performed to test the diagnostic performance in distinguishing HR–/HER2+ and HR+/HER2+ subtypes. P values less than 0.05 were considered statistically significant.

Results

Clinicopathologic features

Of 252 patients, 125 (49.6%) were HR–/HER2+ and 127 (50.4%) were HR+/HER2+ subtypes. Compared with the HR+/HER2+ tumors, HR–/HER2+ tumors were significantly associated with older age (P < 0.001), palpable symptoms (P = 0.037), high histologic grade (P < 0.001), and Ki-67 ≥20 (P<0.001). There were no statistically significant differences between the two groups in cancer stage, mean tumor size, associated DCIS, grade of DCIS, or axillary lymph node metastasis (Supplementary Table 1). All tumors were infiltrating ductal carcinoma, and the mean pathologic tumor size was 2.2 cm (range, 0.2–6.3 cm).

Mammographic imaging features

On mammography, there were no significant differences in imaging presentation between the HR–/HER2+ and HR+/HER2+ tumors. One hundred and fifty-two of 252 (60.3%) HER2+ cancers exhibited calcifications on mammography. When analyzed according to HR status, 72 of 125 (57.6%) HR–/HER2+ and 80 of 127 (63.0%) HR+/HER2+ tumors exhibited mammographic calcifications. The presence, morphology, and distribution of mammographic calcifications were not statistically different between the two groups (Supplementary Table 2).

MRI features

On MR images, HR–/HER2+ tumors were more likely to exhibit multifocality (P = 0.027). However, the amount of FGV, level of BPE, and lesion type were not significantly associated with HR status. Among the lesions that were classified as masses, HR–/HER2+ tumors were more likely to have round or oval shapes (P < 0.001), circumscribed margins (P < 0.001), peritumoral edema on T2W imaging (P < 0.001), and associated NME (P = 0.001) compared with HR+/HER2+ tumors (Fig. 1). The HR+/HER2+ tumors were more likely to have irregular shapes (P < 0.001) and spiculated margins (P < 0.001) (Fig. 2). The internal enhancement pattern and intratumoral SI on T2W images were not associated with HR status. MR kinetic features were acquired by a CAD and 119 of 125 (95.2%) HR–/HER2+ tumors and 123 of 127 (96.9%) HR+/HER2+ tumors exhibited enhancement at the 50% threshold. Among the kinetic features assessed by a CAD, there were no statistically significant differences between two subtypes in terms of the largest percentage enhancement type in the initial phase or the most suspicious enhancement type in the delayed phase (Supplementary Table 3).

Fig. 1.

HR–/HER2+ breast cancer in a 57-year-old woman. (a) Craniocaudal mammogram shows segmental fine pleomorphic calcifications (arrowheads) in the right inner breast. (b) Contrast-enhanced fat-suppressed T1W sagittal MR image shows clustered ring (arrowheads) and non-mass enhancement in the right inner breast. (c) Contrast-enhanced fat-suppressed T1W sagittal MR image shows an oval circumscribed mass (arrow) with rim enhancement in the right subareolar area. Pathologic analysis results confirmed multifocal invasive ductal carcinomas with histologic grade 3 and DCIS.

Fig. 2.

HR+/HER2+ breast cancer in a 33-year-old woman. (a) Mediolateral oblique mammogram shows an irregular spiculated mass (arrow) with segmental fine pleomorphic calcifications (arrowheads) in the right upper breast. (b) Contrast-enhanced fat-suppressed T1W sagittal MR image shows an irregular mass (arrow) with spiculated margin and heterogeneous enhancement in the right upper breast. (c) Color map by CAD shows the mass with a predominantly red overlay (arrow) indicating the washout kinetic pattern based on the most suspicious enhancement type. Pathologic analysis results confirmed invasive ductal carcinoma with histologic grade 2 and DCIS.

Logistic regression analysis

With regard to clinicopathologic features, univariate analysis showed that older age, palpable clinical symptoms, high histological grade, and high Ki-67 index showed association with HR negativity within HER2+ cancers. Among these, the multiple logistic regression analysis showed that high histologic grade (odds ratio [OR], 3.89; P = 0.002), high Ki-67 index (OR, 3.06; P = 0.003), and older age (OR, 2.43; P = 0.006) remained independent indicators associated with HR–/HER2+ cancers (Table 1).

Table 1.

Clinicopathologic features associated with HR negativity within HER2+ cancer by logistic regression analysis.

	Univariate analysis		Multivariate analysis
Feature	Unadjusted OR (95% CI)	P	Adjusted OR (95% CI)	P
Age (years)
≥50 vs. <50	2.779 (1.588–4.861)	<0.001	2.435 (1.288–4.605)	0.006
Clinical symptoms
Palpability vs. Asymptomatic	1.916 (1.008–3.641)	0.047
Histological grade
3 vs. 1 or 2	4.065 (1.891–8.736)	0.001	3.891 (1.623–9.328)	0.002
Ki-67 index
High (≥20%) vs. Low (<20%)	3.47 (1.777–6.778)	≪0.001	3.062 (1.465–6.401)	0.003

With regard to imaging features, univariate analysis showed that round or oval mass shape, circumscribed mass margin, associated NME and peritumoral edema on MR images showed association with HR negativity within HER2+ cancers. Among these, the multiple logistic regression analysis showed that circumscribed mass margin (OR, 4.73; P < 0.001) and associated NME (OR, 3.29; P = 0.001) remained independent indicators associated with HR–/HER2+ tumors (Table 2).

Table 2.

MRI features associated with HR negativity within HER2+ cancer by logistic regression analysis.

	Univariate analysis		Multivariate analysis
Feature	Unadjusted OR (95% CI)	P	Adjusted OR (95% CI)	P
Associated NME
Yes vs. No	3.123 (1.637–5.956)	≪0.001	3.291 (1.563–6.932)	0.001
Mass shape
Irregular vs. Round or Oval	0.260 (0.149–0.454)	≪0.001
Mass margin
Circumscribed vs.Irregular or Spiculated	4.718 (2.436–9.139)	≪0.001	4.731 (2.296–9.748)	<0.001
Peritumoral edema on T2W imaging
Present vs. Absent	2.892 (1.351–6.19)	0.006

NME, non-mass enhancement.

The area under the ROC curve (A_z) from the model combined with imaging and clinicopathologic features associated with HR negativity was 0.79 in distinguishing HR–/HER2+ cancers from HR+/HER2+ cancers (Fig. 3).

Fig. 3.

ROC curve for the multivariate logistic regression analysis in distinguishing HR–/HER2+ from HR+/HER2+ cancers, using age, histologic grade, Ki-67 index, associated NME, and mass margin on MR images. The area under the ROC curve (A_z) from the model combined with independent indicators was 0.79.

Discussion

Our current results suggest that HER2+ breast cancers have different clinicopathologic features and imaging phenotypes according to HR status and that these phenotypes are more evident by MRI than mammography. On MRI, round or oval shapes, circumscribed mass margin, associated NME, and peritumoral edema were correlated with HR–/HER2+ tumors and of these, circumscribed mass margin has the highest odds ratio (OR, 4.731; P < 0.001) in predicting HR negativity on multivariate analysis. However, imaging presentation, calcification features on mammography, and MR kinetic features assessed using a CAD did not differ between the two HER2 subtypes. Our findings, which draw from a large and homogenous study population, further elucidate the relationship between imaging features and the HR and HER2 status of breast cancer and will aid in identifying imaging features that are related to treatment responses or recurrence in HER2+ cancer. Recently, an association of MRI features and response to neoadjuvant chemotherapy and recurrence-free survival has been reported in triple-negative breast cancer (21). In clinical practice, information on tumor shape and margin could be used to select the most appropriate region to biopsy in the tumor, and results from multiple biopsies may alter the management of the patient and impact decisions on the treatment regimen to be employed in a neoadjuvant setting.

Our results are consistent with those of previous studies that correlated imaging findings and breast cancer subtype (10 –15). In our study, HER2+ breast cancers most commonly manifested as masses with microcalcifications on mammography and as enhancing masses with washout kinetics on MRI. However, HER2+ tumors tended to exhibit several different imaging features according to HR status. In general, the imaging features of the HR–/HER2+ tumors were more likely to resemble triple-negative tumors, and the features of the HR+/HER2+ tumors were more likely to resemble luminal A tumors (14,15). Our results suggest that HR positivity can be considered a major contributor to differences in mass shape and margins among HER2+ tumors but that HER2 positivity determines the calcification and MR kinetic features. In an MRI study involving 282 invasive breast tumors, tumor roundness (measured by dividing the area of the tumor by the area of a circle with the same convex perimeter using in-house software) was inversely correlated with ER score (P < 0.001) but not with HER2 overexpression (22). Breast tumors with lower ER expression showed higher mean roundness score and triple-negative tumors showed the highest mean roundness scores compared with the other subtypes. In another study involving 101 cases of DCIS manifested as mammographic calcifications, HER2 gene amplification was positively correlated with the probability of mammographic calcification malignancy (P < 0.001), as determined by radiologists based on the BI-RADS lexicon (23). An inverse relationship between HR expression and HER2 gene amplification has been reported (24). Our pathologic results and previous studies have shown that HR–/HER2+ tumors are significantly more associated with pushing margins, high histologic grade, intratumoral necrosis, and high Ki-67 proliferation index compared with HR+/HER2+ tumors (25).

In our study, HR–/HER2+ tumors were more likely to have peritumoral edema and associated NME on MRI. The incidence of peritumoral edema on T2W imaging has also been reported to be significantly higher in HR–/HER2+ versus HR+/HER2+ tumors (45% versus 13%, P < 0.001) (14). Increased vascular permeability in newly formed tumor vessels and the release of peritumoral cytokines likely lead to peritumoral edema (18). Our findings regarding associated NME are concordant with a recent study with 225 invasive breast cancers (15). Kawashima et al. showed that tumor extension around the mass was significantly more frequent in HR–/HER2+ tumors compared with HR+ tumors (91% versus 47%, P = 0.009).

Our study had some limitations. First, this was a retrospective study at a single institution and selection bias may have been present. We excluded patients who received neoadjuvant chemotherapy prior to MRI. Therefore, our results may not apply to advanced stage HER2+ cancer. Variability in HR and HER2 results between institutions is an important issue and undefined criteria or variable cutoff values have been used in previous imaging studies on breast cancer subtypes (13). In our study, however, HR and HER2 positivity were defined according to the American Society of Clinical Oncology/College of American Pathologists guidelines (19,20) and our HR+ rate of 50.4% within HER2+ cancer was similar to rates of other studies (50–51.8%) (26,27). Second, the inter-observer variability in image interpretation was not assessed in this study. We found that the assessment of mass shapes and margins were subjective despite the participation of experienced radiologists who were blinded to HR and HER2 status. The development of automated and reproducible analysis methodologies to extract more information from image-based features is a requirement for the comprehensive quantification of tumor phenotypes (28 –30). In addition, we did not analyze margin of mass and multifocality on mammography because majority of the patients had dense breasts and was often difficult to define the entire margin of mass. Third, we did not correlate imaging features with prognosis or treatment response. Studies have investigated the relevance of breast cancer subtypes assessed by MRI features for predicting cancer recurrence and monitoring response to therapy during neoadjuvant chemotherapy (21,30 –33).

In conclusion, HER2+ breast cancers have different MRI phenotypes and clinicopathologic features according to HR status. Circumscribed mass margin and associated NME were independent MRI indicators that may predict HR negativity. However, imaging presentations and calcification features on mammography and tumor kinetic features by a CAD did not differ between HR–/HER2+ and HR+/HER2+ tumors. Because clinical outcomes differ between the two subtypes of HER2+ breast cancers, MRI features related to the HR and HER2 status have the potential to be used for the diagnosis and treatment decisions in HER2+ breast cancer patients. Further investigations in a larger study population are warranted to prospectively determine whether the characteristic imaging features observed in our study can be used to help predict prognosis or treatment response in HER2+ cancers.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research received the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (grant no. 2014R1A1A2055402).

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