Comparison of Clinicopathological Features of Pleomorphic and Invasive Lobular Breast Carcinomas.

PURPOSE: Accounting for about 15% of invasive lobular carcinomas and 1% of breast carcinomas, pleomorphic lobular carcinoma is known to be a rare histological subtype of invasive lobular carcinoma. Yet, it is more aggressive and produces a worse prognosis than other breast cancers. Ultimately, the present study compares the clinicopathological features of pleomorphic and invasive lobular breast carcinomas. METHODS: In the study, we retrospectively evaluated the data of 262 patients with histological subtypes of classical and pleomorphic lobular cancers having been recruited for surgical operations. After resorting to Kolmogorov-Smirnov and Shapiro-Wilk tests to check the normality of distribution, the categorical and continuous variables were compared between the groups using the chi-square test and independent samples t test, respectively. In all analyses, we considered a P-value of <.05 to be statistically significant. RESULTS: Our findings revealed that the groups with lobular and pleomorphic groups significantly differed by Ki-67 value, estrogen receptor negativity, grade, multicentricity, multifocality, surgical margin positivity, completion mastectomy, and metachronous contralateral tumor (P < .05). CONCLUSION: We discovered that pleomorphic type was associated with higher grades, estrogen receptor negativity, and Ki-67 expression. The incidence of metachronous breast cancer was high in the pleomorphic group, which may be a noteworthy finding to be considered in follow-ups. In addition, the high rates of multicentricity and multifocality of tumors in the pleomorphic group may be associated with increased surgical margin positivity and a higher likelihood of mastectomy. In a nutshell, our findings may guide patients and surgeons regarding the type of intervention and reconstruction options to be adopted in prospective surgeries.

The role of contrast-enhanced mammography in the preoperative evaluation of invasive lobular carcinoma of the breast.

AIM: To assess the performance of contrast-enhanced mammography (CEM) in the preoperative staging of invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS: The present study was a multicentre, multivendor, multinational retrospective study of women with a histological diagnosis of ILC who had undergone CEM from December 2013 to December 2021. Index lesion size and multifocality were recorded for two-dimensional (2D) mammography, CEM, and when available magnetic resonance imaging (MRI). Comparison with histological data was undertaken for women treated by primary surgical excision. Pearson correlation coefficients and Bland-Altman's analysis of agreement were used to assess differences with a significance level of 0.05. RESULTS: One hundred and fifteen ILC lesions were included, 46 (40%) presented symptomatically and 69 were screening detected. CEM demonstrated superior sensitivity when compared to standard mammography. The correlation between the histological size measured on the surgical excision specimen size was greater than with standard mammography (r=0.626 and 0.295 respectively, p=0.001), with 19% of lobular carcinomas not visible without a contrast agent. The sensitivity of CEM for multifocal disease was greater than standard mammography (70% and 20% respectively, p<0.0001). CEM overestimated tumour size by an average of 1.5 times, with the size difference increasing for larger tumour. When MRI was performed (n=22), tumour size was also overestimated by an average of 1.3 times. The degree of size overestimation was similar for both techniques, with the tumour size on CEM being on average 0.5 cm larger than MRI. CONCLUSION: CEM is a useful tool for the local staging of lobular carcinomas and could be an alternative to breast MRI.

Breast surgery after neoadjuvant chemotherapy in patients with lobular carcinoma: surgical and oncologic outcome.

INTRODUCTION: Breast cancer patients with invasive lobular carcinoma (ILC) have an increased risk of positive margins after surgery and often show little response to neoadjuvant chemotherapy (NAC). We aimed to investigate surgical outcomes in patients with ILC treated with NAC. METHODS: In this retrospective cohort study, all breast cancer patients with ILC treated with NAC who underwent surgery at the Netherlands Cancer Institute from 2010 to 2019 were selected. Patients with mixed type ILC in pre-NAC biopsies were excluded if the lobular component was not confirmed in the surgical specimen. Main outcomes were tumor-positive margins and re-excision rate. Associations between baseline characteristics and tumor-positive margins were assessed, as were complications, locoregional recurrence rate (LRR), recurrence-free survival (RFS), and overall survival (OS). RESULTS: We included 191 patients. After NAC, 107 (56%) patients had breast conserving surgery (BCS) and 84 (44%) patients underwent mastectomy. Tumor-positive margins were observed in 67 (35%) patients. Fifty five (51%) had BCS and 12 (14%) underwent mastectomy (p value < 0.001). Re-excision was performed in 35 (33%) patients with BCS and in 4 (5%) patients with mastectomy. Definitive surgery was mastectomy in 107 (56%) patients and BCS in 84 (44%) patients. Tumor-positive margins were associated with cT ≥ 3 status (OR 4.62, 95% CI 1.26-16.98, p value 0.021) in the BCS group. Five-year LRR (4.7%), RFS (81%), and OS (93%) were not affected by type of surgery after NAC. CONCLUSION: Although 33% of ILC breast cancer patients undergoing BCS after NAC required re-excision for positive resection margins, it is considered safe given that five-year RFS remained excellent and LRR and OS did not differ by extent of surgery.

Tumor microenvironment and immune system preservation in early-stage breast cancer: routes for early recurrence after mastectomy and treatment for lobular and ductal forms of disease.

BACKGROUND: Intra-ductal cancer (IDC) is the most common type of breast cancer, with intra-lobular cancer (ILC) coming in second. Surgery is the primary treatment for early stage breast cancer. There are now irrefutable data demonstrating that the immune context of breast tumors can influence growth and metastasis. Adjuvant chemotherapy may be administered in patients who are at a high risk of recurrence. Our goal was to identify the processes underlying both types of early local recurrences. METHODS: This was a case-control observational study. Within 2 years of receiving adjuvant taxan and anthracycline-based chemotherapy, as well as modified radical mastectomy (MRM), early stage IDC and ILC recurred. Vimentin, α-smooth muscle actin (SMA), platelet-derived growth factor (PDGF), matrix metalloproteinase (MMP1), and clustered differentiation (CD95) were investigated. RESULTS: Of the samples in the ductal type group, 25 showed local recurrence, and 25 did not. Six individuals in the lobular-type group did not experience recurrence, whereas seven did. Vimentin (p = 0.000 and 0.021), PDGF (p = 0.000 and 0.002), and CD95 (p = 0.000 and 0.045) expressions were significantly different in ductal and lobular carcinoma types, respectively. Measurement of ductal type was the sole significant difference found in MMP1 (p = 0.000) and α-SMA (p = 0.000). α-SMA and CD95 were two variables that helped the recurrence mechanism in the ductal type according to the pathway analysis. In contrast, the CD95 route is a recurrent mechanism for the lobular form. CONCLUSIONS: While the immune system plays a larger role in ILC, the tumor microenvironment and immune system both influence the recurrence of IDC. According to this study, improving the immune system may be a viable cancer treatment option.

ASO Author Reflections: Toward Individualized Management of Heterogenous Mixed Invasive Ductolobular Breast Cancers.

Mixed invasive ductolobular breast cancer (MIDLC) is a rare breast cancer with varying lobular and ductal components. Characteristics, management, and outcomes of MIDLC are not well understood due to the rarity of the cancer and the lack of uniform diagnostic criteria and reporting. There is a need for better understanding and individualized management of this heterogeneous spectrum of breast cancers.

The impact of histologic subtype on primary site surgery in the management of metastatic lobular versus ductal breast cancer: a population based study from the National Cancer Database (NCDB).

PURPOSE: Primary site surgery for metastatic breast cancer improves local control but does not impact overall survival. Whether histologic subtype influences patient selection for surgery is unknown. Given differences in surgical management between early-stage lobular versus ductal disease, we evaluated the impact of histology on primary site surgery in patients with metastatic breast cancer. METHODS: The National Cancer Database (NCDB, 2010-2016) was queried for patients with stage IV HR-positive, HER2-negative invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC). We compared clinicopathologic features, primary site surgery rates, and outcomes by histologic subtype. Multivariable Cox proportional hazard models with and without propensity score matching were used for overall survival (OS) analyses. RESULTS: In 25,294 patients, primary site surgery was slightly but significantly less common in the 6,123 patients with ILC compared to the 19,171 patients with IDC (26.9% versus 28.8%, p = 0.004). Those with ILC were less likely to receive chemotherapy (41.3% versus 47.4%, p < 0.0001) or radiotherapy (29.1% versus 37.9%, p < 0.0001), and had shorter OS. While mastectomy rates were similar, those with ILC who underwent lumpectomy had significantly higher positive margin rates (ILC 15.7% versus IDC 11.2%, p = 0.025). In both groups, the odds of undergoing surgery decreased over time, and were higher in younger patients with T2/T3 tumors and higher nodal burden. CONCLUSION: Lobular histology is associated with less primary site surgery, higher positive margin rates, less radiotherapy and chemotherapy, and shorter OS compared to those with HR-positive HER2-negative IDC. These findings support the need for ILC-specific data and treatment approaches in the setting of metastatic disease.

Feasibility of accelerated partial breast irradiation with strut-adjusted volume implant brachytherapy in Japan focusing on dosimetry and acute toxicity: a Japanese multi-institutional prospective study.

BACKGROUND: A Japanese multi-institutional prospective study was initiated to investigate the effectiveness and safety of accelerated partial breast irradiation (APBI) using strut-adjusted volume implant (SAVI) brachytherapy, with subjects registered between 2016 and 2021. Herein, we report the preliminary results on the feasibility of this treatment modality in Japan, focusing on the registration process, dosimetry, and acute toxicities. PATIENTS AND METHODS: Primary registration was conducted before breast-conserving surgery (BCS) and the eligibility criteria included the following: age ≥ 40 years, tumor unifocal and unicentric, ≤ 3 cm in diameter, cN0M0, proven ductal, mucinous, tubular, medullary, or lobular carcinoma by needle biopsy. Secondary registration was conducted after BCS had been performed leaving a cavity for device implantation and pathological evaluations, and the eligibility criteria were as follows: negative surgical margin, tumor ≤ 3 cm in diameter on gross pathological examination, histologically confirmed ductal, mucinous, tubular medullary, colloid, or lobular carcinoma, pN0, L0V0, no extensive ductal component, no initiation of chemotherapy within 2 weeks of the brachytherapy APBI planning with SAVI was performed for the patients successfully entered in the study by the secondary registration process, and the treatment was administered at the dose of 34 Gy in 10 fractions administered twice daily. RESULTS: Between 2016 and 2021, 64 women were enrolled in the study through primary registration, of which 19 were excluded from the secondary registration process, and in one, it was deemed impossible to comply with the dose constraints established during treatment planning. After the exclusion of these latter 20 patients, we treated the remaining 44 patients by APBI with SAVI. The dose constraints could be adhered to in all the patients, but re-planning was necessitated in 3 patients because of applicator movement during the treatment period. Grade 2 acute toxicities were observed in 18% of all patients, but more severe acute toxicities than Grade 2 were not observed in any of the patients. CONCLUSION: APBI with SAVI brachytherapy is feasible in Japan from the aspects of compliance with dose constraints and frequency of acute toxicities.

Impact of pre-operative MRI on surgical management of screening digital breast tomosynthesis-detected invasive lobular carcinoma.

PURPOSE: The purpose of this study is to determine the impact of pre-operative MRI on surgical management of screening digital breast tomosynthesis (DBT)-detected invasive lobular carcinoma (ILC). METHODS: A retrospective medical record analysis was conducted of women with screening DBT-detected ILC and subsequent surgery from 2017-2021. Clinical, imaging, and pathological features were compared between women who did and did not undergo MRI, and between women with and without additional disease detected on MRI, using the Pearson's chi-squared test and Wilcoxon signed-rank test. Concordance between imaging and surgical pathology sizes was also evaluated. RESULTS: Of 125 women (mean age 67 years, range 44-90) with screening-detected ILC, MRI was obtained in 62 women (49.6%) with a mean age of 63 years (range 45-80). Compared to women without MRI, women who had MRI examinations were younger, more likely to have dense breast tissue, and more likely to undergo mastectomy initially rather than lumpectomy (p < 0.001-0.01). Eighteen biopsies were performed based on MRI findings, of which 55.6% (10/18) were malignant. Conventional imaging more frequently underestimated ILC span at the biopsy site than MRI, using a 25% threshold difference (17.5% [7/40] versus 58.5% [24/41], p < 0.001). MRI detected more extensive disease at the biopsy site in six patients (9.7%, 6/62), additional ipsilateral disease in six patients (9.7%, 6/62), and contralateral disease in one patient (1.6%, 1/62). MRI therefore impacted surgical management in 21.0% (13/62) of patients. CONCLUSION: MRI led to the detection of additional disease, thus impacting surgical management, in one-fifth of patients with ILC.

Lobular Neoplasia Diagnosed by MRI-Guided Breast Biopsy: Identifying Upgrade Rate to Malignancy and Outcomes of Clinical and Surgical Management.

OBJECTIVE: The aim of this study was to determine surgical and clinical outcomes of lobular neoplasia (LN) diagnosed by magnetic resonance imaging (MRI) biopsy, including upgrade to malignancy, and to assess for characteristics associated with upgrade. METHOD: A single-institution retrospective study, between 2013 and 2022, of patients with histopathological findings of LN via MRI-guided biopsy was performed using an institutional database and review of the electronic medical records. Decision for excision or surveillance was made by a multidisciplinary team per institutional practice. Patient demographics and imaging characteristics were summarized using descriptive analyses. Upgrade was defined as upgrade to cancer on surgical pathology for patients treated with excision or the development of cancer at the biopsy site during surveillance. The Wilcoxon rank-sum test and Fisher's exact test were used to compare features of the upgraded cohort with the remainder of the group. RESULTS: Ninety-four MRI biopsies diagnosing LN were included. Median age was 57 years (range 37-78 years). Forty-six lesions underwent excision while 48 lesions were surveilled. The upgrade rate was 7.4% (7/94). Upgrades in the excised cohort consisted of pleomorphic lobular carcinoma in situ (LCIS; n = 1), ductal carcinoma in situ (DCIS; n = 3) and invasive lobular carcinoma (ILC; n = 2), while one interval development of DCIS was observed at the site of biopsy in the surveillance cohort. No MRI or patient variables were associated with upgrade. CONCLUSIONS: In this contemporary cohort of MRI-detected LNs, the upgrade rate was low. Omission of surgery for MRI-detected LNs in carefully selected patients may be considered in a shared decision-making capacity between the patient and the treatment team. Larger cohorts are needed to determine factors predictive of upgrade risk.

Immune system and tumor microenvironment in early-stage breast cancer: different mechanisms for early recurrence after mastectomy and chemotherapy on ductal and lobular types.

Background: The most common type of breast cancer is the ductal type (IDC), followed by lobular type (ILC). Surgery is the main therapy for early-stage breast cancer. Adjuvant chemotherapy might be given to those at high risk of recurrence. Recurrence is still possible after mastectomy and chemotherapy and most often occurs in the first two years. We aimed to determine the mechanisms in early local recurrence in both types. Methods: We used an observational method with a cross-sectional study design. The samples were patients with early-stage IDC and ILC, who underwent modified radical mastectomy (MRM) and got adjuvant chemotherapy with taxan and anthracycline base, and experienced recurrence in the first two years after surgery. The materials in this study were paraffin blocks from surgical specimens; we examined vimentin, α-SMA and MMP1, PDGF and CD95 by immunohistochemistry (IHC). Data analysis was done using OpenEpi 3.0.1 and EZR. We used pathway analysis with linear regression. Results: There were 25 samples with local recurrence and 25 samples without recurrence in the ductal type group. The lobular type group consisted of six subjects without recurrence and seven with recurrence. There were significant differences in the expression of vimentin (p=0.000 and 0.021, respectively), PDGF (p=0.000 and 0.002) and CD95 (p=0.000 and 0.045) in ductal and lobular cancer types, respectively. MMP1 (p=0.000) and α-SMA (p=0.000) only showed a significant difference in the ductal type. The pathway analysis showed that in the ductal type, the mechanism of recurrence was enabled by two factors: α-SMA and CD95. Meanwhile, for the lobular type, the recurrence mechanism was through the CD95 pathway. Conclusions: Local recurrence in early-stage IDC and ILC had different mechanisms.  These findings are expected to make cancer treatment in both types more focused and efficient.

Successful Breast Conservation After Neoadjuvant Chemotherapy in Lobular Breast Cancer: The Role of Menopausal Status in Response to Treatment.

BACKGROUND: While neoadjuvant chemotherapy (NAC) has been shown to increase rates of breast conservation surgery (BCS) for breast cancer, response rates in invasive lobular carcinoma (ILC) appear lower than other histologic subtypes. Some data suggest higher response rates to NAC in premenopausal versus postmenopausal patients, but this has not been studied in ILC. We evaluated the rates of successful BCS after NAC in patients with ILC stratified by menopausal status. PATIENTS AND METHODS: We analyzed data from a single-institution cohort of 666 patients with stage I-III hormone receptor positive HER-2 negative ILC. We used t-tests, chi-squared tests, and multivariable logistic regression to investigate rates of NAC use, attempted BCS, and associations between NAC and successful BCS by menopausal status. RESULTS: In 217 premenopausal and 449 postmenopausal patients, NAC was used more often in the premenopausal group (15.2% vs. 9.8%, respectively, p = 0.041). Among those who attempted breast conservation (51.3% of pre- and 64.8% of postmenopausal cohorts), NAC was not associated with successful BCS in either group. Interestingly, for postmenopausal patients, receipt of NAC was significantly associated with increased rates of completion mastectomy in those who had positive margins at the first attempt at BCS. CONCLUSION: NAC was not associated with successful BCS in either premenopausal or postmenopausal patients with ILC. Although premenopausal patients were more likely to receive NAC, these data suggest that menopausal status may not be a good predictor of response to chemotherapy. Better predictors of response and more efficacious treatment for patients with ILC are needed.

Is Choosing Wisely Wise for Lobular Carcinoma in Patients Over 70 Years of Age? A National Cancer Database Analysis of Sentinel Node Practice Patterns.

BACKGROUND: Controversy continues in the treatment of breast cancer in women over 70 years of age. In 2016, the Society of Surgical Oncology recommended against routine use of sentinel lymph node biopsy (SLNBx) as part of the 'Choosing Wisely Campaign'. This study examines the oncologic safety of avoidance of routine SLNBx in patients over 70 years of age with invasive lobular carcinoma (ILC). METHODS: The National Cancer Database was used to identify women with invasive ductal carcinoma (IDC) and ILC diagnosed between 2012 and 2020. Clinical and pathological staging, axillary staging, surgery type, and lymph node positivity between patients with IDC or ILC were compared. RESULTS: Among women with T1 tumors, 85,949 (79.6%) patients with IDC and 12,761 (81.5%) patients with ILC underwent SLNBx (p < 0.001). Among patients who underwent SLNBx, those with IDC were more likely to have positive nodes (n = 7535, 8.8%) than those with ILC (n = 1041, 8.2%; p = 0.02). During the time interval of interest, for both IDC and ILC patients, the rate of axillary lymph node dissection decreased and rates of SLNBx or no axillary staging increased. On multivariate analysis, ILC histology was associated with use of SLNBx, but without nodal positivity. CONCLUSION: A trend de-escalation of axillary staging was identified in this study, however the majority of patients meeting the 'Choosing Wisely' criteria are still undergoing SLNBx. No increased risk of nodal positivity was identified among patients with ILC, suggesting that surgeons can continue to choose wisely and limit the use of SLNBx in women over 70 years of age with T1 ILC tumors.

Does Non-Classic Lobular Carcinoma In Situ at the Lumpectomy Margin Increase Local Recurrence?

BACKGROUND: The clinical significance of nonclassic, lobular carcinoma in situ (NC-LCIS) at the surgical margin of excisions for invasive cancer is unknown. We sought to determine whether NC-LCIS at or near the margin in the setting of a concurrent invasive carcinoma is associated with risk of ipsilateral breast tumor recurrence (IBTR) and locoregional recurrence (LRR). METHODS: Patients with stage 0-III breast cancer and NC-LCIS who underwent lumpectomy between January 2010 and January 2022 at a single institution were retrospectively identified. NC-LCIS margins were stratified as <2 mm, ≥2 mm, or within shave margin. Rates of IBTR and LRR were examined. RESULTS: A total of 511 female patients (median age 60 years [interquartile range (IQR) 52-69]) with NC-LCIS and an associated ipsilateral breast cancer with a median follow-up of 3.4 years (IQR 2.0-5.9) were identified. Final margins for NC-LCIS were ≥2 mm in 348 patients (68%), <2 mm in 37 (7.2%), and within shave margin in 126 (24.6%). Crude incidence of IBTR was 3.3% (n = 17) and that of LRR was 4.9% (n = 25). There was no difference in the crude rate of IBTR by NC-LCIS margin status (IBTR rate: 3.7% ≥2 mm, 0% <2 mm, 3.2% within shave margin, p = 0.8) nor in LRR (LRR rate: 4.9% ≥2 mm, 2.7% <2 mm, 5.6% within shave margin, p = 0.9). CONCLUSIONS: For completely excised invasive breast cancers associated with NC-LCIS, extent of margin width for NC-LCIS was not associated with a difference in IBTR or LRR. These data suggest that the decision to perform reexcision of margin after lumpectomy should be driven by the invasive cancer, rather than the NC-LCIS margin.

The performance of contrast-enhanced mammography and breast MRI in local preoperative staging of invasive lobular breast cancer.

PURPOSE: Breast MRI is considered the best modality for preoperative staging of invasive lobular carcinoma (ILC). However, contrast-enhanced mammography (CEM) shows comparable diagnostic performance to MRI, but evidence of CEM's accuracy in women diagnosed with ILC is scant. We aimed to retrospectively evaluate CEM and MRI accuracy in preoperative staging of ILC. METHODS: ILC cases diagnosed between 2013 and 2021 were collected. For both modalities, tumour diameter was extracted from the reports. Bland-Altman plots were used to assess discrepancies between size measurements according to imaging and histopathological findings. CEM and MRI's ability to detect multifocal/contralateral cancer was expressed as sensitivity, specificity, and diagnostic odds ratios (DORs). Pairwise comparison of women undergoing both CEM and MRI was not performed. RESULTS: 305 ILC-cases fulfilled preset inclusion criteria. Mean age was 63.7 years. Preoperative staging was performed using MRI or CEM in 266 (87.2%) and 77 (25.2%) cases, respectively. MRI and CEM overestimated tumour size by 1.5 and 2.1 mm, respectively. Sensitivity to detect multifocal disease was higher for MRI than for CEM (86% versus 78%), but specificity was lower for MRI (79% versus 92%). For detection of contralateral breast cancer, sensitivity for MRI was 96% versus 88% for CEM, and specificity was 92% and 99%, respectively. For both indications, DOR was higher for CEM, but differences were non-significant (p = 0.56 and p = 0.78). CONCLUSION: CEM and MRI overestimate ILC size with comparable systematic and random errors. MRI's higher sensitivity for detection of multifocal/contralateral cancers is accompanied by lower specificity, but discriminative ability for both modalities was non-significant.