Lobular Histology Research Articles

Abstract P1-18-33: Real-world outcomes with palbociclib, abemaciclib and ribociclib; experience of a tertiary oncology centre in the United Kingdom

Abstract Background 3 CDK4/6 inhibitors (CDKi) were approved 2015-7 and are standard of care for metastatic hormone-positive breast cancer, in first line with letrozole or second with fulvestrant. The Phase III randomised controlled trials (RCTs) show similar hazard ratios (HR) for progression-free survival (PFS) of 0.46-0.58. We compared them head-to-head and examined subgroups for differential response. Methods We retrospectively reviewed all patients who received CDKi up to March 2020 at our Oncology centre and the 4 local hospitals we serve. Kaplan-Meier method was used to generate time-to-event curves and Log-rank test was used to compare differences. Results 208 patients had median age 61 and follow-up 20 months. Palbociclib was most frequently used (128 patients) followed by abemaciclib (60) and ribociclib (20). Overall, median PFS was 20.8 months (95% confidence interval, CI, 17.2-28.0) and median OS was not reached. On the Kaplan-Meier curve there is a visible benefit with ribociclib, but due to the small group size, this did not reach statistical significance (p = 0.143). Patients received CDKi with aromatase inhibitor (176) or fulvestrant (32). Median PFS was 22.8 and 9.5 months respectively; HR 0.32 (95% CI 0.17-0.59). Median OS was not reached in either group; HR 0.22 (95% CI 0.09-0.56). Out of the ER strongly-positive patients (160), those with PR 7-8 did better than those with PR 0-4, with median PFS 28.7 and 14.0 months respectively; HR 0.40 (95% CI 0.22-0.72). Median OS was not reached for PR 7-8, and 31.8 months for PR 0-4. 115 patients received 1 (20%), 2 (13%) or more (12%) subsequent therapies. Patients who received everolimus at any point had better outcomes. Median OS was not reached in the everolimus group, and 28.5 months in the rest; HR 0.22 (95% CI 0.11-0.44). As patients suitable for everolimus may represent a distinct population, a comparison of baseline characteristics is presented [Table 1]. Patients with invasive ductal cancer (IDC) or lobular (ILC) had median PFS 17.1 and 24.2 months respectively; HR 0.69 (95% CI 0.43-1.09). Median OS was not reached in either group; HR 0.54 (95% CI 0.26-1.10). Median number of cycles was 17. Treatment was ongoing in 42% of patients at data cut-off. Dose was reduced in 43% and delayed in 74%. Mean dose intensity was 85%. Reasons for stopping treatment were progressive disease (70%), toxicity (20%) or unrecorded (10%). 60% experienced toxicities of grade 3 or above, or which resulted in dose adjustment. The commonest were neutropenia (38%), diarrhoea (11%) and lethargy (10%). Less frequent were mucositis, nausea, vomiting and anorexia (2% each). Of 68 patients with accessible documentation of radiological response, 41 had partial and 27 had complete response. Conclusions Our outcomes are comparable to those achieved in RCTs, despite poorer baseline characteristics [Table 2]. Our data suggest OS benefit with ribociclib. Predictors of good outcome include subsequent everolimus, strong PR+, strong ER+ and ILC. The prognostic benefit of lobular histology has not been definitively shown elsewhere. Table 1.comparing baseline characteristics between the everolimus subgroup and the restSubsequent therapy included everolimus n=35Subsequent therapy excluded everolimus n=61DemographicsMedian age (range)62 (30-83)58 (34-90)PS 0-1 (%)34 (97%)51 (84%)PS 2-3 (%)1 (3%)8 (13%)Tumour characteristicsLeft-sided breast cancer (%)20 (57%)27 (44%)Right-sided breast cancer (%)10 (29%)25 (41%)Bilateral (%)0 (0%)2 (3%)Data missing (%)5 (14%)7 (11%)Grade 1 (%)1 (3%)1 (2%)Grade 2 (%)17 (49%)24 (39%)Grade 3 (%)10 (29%)24 (39%)Data missing (%)7 (20%)12 (20%)Ductal (%)22 (63%)43 (70%)Lobular (%)8 (23%)7 (11%)Data missing (%)5 (14%)11 (18%)PR 7-817 (49%)18 (30%)ER 7-828 (80%)46 (75%)Visceral disease13 (37%)30 (49%)Metastatic at diagnosis (%)5 (14%)10 (16%)Median metastasis-free interval (range)9.5 years (0-37.7 years)4.6 years (0-36.0 years)Subsequent lines of therapy19 (26%)34 (56%)213 (37%)15 (25%)3 or more13 (37%)12 (20%) Table 2.comparing baseline characteristics between the current study and the key RCTsAuditRCTsMedian age (range)6160PS 0-188%99%PS 2-316%1%Ductal62%38%Lobular16%7%Histology missing22%55%PR 0-418%PR- 12% in 1L, 23% in 2LPR 7-848%PR+ 54% in 1L, 74% in 2LVisceral disease40%49%Bone-only18%23%Metastatic at diagnosis21%34%Not metastatic at diagnosis79%66%Median metastasis-free interval6.9 years51% >12m, 9% <=12m Citation Format: Lei Wang, Muhammad Ibrahim, Anthony Neal. Real-world outcomes with palbociclib, abemaciclib and ribociclib; experience of a tertiary oncology centre in the United Kingdom [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-33.

Impact of lobular versus ductal histology on overall survival in metastatic breast cancer: a French retrospective multicentre cohort study

BackgroundThe impact of the histological lobular subtype on overall survival (OS) in metastatic breast cancer (MBC) is still under debate, with very few data available. Patients and methodsUsing the French national multicentre Epidemiological Strategy and Medico Economics [ESME]) data platform, the primary objective was to compare the OS of patients with invasive lobular carcinoma (ILC) versus invasive ductal carcinoma (IDC) MBC, with adjustment on the main prognostic factors using two approaches: multivariable analysis and matching with a propensity score. Secondary objectives were to compare first-line progression-free survival (PFS1) and describe patients and tumour characteristics. ResultsOf the 16,703 patients with MBC in the ESME database, 13,111 met all inclusion criteria for the present analysis. One-thousand eight-hundred and four (13.8%) patients had ILC and 11.307 (86.2%) IDC. In the multivariable analysis, patients with ILC had a worse OS [hazard ratio (HR): 1.31; 95%CI 1.20–1.42; p < 0.0001] and a worse PFS1 (HR: 1.15; 95%CI 1.07–1.22; p < 0.0001) as compared with those with IDC, independently of hormone receptor and HER2 status. Interestingly, OS was better (HR 0.79; 95% confidence interval [CI] 0.64–0.98; p = 0.0302), worse (HR: 1.17; 95%CI 1.08–1.27; p = 0.0001) or similar (HR: 0.88; 95%CI 0.67–1.15; p = 0.3455) in patients with ILC with triple-negative, hormone receptor-positive/HER2-negative and HER2-positive MBC, respectively, compared with patients with IDC. ConclusionLobular histology is an independent adverse prognostic factor among women with MBC. ILC MBC could be considered a specific entity. Dedicated prospective studies are needed to tailor the management of these patients.

Factors Associated With the Decision to Decline Chemotherapy in Patients With Early-stage, ER+/HER2- Breast Cancer and High-risk Scoring on Genomic Assays

IntroductionThe rate of refusal of chemotherapy ranges from 3% to 19%, but varies widely by patient profile and treatment setting. Using a large national registry, we explore factors significantly associated with the decision to decline chemotherapy in patients with early-stage, HR+/HER2- breast cancer (BC) despite high risk scoring on multigene sequencing analysis for OncotypeDX (ODX) or MammaPrint (MP), in which the survival benefit of chemotherapy is clear. Patients and MethodsPatients with HR+/HER2- BC and high risk scoring on ODX (score >26) or MP were selected from the National Cancer Database (2004-2017). Only those who refused to get chemotherapy despite their physician's recommendations were included. Univariate frequency and proportion statistics were used to describe the patient cohort. Bivariate Chi-square analysis evaluated the association between refusal of recommended chemotherapy and sociodemographic characteristics. Significant variables (P < .05) were included in a multivariable logistic regression model. ResultsN = 43,533 patients were included (88.7% ODX, 11.3% MP). A total of n = 4415 (10.1%) patients declined chemotherapy despite recommendation by the patient's primary oncologist. Age >70 (OR: 3.46, 95% CI: 2.96-4.04, P < .001), black race (OR: 1.20, 95% CI: 1.07-1.36, P = .01), non-private insurance, lobular carcinoma histology (OR: 1.21, 95% CI: 1.09-1.35, P < .001), and tumor grade of I significantly predicted chemotherapy decline. ConclusionIdentifying and addressing many of the factors that contribute to under-treatment in minorities is to be key to reducing cancer disparity and improving equity in cancer care and outcome.

The 21-gene recurrence score in early non-ductal breast cancer: a National Cancer Database analysis

The 21-gene recurrence score (RS) is prognostic for recurrence and predictive of chemotherapy benefit in early estrogen receptor-positive (ER +) HER2-negative (HER2-) breast cancer (BCA). We evaluated clinicopathologic characteristics, RS and chemotherapy benefit in invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and carcinomas of mixed histologies (ductal + lobular (DLC), ductal + other (DOC), lobular + other (LOC)). Women diagnosed between 1/1/2010 and 1/1/2014 with ER + HER2- BCA, measuring <5 cm, with 0–3 involved axillary nodes, surgery as first treatment, and available RS, were identified from the NCDB. Associations between categorical variables were examined using chi-square test. Cox proportional hazards model was used to examine overall survival (OS) differences among histology subtypes. IDC was associated with smaller size, high grade, and RS > 26. ILC was associated with larger size, and least likely to be high grade (p < 0.0001). Lobular histology was associated with lower incidence of RS > 26. IDC patients (pts) were more likely to receive chemotherapy than pts with other histologies (p < 0.0001). OS for IDC, ILC and DOC were similar. DLC was associated with improved OS (HR 0.82, p = 0.02). Adjuvant chemotherapy was associated with improved OS in IDC (HR = 0.76, p < 0.0001) but not in ILC (HR = 0.99, p = 0.93), DLC (HR = 1.04, p = 0.86), DOC (HR = 0.87, p = 0.71), or LOC (HR = 2.91, p = 0.10). Lobular and mixed BCA histologies have distinct clinicopathologic features compared with IDC, and are less likely to have high RS. OS is similar for IDC and ILC. Although chemotherapy benefit was seen only in IDC, benefit for ILC with RS > 26 cannot be excluded.

Leptomeningeal carcinomatosis and breast cancer: a systematic review of current evidence on diagnosis, treatment and prognosis.

Leptomeningeal carcinomatosis (LC) is a rare but challenging manifestation of advanced breast cancer with a severe impact on morbidity and mortality. We performed a systematic review of the evidence published over the last two decades, focusing on recent advances in the diagnostic and therapeutic options of LC. Lobular histology and a triple-negative intrinsic subtype are well-known risk factors for LC. Clinical manifestations are diverse and often aspecific. There is no gold standard for LC diagnosis: MRI and cerebrospinal fluid cytology are the most frequently used modalities despite the low accuracy. Current standard of care involves a multimodal strategy including systemic and intrathecal chemotherapy in combination with brain radiotherapy. Intrathecal chemotherapy has been widely used through the years despite the lack of data from randomized controlled trials and conflicting evidence on patient outcomes. No specific chemotherapeutic agent has shown superiority over others for both intrathecal and systemic treatment. Although endocrine therapy was heuristically considered unable to exert significant control on central nervous system metastatic disease, retrospective data suggest a favourable toxicity profile and even a possible positive impact on survival. In recent years, encouraging data on the use of targeted agents has emerged but further research in this field is required. Palliative treatment in the form of whole brain or stereotactic radiotherapy is associated with improvement in clinical manifestations and quality of life, with no proven impact on survival. The most investigated prognostic factors include performance status, non-triple-negative disease and multimodal treatment. Validation of prognostic scores is necessary to aid clinicians in the identification of patient subgroups that are most likely to benefit from an intensive therapeutic approach.

Final Analysis of a Phase 2 Trial of Once Weekly Hypofractionated Whole Breast Irradiation for Early-Stage Breast Cancer

We hypothesize that 5-fraction once weekly hypofractionated (WH) whole breast irradiation (WBI) would be safe and effective after breast-conserving surgery for medically underserved patients with breast cancer. We report the protocol-specified primary endpoint of in-breast tumor recurrence (IBTR) at 5 years. After provided informed consent, patients were treated with WH-WBI after breast-conserving surgery were followed prospectively on an institutional review board-approved protocol. Women included in this study had stage 0-II breast cancer treated with negative surgical margins and met prespecified criteria for being underserved. WH-WBI was 28.5 or 30 Gy delivered to the whole breast with no elective coverage of lymph nodes. The primary endpoint was IBTR at 5 years. Secondary endpoints were distant disease-free survival, recurrence-free survival, overall survival, adverse events, and cosmesis. One hundred fifty-eight patients received WH-WBI on protocol from 2010 to 2015. Median follow-up was 5.5 years (range, 0.2-10.0 years). Stage distribution was 22% ductal carcinoma in situ, 68% invasive pN0, and 10% invasive pN1. Twenty-eight percent of patients had grade 3 tumors, 10% were estrogen receptor negative, and 24% required adjuvant chemotherapy. There were 6 IBTR events. The 5-, 7-, and 10-year risks of IBTR for all patients were 2.7% (95% confidence interval [CI], 0.89-6.34), 4.7% (95% CI, 1.4-11.0) and 7.2% (95% CI, 2.4-15.8), respectively. The 5-, 7-, and 10-year rates of distant disease-free survival were 96.4%, 96.4%, and 86.4%; the recurrence-free survival rates were 95.8%, 93.6%, and 80.7%; and the overall survival rates were 96.7%, 88.6%, and 76.7%, respectively. Improvement in IBTR-free time was seen in ductal carcinoma in situ, lobular histology, low-grade tumors, T1 stage, Her2-negative tumors, and receipt of a radiation boost to the lumpectomy bed. Postoperative WH-WBI has favorable disease-specific outcomes that are comparable to those seen with conventional and moderately hypofractionated radiation techniques. WH-WBI could improve access to care for underserved patients with stage 0-II breast cancer.

Five-Year Report of the Institutional Phase II Trial of Once Weekly Hypofractionated Whole Breast Irradiation for Early-Stage Breast Cancer

Elderly and underserved patients often have difficulty completing a traditional course of conventional or hypofractionated breast irradiation after breast conserving surgery (BCS). We hypothesized that five-fraction once weekly hypofractionated whole breast irradiation (WH-WBI) would be safe and effective following BCS in this group of patients. We report a planned 5-year analysis of our institutional phase II trial.Patients treated with WH-WBI after BCS were followed prospectively on an institutional IRB-approved protocol. Women included in this study had stage 0-II breast cancer treated with breast BCS with negative margins and met pre-specified criteria for being underserved. WH-WBI was 28.5 or 30 Gy delivered to the whole breast using tangential beams with no elective coverage of lymph nodes. Radiotherapy boost was utilized at the discretion of the treating radiation oncologist ranging from 5.7 Gy in one fraction to 10 Gy in five fractions. The primary endpoint was ipsilateral breast tumor recurrence (IBTR). Secondary endpoints were distant disease-free survival (DDFS), recurrence free survival (RFS), overall survival (OS), adverse events and cosmesis.158 patients received WH-WBI on protocol from 2011 to 2015. Median follow up was 5.5 years (range, 0.2-10.0). Stage distribution was DCIS 22%; invasive pN0 68%; invasive pN1 10%. 28% of patients had grade 3 tumors, 10% were estrogen receptor negative and 24% required adjuvant chemotherapy. 80 patients received 30 Gy and 78 received 28.5 Gy with median follow up times of 6.2 and 5.2 years, respectively. There were six IBTR events, five in the 30 Gy group. The 5-, 7- and 10-year risks of IBRT for all patients were 2.7% (95% CI 0.89-6.34), 4.7% (95% CI 1.4-11.0) and 7.2% (95% CI 2.4-15.8) respectively. The 5, 7 and 10-year rates of DDFS were 96.4, 96.4 and 86.4%, RFS were 95.8%, 93.6 and 80.7%, and OS were 96.7, 88.6 and 76.7%, respectively. Improvement in IBTR-free time was seen in DCIS, lobular histology, low grade tumors, T1 stage, Her2 negative tumors and 28.5 Gy dose (all P < 0.0001). The cosmetic outcomes have been reported in a separate publication.WH-WBI after BCS had favorable disease-specific outcomes and comparable to those seen with conventional and other hypofractionated radiation techniques for a medically underserved population of women with stage 0-II breast cancer. This combined with prospective data from the FAST and FAST-Forward trials support a five-fraction whole breast irradiation approach after BCS.

Magnetic resonance imaging before breast cancer surgery: results of an observational multicenter international prospective analysis\xa0(MIPA)

ObjectivesPreoperative breast magnetic resonance imaging (MRI) can inform surgical planning but might cause overtreatment by increasing the mastectomy rate. The Multicenter International Prospective Analysis (MIPA) study investigated this controversial issue.MethodsThis observational study enrolled women aged 18–80 years with biopsy-proven breast cancer, who underwent MRI in addition to conventional imaging (mammography and/or breast ultrasonography) or conventional imaging alone before surgery as routine practice at 27 centers. Exclusion criteria included planned neoadjuvant therapy, pregnancy, personal history of any cancer, and distant metastases.ResultsOf 5896 analyzed patients, 2763 (46.9%) had conventional imaging only (noMRI group), and 3133 (53.1%) underwent MRI that was performed for diagnosis, screening, or unknown purposes in 692/3133 women (22.1%), with preoperative intent in 2441/3133 women (77.9%, MRI group). Patients in the MRI group were younger, had denser breasts, more cancers ≥ 20 mm, and a higher rate of invasive lobular histology than patients who underwent conventional imaging alone (p < 0.001 for all comparisons). Mastectomy was planned based on conventional imaging in 22.4% (MRI group) versus 14.4% (noMRI group) (p < 0.001). The additional planned mastectomy rate in the MRI group was 11.3%. The overall performed first- plus second-line mastectomy rate was 36.3% (MRI group) versus 18.0% (noMRI group) (p < 0.001). In women receiving conserving surgery, MRI group had a significantly lower reoperation rate (8.5% versus 11.7%, p < 0.001).ConclusionsClinicians requested breast MRI for women with a higher a priori probability of receiving mastectomy. MRI was associated with 11.3% more mastectomies, and with 3.2% fewer reoperations in the breast conservation subgroup.Key Points• In 19% of patients of the MIPA study, breast MRI was performed for screening or diagnostic purposes.• The current patient selection to preoperative breast MRI implies an 11% increase in mastectomies, counterbalanced by a 3% reduction of the reoperation rate.• Data from the MIPA study can support discussion in tumor boards when preoperative MRI is under consideration and should be shared with patients to achieve informed decision-making.

Factors predicting one or two sentinel lymph nodes to be accepted for sentinel lymph node biopsy alone after neoadjuvant therapy in initially node-positive breast cancer patients

BackgroundCurrent guidelines recommend harvesting ≥3 sentinel nodes if sentinel lymph node biopsy (SLNB) alone is considered after neoadjuvant therapy (NAT) for initially node-positive (cN+) breast cancer. We attempted to investigate factors predicting one or two sentinel lymph nodes harvested to be accepted for SLNB alone after NAT in initially cN + patients. MethodsOverall, 157 patients who received NAT (clinically T1–3/N1–2/M0) and underwent SLNB were identified from a prospectively maintained database. Significant factors were identified using a multiple logistic regression model. ResultsThe overall SLN identification rate was 83.4%. Failed SLN identification was associated with a 2-day protocol using a single tracer (odds ratio: 0.331 [95% confidence interval {CI}: 0.132–0.830], p = 0.018), age >52 years (0.345 [0.131–0.913], p = 0.032), and lobular histology (0.156 [0.026–0.944], p = 0.043). The overall false-negative SLNB rate was 14.7%. Its increased risk was associated with radioactivity count >530 for any SLN during SLNB (96.4 [4.00–2320], p = 0.005), age ≥57 years (34.2 [1.92–610], p = 0.016), and taxane use (105 [1.02–10700], p = 0.049); its decreased risk was associated with more harvested SLNs (0.191 [0.054–0.669], p = 0.01) and dual tracers (0.101 [0.012–0.843], p = 0.034). A predictive model using these factors achieved an area under the curve of 0.935 (95% CI: 0.878–0.991). ConclusionWhen taxane was administered during NAT, the false-negative rate was predicted at <5% for patients aged <57 years, if 1–2 SLNs were harvested using dual tracers, and when the count of every SLN was lower than 530 after NAT in cN + breast cancer.

Rates of margin positive resection with breast conservation for invasive breast cancer using the NCDB

BackgroundPrevious studies suggest the rate of positive surgical margin (PSM) after lumpectomy for breast cancer is approximately 20 %. The risk of PSM at time of resection is often a source of fear for patients, driving some to elect to undergo mastectomy. This study describes rates and predictors of positive margins for invasive breast cancers in the National Cancer Database (NCDB). Materials and methodsFrom 2004 to 2013, patients with non-metastatic invasive breast cancers who underwent breast conservation surgery were identified from the NCDB. Patients’ demographic, clinical, and facility of treatment characteristics were collected and compared. Per SSO-ASTRO-ASCO criteria, margin negative is defined as no gross or microscopic disease (i.e. no tumor on ink). Bivariate tests and multivariate logistic regression were conducted to identify independent predictors of patients with PSM at the time of resection. ResultsA total of 707,798 patients were identified with non-metastatic invasive breast tumors who underwent lumpectomy. Rate of PSM across the entire cohort was 5.02 %. Over time, the rate of PSM decreased significantly from 6.54 % in 2004 to 3.91 % in 2013 (p < 0.001). Pure lobular histology predicted for the highest rate of PSM compared with IDC (8.63 vs 4.55 %; p < 0.001). In adjusted analysis, high grade, non-ductal histology and HER2 amplification were significantly associated with PSM with breast conservation while estrogen and progesterone status were not. ConclusionThis study demonstrates a 5 % risk of PSM at time of breast conservation surgery using a large, modern national database. Patients with invasive lobular and mixed histology have a nearly two-fold risk of PSM compared to invasive ductal cancers. These results provide important data points to help appropriately counsel patients regarding the risk of PSM.

Breast Cancer Skip Metastases: Frequency, Associated Tumor Characteristics, and Role of Staging Nodal Ultrasound in Detection.

BACKGROUND. Staging nodal ultrasound (US) evaluates locations beyond those assessed during routine surgical dissection and has an increasing role in breast cancer management given the growing use of neoadjuvant systemic therapy before surgical staging. OBJECTIVE. The purpose of this study is to identify the patterns of nodal spread of breast cancer observed at staging nodal US and to determine the frequency of skip metastases and associated tumor characteristics. METHODS. This retrospective study included 1269 consecutive patients (31 with bilateral synchronous cancers) who had 1300 newly diagnosed, untreated, invasive breast cancers and underwent US examination of the ipsilateral regional nodal basins from January 2016 through March 2017. Cases with suspicious nodes on US underwent fine-needle aspiration (FNA) biopsy. Cases with benign results on FNA and no suspicious nodes on US underwent sentinel lymph node biopsy. Results of US with FNA were compared with final surgical pathology. Skip metastases were defined as spread across discontiguous nodal levels or distant metastases in the absence of ipsilateral nodal metastases. The incidence and patterns of spread of skip metastases were summarized; associations with tumor characteristics were tested using the Fisher exact test. RESULTS. A total of 591 metastatic cases (45.5%) were confirmed by needle biopsy or sentinel lymph node biopsy, comprising 463 nodal metastases (N+) confirmed by FNA, 121 nodal metastases (N+) confirmed by sentinel lymph node biopsy, and seven distant organ metastases without nodal metastases (N0M1) confirmed by CT-guided biopsy. US with FNA had sensitivity of 86.0%, specificity of 100.0%, PPV of 100.0%, NPV of 89.5%, and accuracy of 93.6%. There were 34 skip metastases, for an incidence of 2.6% (34/1300) (95% CI, 1.8-3.6%) among all invasive cancers and 7.2% (34/470) (95% CI, 5.1-9.9%) among metastatic cancers detected by US and FNA. Skip metastases occurred to axillary level III (n = 4), the supraclavicular nodal basin (n = 21), the contralateral axilla (n = 2), and distant organs (n = 7). Cancers with skip metastases, compared with those with nonskip metastases, had higher rates (p = .005) of lobular histology (23.5% vs 6.7%) and mixed ductal and lobular histology (11.8% vs 6.7%). Skip metastases were not associated with grade, T category, or molecular subtype (p > .05). CONCLUSION. Skip metastases to locations beyond standard surgical axillary dissection occur in 7.2% of metastatic breast cancers. CLINICAL IMPACT. Staging nodal US identifies skip metastases that otherwise would be undetected, helping to achieve more accurate staging and minimize undertreatment.

Determining breast cancer biomarker status and associated morphological features using deep learning

BackgroundBreast cancer management depends on biomarkers including estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (ER/PR/HER2). Though existing scoring systems are widely used and well-validated, they can involve costly preparation and variable interpretation. Additionally, discordances between histology and expected biomarker findings can prompt repeat testing to address biological, interpretative, or technical reasons for unexpected results.MethodsWe developed three independent deep learning systems (DLS) to directly predict ER/PR/HER2 status for both focal tissue regions (patches) and slides using hematoxylin-and-eosin-stained (H&E) images as input. Models were trained and evaluated using pathologist annotated slides from three data sources. Areas under the receiver operator characteristic curve (AUCs) were calculated for test sets at both a patch-level (>135 million patches, 181 slides) and slide-level (n = 3274 slides, 1249 cases, 37 sites). Interpretability analyses were performed using Testing with Concept Activation Vectors (TCAV), saliency analysis, and pathologist review of clustered patches.ResultsThe patch-level AUCs are 0.939 (95%CI 0.936–0.941), 0.938 (0.936–0.940), and 0.808 (0.802–0.813) for ER/PR/HER2, respectively. At the slide level, AUCs are 0.86 (95%CI 0.84–0.87), 0.75 (0.73–0.77), and 0.60 (0.56–0.64) for ER/PR/HER2, respectively. Interpretability analyses show known biomarker-histomorphology associations including associations of low-grade and lobular histology with ER/PR positivity, and increased inflammatory infiltrates with triple-negative staining.ConclusionsThis study presents rapid breast cancer biomarker estimation from routine H&E slides and builds on prior advances by prioritizing interpretability of computationally learned features in the context of existing pathological knowledge.

Targeted Axillary Dissection after Chemotherapy: Feasibility Study with Clip and Carbon Dye Tattoo – Neotarget Trial

Background: Axillary staging in patients with complete response after neoadjuvant chemotherapy (NAC) is still controversial. Our objective was to test tattoo alone and subsequentially tattoo plus clip as markers in the targeted axillary dissection of ycN0 patients. Methods: Prospective cohort of cT1-T3, cN1 (proven histologically), M0 patients scheduled to receive NAC. Exclusion criteria were lobular histology, prior axillary surgery, and clinical N2/3. In cohort 1 this positive node (Neotarget node) was tattooed at diagnosis. If ycN0, a targeted axillary dissection was performed. After an interim analysis with negative results we changed the protocol in order to do a double marking procedure (Cohort 2): the positive node was clipped at diagnosis and after NAC a tattoo was done before surgery. Results: Thirteen patients in Cohort 1 and 18 patients in Cohort 2. Failure to identify the Neotarget node with multiple nodes retrieved in 9/13 (69%) of Cohort 1 patients. Also in 5/13 (38%) of Cohort 1 patients and 3/18 (17%) of Cohort 2 there was a failure to clearly identify tattooed nodes. In Cohort 2, clip identification by surgical specimen radiography allowed the identification of the tagged node in 17/18 (94,4%) of cases. The concordance between the clipped node and sentinel nodes was 16/18 (89%). Conclusions: The introduction of double marking by clipping the metastatic node and verifying their removal by surgical specimen radiography, using carbon ink as a tracer, allowed the identification of the metastatic node in 94% of cases, with a simple, reproducible, and easy-to-implement targeted axillary dissection procedure.

Effectiveness of a Short Duration of Neoadjuvant Endocrine Therapy in Patients with HR+ Breast Cancer—An NCDB Analysis (2004–2016)

BackgroundNational medical/surgical organizations have recommended the use of neoadjuvant endocrine therapy (NET) to bridge surgery delay of weeks to months for patients with hormone receptor positive (HR+) breast cancer during the ongoing coronavirus disease 2019 (COVID-19) pandemic. The effects of NET of varying durations on pathologic response are unclear. Using the National Cancer Database (NCDB), we evaluated objective response to short (< 9 weeks), moderate (9–27 weeks), and long (> 27 weeks) duration of NET.Patients and MethodsThe study cohort included female patients diagnosed with nonmetastatic invasive HR+ breast cancer, stratifying by those who received NET versus no NET between 2004 and 2016. Pathologic response was grouped into four categories (complete, downstaged, stable, upstaged) by comparing clinical and pathologic staging data. Objective response to NET included complete, downstaged, and stable pathologic response. Clinical characteristics were compared using χ2 and analysis of variance (ANOVA) tests. Multivariable logistic regression was used to determine factors associated with NET use and objective response according to NET duration.ResultsA minority (1.2%) received NET in our cohort. Factors associated with NET use included older age, non-Black patients, more advanced clinical stage, higher comorbidity score, government insurance, and lobular histology. Objective response rate (ORR) was 56.7%, 52.1%, and 49.0% after short, moderate, and long NET duration, respectively.ConclusionShort NET duration did not result in an inferior ORR. Future study to evaluate the interaction between surgery delay and NET use on clinical outcome will provide insights into the safety of NET to bridge potential surgery delay in patients with HR+ breast cancer.Supplementary InformationThe online version contains supplementary material available at 10.1245/s10434-021-10287-5.

Composite scoring combining OncotypeDX risk with circulating tumor cell status improves prognostication.

e12577 Background: Genomic assays, such as the 21-gene OncotypeDX (ODX) and the 70-gene MammaPrint (MP) panels, can be used to personalize treatment for women with early-stage, hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer (BC). We previously showed that 1) circulating tumor cell (CTC) status has prognostic and predictive value in BC, and that 2) there is no clear association between ODX risk and CTCs. We, hereby, assess the prognostic value of composite scoring combining ODX and CTC data. Methods: This analysis of the 2004-2017 National Cancer Database registry includes patients with early-stage (AJCC I-II), HR+/HER- BC, as well as ODX, MP, and CTC data. A composite model was created with ODX and CTC data: low-risk escalated to intermediate-risk, or intermediate- to high-risk, if positive for CTCs. The association between a) ODX, b) ODX-CTC composite, or c) MP and overall survival (OS) was examined using Cox regressions, controlling for age (50-70); and stratifying by race (White vs. Black) and tumor histology (ductal vs. lobular). Prognostic value was evaluated using Harrell’s C-index (i.e. area under ROC curve) for each model. Results: N = 841,716 patients with early-stage, HR+/HER2- BC were identified. N = 271,416 (32.2%) had ODX data, n = 12,417 (1.5%) had MP data, and n = 1,141 (0.14%) had both ODX and CTC data. Due to CTC-positivity, n = 46 patients were upstaged from low- to intermediate-risk (23.1% of all low-risk), while n = 63 patients were upstaged from intermediate- to high-risk (20.5% of all intermediate-risk) in the composite ODX-CTC model. All 3 prognostic scoring systems were associated (p &lt; 0.05) with OS as per Cox regressions. As indicated by a C-index closer to 1, MP appears superior to ODX alone at differentiating high- from low-risk based on OS (0.597 versus 0.565) patients. However, composite ODX-CTC scoring was superior to MP alone (0.673 versus 0.597). This model could not be validated in Black patients (versus White) or those with lobular histology (compared to ductal) due to limited ODX-CTC data in these groups. Conclusions: Composite ODX-CTC risk scoring appears superior to MP alone. If confirmed, this prognostic model would more accurately identify early-stage, HR+/HER2- patients requiring escalated systemic therapy including chemotherapy compared to low-risk BC. More data is needed in ethnic minorities and patients with atypical histology to validate these promising results.[Table: see text]

Outcome and immune landscape of HER2-positive invasive lobular carcinoma in the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) trial.

535 Background: Invasive lobular carcinoma (ILC) is a rarer form of breast cancer, accounting for 10% of the disease cases. HER2 overexpression in ILC is infrequent and limited data exist regarding clinical characteristics and outcome of HER2-positive (HER2+) ILC patients (pts) treated with adjuvant trastuzumab. Methods: Patient characteristics were compared between ILC and invasive ductal carcinoma (IDC) using Wilcoxon rank sum test for continuous variables and Chi-square test for categorical variables. Kaplan-Meier (KM) method was used to estimate the freedom from mortality and recurrence. Cox regression model was used to evaluate the association between ILC and outcomes adjusted for other characteristics. NanoString technology was used to quantify mRNA to develop immune-related gene signatures. Results: From a total of 3,304 pts, 122 (3.7%) pts had ILC. Pts with ILC were significantly older (median age 54 vs. 49 years), had larger tumors, lower grade, more ER and PR positive tumors, and more lymph node involvement (25.4% had N3 disease compared to 12.7% in IDC). Overall, with KM analysis, pts with ILC had significantly worse overall survival (OS, p = 0.005) and recurrence-free survival (RFS, p = 0.046) compared to IDC. The 15-year freedom from recurrence was merely 57.67% in ILC compared to 72.68% in IDC. A significant number of hormone receptor-positive (HR+) ILC pts developed late recurrence with cumulative event rates increasing from 23% at 5 years to 42% at 15 years. Nevertheless, in multivariate Cox regression analysis adjusting for other clinical characteristics, including age, tumor size, grade, ER/PR, and lymph node status, lobular histology was not significantly associated with worse outcome for OS (HR = 1.19, 95%CI 0.67-2.1, p = 0.55) and RFS (HR = 1.5, 95%CI 0.9-2.5, p = 0.12), as compared with IDC. However, ILC pts appeared to have similar degree of benefit from trastuzumab, with RFS HR = 0.58 compared to HR = 0.67 in the entire population. For immune landscape, there was no significant difference in gene signatures related to CD45, CD8, B cells, or cytotoxic cells. However, ILC had more enrichment in mast cell gene signature and fewer macrophage, NK CD56dim, and regulatory T cell signatures compared to IDC (p &lt; 0.05). Conclusions: HER2+ ILC has distinct clinical characteristics and immune landscape compared to IDC. ILC pts appeared to have worse outcome compared to IDC likely because ILC pts often presented with more locally advanced disease. However, similar benefit of trastuzumab was observed in ILC pts. Due to high risk of late relapse in HR+ HER2+ ILC, extended adjuvant endocrine therapy should be considered in this group of high-risk pts. Clinical trial information: NCT00005970.

Breast cancer patients treated with intrathecal therapy for leptomeningeal metastases in a large real-life database

BackgroundLeptomeningeal metastasis (LM) is a rare complication of metastatic breast cancer (MBC), with high morbidity/mortality rates. Our study aimed to describe the largest-to-date real-life population of MBC patients treated with intrathecal (IT) therapy and to evaluate prognostic models.MethodsThe Epidemiological Strategy and Medical Economics (ESME) MBC database (NCT03275311) includes all consecutive patients who have initiated treatment for MBC since 2008. Overall survival (OS) of patients treated with IT therapy was estimated using the Kaplan–Meier method. Prognostic models were constructed using Cox proportional hazards models. Performance was evaluated using C-index and calibration plots.ResultsOf the 22 266 patients included in the database between 2008 and 2016, 312 received IT therapy and were selected for our analysis. Compared with non-IT-treated patients, IT-treated patients were younger at MBC relapse (median age: 52 years versus 61 years) and more often had lobular histology (23.4% versus 12.7%) or triple-negative subtype (24.7% versus 13.3%) (all P < 0.001). Median OS was 4.5 months [95% confidence interval (CI) 3.8-5.6] and 1-year survival rate was 25.6%. Significant prognostic factors associated with poorer outcome on multivariable analysis were triple-negative subtype (hazard ratio 1.81, 95% CI 1.32-2.47), treatment line ≥3 (hazard ratio 1.88, 95% CI 1.30-2.73), ≥3 other metastatic sites (hazard ratio 1.33, 95% CI 1.01-1.74) and IT cytarabine or thiotepa versus methotrexate (hazard ratio 1.68, 95% CI 1.28-2.22), while concomitant systemic therapy was associated with better OS (hazard ratio 0.47, 95% CI 0.35-0.62) (all P < 0.001). We validated two previously published prognostic scores, the Curie score and the Breast-graded prognostic assessment, both with C-index of 0.57.ConclusionsMBC patients with LM treated with IT therapy have a poor prognosis. We could identify a subgroup of patients with better prognosis, when concomitant systemic therapy and IT methotrexate were used.

The Impact of Preoperative Breast MRI on Surgical Margin Status in Breast Cancer Patients Recalled at Biennial Screening Mammography: An Observational Cohort Study

BackgroundThis study aimed to examine the association between preoperative magnetic resonance imaging (MRI) and surgical margin involvement, as well as to determine the factors associated with positive resection margins in screen-detected breast cancer patients undergoing breast-conserving surgery (BCS).MethodsBreast cancer patients eligible for BCS and diagnosed after biennial screening mammography in the south of The Netherlands (2008–2017) were retrospectively included. Missing values were imputed and multivariable regression analyses were performed to analyze whether preoperative MRI was related to margin involvement after BCS, as well as to examine what factors were associated with positive resection margins, defined as more than focally (>4 mm) involved.ResultsOverall, 2483 patients with invasive breast cancer were enrolled, of whom 123 (5.0%) had more than focally involved resection margins. In multivariable regression analyses, preoperative MRI was associated with a reduced risk of positive resection margins after BCS (adjusted odds ratio [OR] 0.56, 95% confidence interval [CI] 0.33–0.96). Lobular histology (adjusted OR 2.86, 95% CI 1.68–4.87), large tumor size (per millimeter increase, adjusted OR 1.05, 95% CI 1.03–1.07), high (>75%) mammographic density (adjusted OR 3.61, 95% CI 1.07–12.12), and the presence of microcalcifications (adjusted OR 4.45, 95% CI 2.69–7.37) and architectural distortions (adjusted OR 1.85, 95% CI 1.01–3.40) were independently associated with positive resection margins after BCS.ConclusionsPreoperative MRI was associated with lower risk of positive resection margins in patients with invasive breast cancer eligible for BCS using multivariable analysis. Furthermore, specific mammographic characteristics and tumor characteristics were independently associated with positive resection margins after BCS.

Prognostic Factors and Survival Outcomes among Patients with Breast Cancer and Brain Metastases at Diagnosis: A National Cancer Database Analysis

Introduction: The aim of this study was to assess for clinicopathologic and socioeconomic features that predict improved survival for patients with advanced breast cancer with synchronous brain metastases at diagnosis. Methods: We utilized the National Cancer Database (NCDB) to identify all patients with brain metastases present at diagnosis, with adequate information on receptor status (ER, PR, Her2), clinical T stage of cT1-4, clinical M1, with 3,943 patients available for analysis. The association between brain metastases patterns and patient/disease variables was examined by robust Poisson regression model. Cox proportional hazards model was used to quantify the associations between overall survival (OS) and these variables. Results: In univariable analysis, OS was significantly associated with the number of sites of metastases (p < 0.0001). Patients with 2 or more additional extracranial sites of metastases had significantly worse OS (median 8.8 months, 95% confidence interval [CI] 7.8, 9.9) than patients with brain metastases only (median OS 10.6 months, 95% CI 9.4, 12.9) or brain metastases plus one other extracranial site of metastases (median OS 13.1 months, 95% CI 11.8, 14.4). Risk factors which predicted poor prognosis included triple-negative disease, high comorbidity score, poorly differentiated tumors, invasive lobular histology, multi-organ involvement of metastases, and government or lack of insurance. Factors which improve survival include younger age and Hispanic race. Discussion/Conclusion: Using a large NCDB, we identified various factors associated with prognosis for patients with brain metastases at the time of breast cancer diagnosis. Insurance status and related socioeconomic challenges provide potential areas for improvement in care for these patients. This information may help stratify patients into prognostic categories at the time of diagnosis to improve treatment plans.

Abstract PD10-06: Clinical behavior and outcomes of BRCA-mutated breast cancer in young patients according to type of BRCA mutation and hormone receptor status: Results from an international cohort study

Abstract Background: Young breast cancer patients (pts) carrying a germline BRCA mutation (mBRCA) have similar outcomes as non-carriers. However, there is currently lack of evidence regarding the impact of mBRCA type and hormone receptor status on clinical behavior and outcomes of mBRCA breast cancer. We aim to address these questions in the largest dataset to date of young mBRCA breast cancer pts. Methods: This was an international, multicenter, hospital-based, retrospective cohort study. Women harboring deleterious germline mBRCA1 or mBRCA2 that received a diagnosis of stage I-III invasive early breast cancer at age ≤40 years between January 2000 and December 2012 were included. Baseline pts, tumor, and treatment characteristics, pattern and risk over time of disease-free survival (DFS) events, and survival outcomes (DFS, distant recurrence-free interval [DRFI] and overall survival [OS]) were compared between mBRCA1 and mBRCA2 pts overall and by hormone receptor status. Multivariate Cox proportional hazard models were used to compare hazard rates (HRs). Results: 1,236 young mBRCA breast cancer pts were included. Among 808 and 428 pts with mBRCA1 or mBRCA2, respectively, 191 (23.6%) and 356 (83.2%) had hormone receptor-positive tumors while 617 (76.4%) and 72 (16.8%) hormone receptor-negative disease (p&amp;lt;0.001). Compared to mBRCA2 breast cancer pts, those with mBRCA1 were younger, more likely to have reported Jewish ancestry, had more grade 3 tumors, less nodal involvement, lobular histology and HER2 positivity, and received more frequently chemotherapy (all p&amp;lt;0.001). More mBRCA1 pts with hormone receptor-positive tumors did not receive adjuvant endocrine therapy (14.7% vs. 4.2%, p&amp;lt;0.001). No difference between mBRCA1 and mBRCA2 pts was observed in risk-reducing mastectomy (43.9% vs. 46.0%; p=0.371) or salpingo-oophorectomy (48.3% vs. 48.8%; p=1.0). Median follow-up was 7.9 years (range 5.6-10.6 years). Second primary breast cancers (17.0% vs. 12.2%, p=0.025) and non-breast primary malignancies (4.3% vs. 1.9%, p=0.033) were more frequent among mBRCA1 pts compared to mBRCA2 pts, while distant recurrences were less frequent (10.4% vs. 15.4%, p=0.013). 8-year DFS was 62.8% and 65.9% for mBRCA1 and mBRCA2 pts, respectively (adjusted HR 0.76; 95% CI 0.60-0.96). The worse DFS in mBRCA1 was observed regardless of hormone receptor status (pinteraction=0.848): hormone receptor-positive (adjusted HR 0.77; 95% CI 0.58-1.03) and hormone receptor-negative (adjusted HR 0.73; 95% CI 0.48-1.13). No differences in DRFI and OS were observed between mBRCA1 and mBRCA2 pts. Compared to pts with hormone receptor-negative disease, those with hormone receptor-positive breast cancer had higher chances of developing distant (± loco-regional) recurrences (16.1% vs. 9.0%; p&amp;lt;0.001) and less frequent second primary malignancies (BC: 12.1% vs. 17.9%, p=0.005; non-BC: 2.8% vs. 4.0%, p=0.216). No differences in DFS and OS were observed between pts with hormone receptor-positive or negative breast cancer. However, there was a trend towards worse DRFI in women with hormone receptor-positive breast cancer as compared to those with hormone receptor-negative disease (8-year DRFI: 83.4% vs. 90.1%; adjusted HR 1.39; 95% CI 0.94-2.05). Conclusions: In this large unique dataset, young mBRCA1 breast cancer pts had worse DFS than those with mBRCA2 mostly due to higher rates of second primary malignancies. Hormone receptor positivity had no positive prognostic value in young mBRCA breast cancer pts with a trend towards worse DRFI in those with hormone receptor-negative disease. These results provide important information for counseling young mBRCA breast cancer pts regarding treatment, prevention and follow-up care strategies. Citation Format: Matteo Lambertini, Marcello Ceppi, Anne-Sophie Hamy, Olivier Caron, Philip D. Poorvu, Estela Carrasco, Albert Grinshpun, Kevin Punie, Christine Rousset-Jablonski, Alberta Ferrari, Shani Paluch-Shimon, Angela Toss, Claire Senechal, Fabio Puglisi, Katarzyna Pogoda, Jose Alejandro Pérez-Fidalgo, Laura De Marchis, Riccardo Ponzone, Luca Livraghi, Maria Del Pilar Estevez-Diz, Cynthia Villarreal-Garza, Maria Vittoria Dieci, Florian Clatot, Francois P. Duhoux, Rossella Graffeo, Luis Teixeira, Octavi Córdoba, Amir Sonnenblick, Arlindo R. Ferreira, Ann H. Partridge, Antonio Di Meglio, Claire Saule, Fedro A. Peccatori, Marco Bruzzone, Lucia Del Mastro, Lieveke Ameye, Judith Balmaña, Hatem A. Azim, Jr. Clinical behavior and outcomes of BRCA-mutated breast cancer in young patients according to type of BRCA mutation and hormone receptor status: Results from an international cohort study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-06.