Lobular Histology Research Articles

Abstract P5-02-30: Histology-based survival outcomes in HR+/HER2- metastatic breast cancer treated with targeted therapies plus endocrine therapy based on HER2 expression

Abstract Background: About 55% of hormone receptor (HR)-positive metastatic breast cancer (mBC) show a low-level expression of human epidermal growth factor receptor 2 (HER2-low). HER2-low is defined as HER2 immunohistochemistry (IHC) expression of 1+ or 2+ with a negative HER2 amplification by in situ hybridization. The efficacy of the antibody-drug conjugate trastuzumab deruxtecan in HER2-low HR+ mBC has been practice changing. However, there are conflicting data on the prognostic value of low HER2-expression in HR+ mBC with some reports showing no impact on prognosis and other showing inferior outcomes in HER2-low patients when treated with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) in combination with endocrine therapy (ET). Methods: We retrospectively searched for patients treated at MD Anderson Cancer Center with a diagnosis of HR+ treated with ET in combination with a targeted therapy (CDK4/6is, everolimus or alpelisib). Patients were divided into 3 groups: All histologies, ductal histology (IDC) and lobular histology (ILC). We obtained data on demographics, estrogen (ER) and progesterone (PR) receptor status, HER2 expression, menopausal status, treatment duration and survival status. The Kaplan-Meier product-limit method was used to compare progression-free survival (PFS) and overall survival (OS) between the three different groups stratified by HER2 expression (HER2 low versus HER2 0). Results: We identified 1,649 patients (64% HER2-low, 36% HER2 0) with HR+/HER2- treated with targeted therapy (CDK4/6is, everolimus or alpelisib) in combination with ET. The median age was around 50 years in all groups, 75% were White, 55% premenopausal, 95% ER-positive and 83% PR-positive. 68% were treated with CDK4/6is (919 patients treated in first line (1L) and 202 treated in second line), 30% everolimus and 2% with alpelisib. In the patients who received first 1L CDK4/6is, 70% received an aromatase inhibitor as their ET backbone and 30% received fulvestrant. All the patients who received 1L fulvestrant recurred while on adjuvant AI. PFS and OS were not statistically different between the HER2-low and HER2 0 groups treated with targeted therapies (TT) plus ET or 1L CDK4/6is plus ET regardless of the histology (Table 1). Conclusion: In this single institution analysis, HER2-low status did not have a significant impact on prognosis in HR+/HER2- mBC treated with TT plus ET or 1L CDK4/6is plus ET. Table 1. Progression-free Survival and Overall Survival in HR+/HER2- mBC patients treated with targeted therapies (TT) plus endocrine therapy (ET) In patients treated with TT + ET in all histologies (A), in IDC (B) and in ILC (C). In patients treated in 1L with CDK4/6is + ET in all histologies (D), in IDC (E) and in ILC (F) Citation Format: Jason Mouabbi, Akshara Singareeka Raghavendra, Roland Bassett, Amy Hassan, Debu Tripathy, Rachel M. Layman. Histology-based survival outcomes in HR+/HER2- metastatic breast cancer treated with targeted therapies plus endocrine therapy based on HER2 expression [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-30.

Abstract HER2-11: HER2-11 Epidemiology and Prognosis of HER2-Low Breast Cancer (BC) in the National Cancer Data Base (NCDB)

Abstract Title: Epidemiology and Prognosis of HER2-Low Breast Cancer (BC) in the National Cancer Data Base (NCDB) Background: Characterization of HER2 status has focused on HER2 overexpressing BC, which are uniquely sensitive to HER2-directed therapy. However, approximately 60% of BC traditionally characterized as HER2-negative express low levels of HER2 on immunohistochemistry (IHC). Although these ‘HER2-low’ cancers are insensitive to traditional HER2 blockade, a recent randomized clinical trial showed that antibody drug conjugates such as trastuzumab deruxtecan (T-DXd) are effective in this population. Given the heterogenity of low level HER2 expression and the impact of T-DXd on outcomes in this population, further data on the epidemiology and prognosis of HER2-low BC is needed. Methods: We conducted a retrospective cohort study of patients (pts) in the NCDB diagnosed from 2010 to 2019 with invasive BC classified as HER2-negative, and with HER2 IHC results available. We compared demographics and other clinical characteristics of HER2 0 vs HER2-low (defined as IHC score of 1+ or 2+) cases in this cohort. A logistic regression was used to quantify the independent association of demographic and clinical factors with HER2-low status, and odds ratios (OR) and 95% confidence intervals (CI) were reported. Overall survival (OS) was compared for HER2 0 vs HER2-low by receptor subtype and stage, and a multivariable Cox model was fit to also control for age, race/ethnicity, comorbidity score, treatment facility type, grade, and histologic type. In pts who received neoadjuvant chemotherapy (NAC), a logistic regression was used to determine if pathological complete response (pCR) rate was different between HER2-low and HER2 0 pts. Results: We identified 1,191,389 pts, including 394,937 HER2 0 and 796,452 HER2-low; median follow-up was 54 months with 84.1% of pts surviving. Hispanic and Black pts and pts with higher grade, non-ductal, triple-negative breast cancer (TNBC) and affect minority Hispanic and Black women (table 1). On multivariable analysis, TNBC (odds ratio [OR] 0.48, 95% confidence interval [CI] 0.47 – 0.49), lobular (OR 0.74, 95% CI 0.73 – 0.75) and other non-ductal histology (OR 0.66, 95% CI 0.64 – 0.67) had lower likelihood of HER2-low status. Hispanic ethnicity remained associated with lower likelihood of HER2-low (OR 0.89, 95% CI 0.87 – 0.91), whereas Black race was associated with a slight increased likelihood of HER2-low status (OR 1.06, 95% CI 1.04 – 1.08). In multivariable survival analysis of TNBC patients, HER2-low BC was associated with improved OS for stage 2 (hazard ratio [HR] 0.93, 95% CI 0.90 – 0.96), stage 3 (HR 0.92, 95% CI 0.88 – 0.96) and stage 4 (HR 0.92, 95% CI 0.87 – 0.97) cancer. By contrast, survival analysis of hormone receptor positive cancer showed that HER2-low BC was associated with improved OS only for stage 4 disease (HR 0.96, 95% CI 0.92 – 0.99). In 62,667 pts receiving NAC, HER2-low status was associated with a lower likelihood of pCR (OR 0.88, 95% CI 0.84 – 0.92). Conclusions: HER2-low BC is most frequently HR+ with a ductal histology, and is associated with a lower likelihood of response to chemotherapy but an improved OS, especially for metastatic cases. This lower pCR in the HER2-low population could be explained by a higher proportion of these tumors being HR+. There are racial/ethnic differences in the incidence of HER2-low BC, largely mediated by differences in rates of TNBC, and fewer Black and Hispanic pts will be candidates for therapies targeting low level HER2 expression. Citation Format: Daniel Peiffer, Frederick M. Howard, Nan Chen, Olwen M. Hahn, Rita Nanda, Olufunmilayo I. Olopade, Dezheng Huo. HER2-11 Epidemiology and Prognosis of HER2-Low Breast Cancer (BC) in the National Cancer Data Base (NCDB) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr HER2-11.

Abstract PD7-05: Survival of patients with brain metastases at initial breast cancer diagnosis over the last decade

Abstract Background Brain metastases (BM) is a challenging presentation of breast cancer (BC) and has historically been associated with poor prognosis. The risk of BM is higher in patients (pts) with hormone receptor (HR) negative, human epidermal growth factor receptor 2 (HER2)-positive, or triple negative (TN) tumors. There have been significant advances in the treatment of metastatic BC over the past several years, and long-term outcomes after a diagnosis of breast cancer brain metastases (BCBM) are lacking; therefore, this study aimed to identify clinical predictors of BM at initial BC diagnosis, to describe trends in overall survival (OS) over the past decade, and to identify factors associated with OS after BM diagnosis. Methods We evaluated pts with de novo stage IV BC using the Surveillance, Epidemiology and End Results (SEER) database from 2010-2019. A multivariate logistic regression model was conducted among all pts with stage IV BC to assess predictors of BM at initial BC diagnosis. OS probabilities were estimated using the Kaplan-Meier method and log rank test was used to compare differences between groups. Among pts with BM at initial BC diagnosis, univariate analyses were performed to determine the effects of each variable on OS. A Cox proportional hazards regression was used to assess the independent association of several variables with OS. Results A total of 425,110 pts with BC were identified from 2010-2019; 25,113 had stage IV BC at diagnosis and among these, 1,939 pts had BM at initial BC diagnosis. For this last group median age was 60 years and median follow up was 54 months. We performed a logistic regression model to evaluate the factors correlated with BM at initial BC diagnosis among all stage IV BC pts and found that lobular vs ductal histology (OR 0.68; 95% CI 0.55-0.85), HR-/HER2+ vs HR+/HER2- tumors (OR 1.93; 95% CI 1.64-2.29), and the presence of bone (OR 1.19; 95% CI 1.07-1.32), liver (OR 1.25; 95% CI 1.12-1.39), lung (OR 1.72; 95% CI 1.55-1.89), or lymph node (OR 1.21; 95% CI 1.03-1.42) metastases, were significantly associated with this presentation. The table shows OS by tumor subtype among all pts with BM at initial BC diagnosis, as well as the survival rate at 2, 5 and 8 years. We observed significant differences in survival by tumor subtype, where pts with HR+/HER2+ disease had the longest OS (median 18 months; 95% CI: 13-22 months; p = < 0.0001) and the highest rate of OS at 8 years (12.2%; 95% CI 7.61%-17.95%). In contrast, TN BC had a median OS of 6 months (95% CI 5-8 months) and a rate of OS at 8 years of 2.57% (95% CI 0.1%-5.48%). Multivariate analysis among pts with BM at initial BC diagnosis revealed differences in OS in those who were >64 years vs < 50 years (Hazard Ratio [HzR] 1.51; 95% CI 1.29-1.77), married vs single (HzR 0.79; 95% CI 0.70-0.91), lower vs higher income (HzR 1.45; 95% CI 1.19-1.76), tumor grade III/IV vs grade I (HzR 1.68; 95% CI 1.24-2.28), TN subtype vs HR+/HER2- (HzR 2.13; 95% CI 1.81-2.49), as well as pts with additional liver (HzR 1.34; 95% CI 1.20-1.51) or lung metastases (HzR 1.34; 95% CI 1.20-1.49). We did not observe significant changes in OS over time (adjusted HzR 0.996 per year; 95% CI: 0.96-1.02, p = 0.837). Conclusions: Over the last decade, the median OS of pts with BM at initial BC diagnosis has remained poor. However, a substantial minority of pts survive 5 or more years, with long-term survival rates higher in pts with HER2+ tumors. In addition to tumor subtype, OS varied according to age, the presence of metastases to other organs, and sociodemographic factors. Citation Format: Jorge Avila, Julieta Leone, Carlos T. Vallejo, Nancy U. Lin, Jose P. Leone. Survival of patients with brain metastases at initial breast cancer diagnosis over the last decade [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD7-05.

Risk Factors, Patterns, and Distribution of Bone Metastases and Skeletal-Related Events in High-Risk Breast Cancer Patients

More than a quarter of breast cancer patients are at risk to develop recurrent metastases to the bone. This study was designed to identify risk factors and predilections of bone metastasis and skeletal-related events (SRE) in a population of breast cancer survivors initially diagnosed in advanced stages and with high-risks of relapse. Associated risk factors, distribution, and attainable treatment of bone metastasis and SRE were analyzed in a cohort of 1,329 breast cancer patients. The association with dependent variables was subsequently analyzed using multivariable logistic regression. Sociodemographic and adverse clinical characteristics were included as covariates of progression into bone metastasis and SREs. Of 1329 breast cancer patients, 246 patients (18.5%) were diagnosed as metastatic breast cancer in which 232 of them (94.3%) had bone metastases. Spines were the most common sites of bone metastases (25.6%). In multivariable analysis, advanced stage at diagnosis (OR=1.840, 95%CI:1.198-2.826, P=0.005), luminal subtype (OR=1.788, 95%CI:1.206-2.652, P=0.045), lobular histology (OR=1.795, 95%CI:1.012-3/184, P=0.046), positive axillary lymph node (OR=1.771, 95%CI:1.087-2.886, P=0.022), multiple metabolic comorbidities (OR=2.193, 95%CI:1.371-3.508, P=0.001), early menopause (OR=2.136, 95%CI:1.116-4.464, P=0.046) were significantly associated with risk of recurrent bone metastases. SREs occurred in 89 (68.5%) patients. Several risk factors for SREs were early menopausal age (OR=2.342, P=0.024), advanced stages (OR=1.404, P=0.039), lobular histology (OR=2.279, P=0.007), and having multiple metabolic comorbidities (OR=1.728, P=0.039). Bone metastases and SREs are relatively high in breast cancer patients diagnosed in advanced stages. Luminal subtypes, having multiple metabolic comorbidities, and lobular histology are associated with higher risks of recurrent bone metastases. Living in rural areas and advanced stage at diagnosis as a risk factors for bone metastases might represent a social gradient of care delivery.

Saturday, June 18, 20223:45 PM - 4:45PM MSS01 Presentation Time: 3:45 PM: A Single-Institution Retrospective Study of Three-Fraction HDR Accelerated Partial Breast Irradiation

<h3>Purpose</h3> Accelerated partial breast irradiation (APBI) delivered with high-dose-rate brachytherapy is a standard of care treatment which is typically delivered over 8-10 fractions. The TRIUMPH-T multi-institutional study recently demonstrated promising results using a shorter three fraction regimen. However, there are limited additional published series using this regimen. Here, we report our experience and outcomes for patients treated as per the TRIUMPH-T regimen. <h3>Materials and Methods</h3> Retrospective single-institution analysis of patients who underwent lumpectomy followed by APBI (22.5 Gy in 3 fractions delivered over 2-3 days) using a SAVI applicator between November 2016 and January 2021. Per the TRIMPH-T protocol guidelines, the planning treatment volume (PTV) was 1 cm beyond the surgical cavity, limited to 0.5 cm from the skin surface, and subtracted from chest wall and SAVI cavity. Dose-volume metrics were obtained from the clinically treated plan. Chart review was performed to determine locoregional recurrence and toxicities according to CTCAEv5.0. <h3>Results</h3> From 2016-2021, 31 patients were treated per the TRIUMPH-T protocol. The median age was 64 years (range 46-82). 77% of patients had invasive ductal carcinoma, median tumor size was 1.2 cm (range 0.4-2.0), 84% were Grade 1-2, 90% were N0 (3 DCIS patients were Nx), and 100% were ER+. Median follow-up was 31 months (range 6-62 months) from completion of brachytherapy. PTV median dose metrics were as follows: D90: 94.6% (range 90-110%), V150: 22.0cc (range 12.5-38.2cc), V200: 11.0cc (range 3.5-21.2cc), and DHI: 0.51 (range 0.36-0.68). Median D0.03cc for the skin (3 mm inner margin on body) and rib were 68.3% (range 29.9-91.6%) and 70.6% (range 15.7-124.2%), respectively. There were no acute/late grade 3 or higher toxicities. Cumulative late Grade 1 and 2 toxicities were seen in 58% and 6% of patients, respectively. Grade 1-2 fibrosis was seen in 32% of patients. Other toxicities included grade 1 breast pain (26%), grade 1-2 seroma formation (23%), grade 1 hyperpigmentation (6%), symptomatic fat necrosis (6%), and breast infection (3%). Of note, four patients experienced locoregional recurrence: three ipsilateral breast tumor recurrences (two in the same quadrant as the lumpectomy cavity), and one nodal recurrence (patient was cN0/pN0). All three ipsilateral breast tumor recurrences occurred in patients who would be classified as "cautionary" based on ASTRO consensus guidelines due to age ≤50, lobular histology, or high grade. There were no distant recurrences or deaths of any cause. <h3>Conclusions</h3> Three-fraction HDR brachytherapy APBI delivered per the TRIMUPH-T protocol was well-tolerated in our cohort with no grade 3 or higher toxicities and an acceptably small percentage of grade 2 toxicities. Given the small sample size, the number of recurrences suggests that attention to appropriate patient selection is necessary until more long-term follow-up data is available.

Risk of metachronous contralateral breast cancer in patients with primary invasive lobular breast cancer: Results from a nationwide cohort.

Lobular primary breast cancer (PBC) histology has been proposed as a risk factor for contralateral breast cancer (CBC), but results have been inconsistent. We investigated CBC risk and the impact of systemic therapy in lobular versus ductal PBC. Further, CBC characteristics following these histologic subtypes were explored. We selected 74,373 women diagnosed between 2003 and 2010 with stage I-III invasive PBC from the nationwide Netherlands Cancer Registry. We assessed absolute risk of CBC taking into account competing risks among those with lobular (n= 8903), lobular mixed with other types (n= 3512), versus ductal (n= 62,230) histology. Hazard ratios (HR) for CBC were estimated in a cause-specific Cox model, adjusting for age at PBC diagnosis, radiotherapy, chemotherapy and/or endocrine therapy. Multivariable HRs for CBC were 1.18 (95% CI: 1.04-1.33) for lobular and 1.37 (95% CI: 1.16-1.63) for lobular mixed versus ductal PBC. Ten-year cumulative CBC incidences in patients with lobular, lobular mixed versus ductal PBC were 3.2%, 3.6% versus 2.8% when treated with systemic therapy and 6.6%, 7.7% versus 5.6% in patients without systemic therapy, respectively. Metachronous CBCs were diagnosed in a less favourable stage in 19%, 26% and 23% and less favourable differentiation grade in 22%, 33% and 27% than the PBCs of patients with lobular, lobular mixed and ductal PBC, respectively. In conclusion, lobular and lobular mixed PBC histology are associated with modestly increased CBC risk. Personalised CBC risk assessment needs to consider PBC histology, including systemic treatment administration. The impact on prognosis of CBCs with unfavourable characteristics warrants further evaluation.

1710P Genomic landscape (GL) with potential of methylthioadenosine phosphorylase (MTAP) loss in clinically advanced breast cancer (CABC)

Homozygous deletion of MTAP causes intracellular arginine accumulation enabling anti-tumor effects of MTA2/PRMT5 inhibitors via a synthetic lethality mechanism. 7,301 cases of MBC underwent hybrid-capture based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and MSI status was determined on 114 loci. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). 208 (2.84%) of CABC featured MTAP loss. MTAP loss patients were younger (p=.002) and were more frequently ER- (30% v 50%; p<.0001), triple negative (TNBC) (47% v 27%; p<.0001) and less frequently HER2+ (2% v 8%; p=.0001) than MTAP intact MBC. Lobular histology and CDH1 mutations were more frequent in MTAP intact (14%) than MTAP loss MBC (p<.0001). CDKN2A (100%) and CDKN2B (97%) loss (9p21 co-deletion) were significantly associated with MTAP loss (p<.0001). Likely associated with the increased TNBC cases, BRCA1 mutation was also more frequent in MTAP loss MBC (10% v 4%; p<.0001). There was no clear pattern for predictive Immuno-Oncology (IO) drug biomarkers with higher TMB > 20 mut/Mb levels found in the MTAP intact MBC (p<.0001) and higher PD-L1 low expression (1-49%% TPS) in the MTAP loss MTAP (p=.002) CABC cases.Table: 1710PCases with MTAP intactCases with MTAP lossNumber7093208Mean age*57.854.5ER+/PR+ Status by IHC**70.0%/ 49.0%50.00%/29.90%HER2+ Amplification by CGP*7.80%1.92%TNBC Status*27.00%47.28%TP53*51.7061.30CDKN2A**3.10100.00CDKN2B**1.3096.70CDH1*14.300.90PTEN*13.1021.70PIK3CA**36.823.60BRCA1**3.709.90ERBB2 amplification*7.801.92ERBB2 sequence mutation*11.206.60EGFR *2.605.20MSI HighFrequency0.03%0.05%cases tested7077205TMB > 10%/>20%7.84%/7.40%5.32%/0.96%PD-L1 Positive IC expression (Dako 22C3)Low (1-49%)*11.45%42.90%High (> 50%)2.86%0.00%*Significant (P<0.05), **(P<0.0001). Open table in a new tab *Significant (P<0.05), **(P<0.0001). MTAP loss is associated with ER-, HER2- and TNBC status, features a distinctive GL with potential to impact both targeted and immunotherapies and enables emerging clinical trials testing MTA2 and PRMT5 inhibitors for patients with CABC.

The prevalence and predictors of adjuvant chemotherapy use among patients treated with neoadjuvant endocrine therapy.

Neoadjuvant endocrine therapy (NET) facilitates clinical response and breast conservation in hormone receptor-positive (HR-positive) breast cancer. Patient selection for adjuvant chemotherapy (CT) post-NET is unclear and potentially evolving with use of genomic assays. We evaluated post-NET CT use in a national dataset. Using the National Cancer DataBase, we identified patients with cT2-3N0-3M0 HR-positive/human epidermal growth factor receptor 2-negative breast cancer treated between 2010 and 2017 with 3-12months of NET prior to breast surgery. CT use was evaluated in the overall population, in patients with a pathologic complete response (pCR) and in patients with ypT1-2N0 disease (approximating PEPI 0). Exploratory analysis included patients > 50years with ypN0-1, and 21-gene recurrence score (RS) ≤ 25 (approximating TAILORx/RxPONDER populations not benefiting from CT). Multivariable logistic regression was used to identify factors associated with CT. Among 3624 eligible patients, 20.4% (740/3624) received CT. On multivariable analysis, age ≤ 50, lobular histology, grade 2, progesterone receptor negativity, ypT3, ypN + and RS ≥ 18 were associated with CT receipt. Co-morbidity, longer NET duration, ypT4, ypNx, and RS < 18 were associated with CT omission. CT was administered to 3.3% (1/30) of patients experiencing pCR and 5.5% (82/1483) with ypT1-2N0 disease. Among patients > 50years with ypT0-3N0-1 residual disease, 13.8% (355/2569) received CT; RS was available for 24.8% (88/355) and 60% (53/88) had a score 0-25. A minority of patients receive CT post-NET. This decision appears to be driven by younger age, RS and pathological nodal status. Increased consideration of these factors prior to neoadjuvant treatment choice may be warranted.

Prevalence of Pathologic N2/N3 Disease in Postmenopausal Women with Clinical N0 ER+/HER2- Breast Cancer.

The RxPONDER trial demonstrated that the 21-gene recurrence score can be used to guide adjuvant systemic therapy decisions in postmenopausal women with pN1 ER+/HER2- breast cancer. As such, a sentinel lymph node biopsy (SLNB) may not provide systemic treatment-altering information for many patients, and omission of SLNB in patients with low probability of pN2/N3 disease could be considered. Postmenopausal women (aged ≥ 50 years) diagnosed with cN0cM0, ER+/HER- breast cancer from 2013 to 2017 were identified in the National Cancer Database. The primary outcome was the prevalence of pN2/N3 disease. Of 325,692 postmenopausal women with cN0 ER+/HER2- breast cancer, 7106 (2.2%) were pN2/N3. In total, 81.7% had cT1 tumors, 16.8% T2, 1.3% T3, and 0.2% T4. In patients with T1 tumors, the prevalence of pN2/N3 disease was 1.2% compared with 17.2% in patients with T3/T4 tumors. In multivariable models, cT stage was the strongest predictor of pN2/N3 disease (adjusted odds ratio [aOR] 14.9 [12.1-18.4]). Lobular histology (aOR 2.4 [2.3-2.6]), higher grade (aOR 2.9 [2.6-3.1]), and young age (aOR 1.5 [1.3-1.7]) were also associated with increased prevalence of pN2/N3. We created a model using histology, grade, and T stage that stratifies patients with low prevalence of pN2/3 disease (< 1%) and those at high risk (> 20%). In postmenopausal women with cN0 ER+/HER2- breast cancer, the prevalence of pN2/N3 disease is low, indicating a potential opportunity to use the results of RxPONDER to extend criteria to omit SLNB. Prospective study is needed to determine safety, including risk of nodal recurrence, of omission of SLNB in carefully selected patients.

Breast Cancer with Low Recurrence Score on Oncotype DX©: Interplay Between Early Recurrence, Lobular Histology and BRCA Mutation.

The 21-gene recurrence score assay Oncotype DX© (ODX) has clear prognostic and predictive value regarding adjuvant chemotherapy. However, recent studies have shown the clinical distinctiveness of both BRCA1/2-driven early breast cancer (EBC) and invasive lobular (ILC) breast cancers. We evaluated the association between BRCA1/2-driven EBC/ILC and Oncotype DX failure despite a recurrence score ≤ 20. Here, we describe a small cohort of 16 patients from our center who, despite a low recurrence score (RS) ≤ 20, suffered from early disease recurrence. Clinical parameters of our cohort of patients were compared to a cohort from the general population of Clalit Health Service (CHS). Median age at diagnosis in our cohort was significantly younger. BRCA mutational status was available in 14 patients in our cohort. A high percentage of these patients had BRCA1/2 mutations (35.7%), either germline (in 3) or somatic (in 2). Half of our cohort was diagnosed with lobular carcinoma (ILC) relative to 10-15% in the general population of BC (p = 0.02). The median time to recurrence was 44months. BRCA1/2 mutation and ILC are highly represented in this cohort. Although our cohort is small, these data may suggest that a RS ≤ 20 in these subgroups may not reflect a low risk of recurrence.

Poziotinib Inhibits HER2-Mutant-Driven Therapeutic Resistance and Multiorgan Metastasis in Breast Cancer.

Evaluation of the functional impact of HER2 mutations on therapy-induced resistance and metastasis identifies robust antitumor activity of poziotinib and supports the clinical evaluation of poziotinib in ER+ HER2 mutant breast cancer.

Abstract 5793: Comprehensive characterization of FGF/FGFR alterations in invasive breast cancers

Abstract BACKGROUND FGFR signaling is central for cancer cell proliferation, migration, angiogenesis, and survival. The frequency and type of FGF/FGFR aberrations are not well-characterized across invasive breast cancer subtypes and metastatic sites of disease. In hormone receptor positive breast cancers, FGFR1 amplification correlates with early progression on endocrine therapy and promotes resistance to CDK4/6 inhibition. Our study evaluated the incidence and characterization of FGF alterations in invasive breast cancers and examined differences based on histologic subtype, molecular subtype and site. METHODS Breast cancer samples underwent molecular profiling by Caris Life Sciences. Analyses included NGS of DNA (592 Gene Panel, NextSeq, and WES, NovaSEQ), and IHC (Caris Life Sciences, Phoenix, AZ). Biomarker results were compiled from cases within the breast cohort including data from any sequencing panel, gene expression/RNA seq panel, and IHC. All results listed below were statistically significant (p &amp;lt; 0.05) as determined by chi-square test and Benjamini Hochberg correction. RESULTS 12058 breast cancer tumors were analyzed: 4189 from primary breast specimens (35%) and 7869 from metastatic sites (65%). 4305 (36%) were ductal and 671 (6%) were lobular histology with remaining other/unknown. 6413 (53%) were HR+HER2-, 3504 (29%) were triple negative, 403 (3%) were HR+HER2+ and 363 (3%) were HR-HER2+ with 1375 (13%) of unknown subtype. In the entire cohort, the most commonly amplified genes were FGF19 (11.49%), FGF3 (10.75%), FGF4 (9.98%), CCND1 (12.36%), and FGFR1 (9.08%). FGFR1-4 amplification was present in 11.01% of all cases. FGF19 amplification was more prevalent in lobular breast cancer compared to ductal (12.1% vs 9.1%). FGF19, FGF23, FGF3, FGF4, FGF6 amplification varied across molecular subtypes being most prevalent in HR+/HER2- (15.7%), HR+/HER2+ (12.1%), and least prevalent in HR-/HER+ tumors (3.4%). FGFR1 amplification was most common among FGFR1-4 amplifications and most prevalent in HR+HER2- (12%). Across metastatic sites, FGF ligands displayed different patterns of amplification with FGF19, FGF3 and FGF4 amplification most prevalent in liver and bone metastases. FGFR1 amplification was statistically different across metastatic sites and most prevalent in liver metastases (16%) followed by bone (10%). Patients receiving CDK4/6 inhibitors with FGFR1 amplification had shorter time on treatment than FGFR1 wild type (HR = 0.892, p = 0.03). CONCLUSION FGF alterations in invasive breast cancers vary by molecular subtype and site of disease. FGFR1, FGF19, FGF23, FGF3, FGF4, and FGF6 amplifications were statistically different across subtypes (most prevalent in HR+/HER2- and HR+/HER2+) and metastatic sites (most prevalent in liver and bone metastases). The prevalence in HR+ subtypes lend support to the role of FGF in endocrine resistance. Citation Format: Kush C. Gaur, Justin Tiu-Lim, Julie McGrath, Phil Walker, Michael Korn, Joanne Xiu, Arielle Heeke, Virginia Kaklamani, Antoinette Tan, Janice Lu, Darcy Spicer, Evanthia Roussos-Torres, Priya Jayachandran, Audrey Saghian, Amir Goldkorn, Irene Kang. Comprehensive characterization of FGF/FGFR alterations in invasive breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5793.

The effect of tumor size on nodal disease burden in clinically node negative breast cancer.

e12575 Background: Randomized trials have shown no difference in outcomes for cT1-2N0 breast cancer patients with 1-2+ sentinel lymph nodes (SLNs) undergoing sentinel lymph node biopsy (SLNB) alone compared to axillary dissection (ALND). No studies have yet evaluated whether these results can be applied to cT3N0 patients. Our objective was to evaluate nodal burden in cT3N0 compared to cT1-2N0 patients. Methods: Patients with cT1-3N0 breast cancer undergoing upfront surgery were identified from the National Cancer Database (NCDB) from 2012 through 2017. Analysis was limited to those with ≥ 3 lymph nodes (LNs) retrieved. Clinical and pathologic characteristics were examined using Wilcoxon Rank sum tests, Chi square, or Fisher’s exact tests. Univariate and multivariable logistic regression analyses were performed to examine characteristics associated with increased nodal burden (≥ 3 +LNs). Results: During the study period, we identified 198,137 cN0 patients with ≥ 3 LNs retrieved, of which 191,672 (97%) were cT1-2 and 6,465 (3%) were cT3. Most patients had ductal histology (83%) and ER+/HER2- subtype (83%). Of cT1-2 patients, 7% (13,902/191,672) had ≥ 3 +LNs compared to 28% (1,791/6,465) of cT3 patients. Among patients with ≥ 3 +LNs, the majority (91%) underwent ALND with a median of 14 (interquartile range [IQR] 9,19) LNs retrieved. Of these patients, cT3 disease was associated with an increased number of +LNs compared to cT1-2 disease (median [IQR], 6 [4,10] vs. 4 [3,7], p&lt;0.01). On multivariable analysis, invasive lobular carcinoma (ILC) (OR 2.11, 95% CI 1.34-3.30), lymphovascular invasion (LVI) (OR 5.22, 95% CI 4.43-6.16), and pathological tumor size &gt; 8 cm (OR 2.76, 95% CI 2.16-3.53) were independently associated with ≥ 3 +LNs in cT3 patients. Triple-negative breast cancer (TNBC) was associated with lower odds of ≥ 3 +LNs (OR 0.50, 95% CI 0.36-0.68). In those with tumors 5-8 cm in size, 364 (27%) of 1,363 patients with IDC had ≥ 3 +LNs, compared to 152 (48%) of 315 patients with ILC. Conclusions: cT3N0 patients have increased nodal burden compared to cT1-2N0 patients. Caution should be used in extrapolating guidelines for cT1-2N0 patients to high-risk cT3N0 patients with large tumors, LVI, and lobular histology.[Table: see text]

Utilizing Natural Language Processing (NLP) to identify breast cancer associated-lung metastases from pathology reports to delineate characteristics and challenges of this common site of breast cancer recurrence.

e13592 Background: NLP (artificial intelligence) can automate the identification of records in large datasets. The purpose of this study was to evaluate the feasibility of NLP to identify breast cancer-associated lung metastases to understand clinical characteristics and challenges posed by this common site of breast cancer recurrence. Methods: Patients with pathologically confirmed breast cancer associated-lung metastases seen at a large academic center between 3/2012-5/2019 were identified using NLP of institutional pathology reports, with an IRB approved protocol. Chart review was performed to confirm breast cancer associated-lung metastases and determine clinical and pathological features. Results: Using NLP, 32 patients with pathology reports denoting breast cancer associated-lung metastases were identified, with pathologic confirmation of lung biopsy tissue in the majority of cases (24), and pleural fluid specimens (8) on the remainder. Ten of 32 (31%) were HR+/HER2-, 3/32 (9.3%) HER2+, and 19/32 (59%) TNBC. The majority were invasive ductal carcinoma (21/26) with the remainder invasive lobular carcinoma (2/26) or mixed histology (3/26). Median age at lung metastasis diagnosis was 62 years (range 31-88). The median time to development of lung metastasis following primary breast cancer was 5.6 years (range 0-24.8 years). Fifty six percent of lung metastases were detected on imaging and 44% by symptoms including dyspnea, cough, or pain. Tumor tissue genotyping results on the lung metastases were available for 8 patients showing PI3KCA (5), TP53 (3), SMARCA4 (2), ERBB2 (1), FGFR3 (1), ATM (1), CDK4 (1), MYC (1), and ESR1 (1). Treatment after diagnosis of lung metastases included hormone therapy (61%), chemotherapy (84%), lung irradiation (26%), and surgical resection of lung metastases (6%). Lung metastases were associated with considerable morbidity including pleural effusion (15%), dyspnea (6%), pneumothorax (3%), hemothorax (3%), and atelectasis (3%). Patients diagnosed with lung metastases had brain (32%), bone (35%), renal (6%), skin (3%) and adrenal (3%) metastases during disease course. Conclusions: NLP can help identify organ specific metastases from pathology reports, such as breast cancer associated-lung metastases, which can then facilitate observational, translational, and clinical research to characterize and address challenges posed by this common site of breast cancer recurrence. This cohort of patients highlights the morbidity of breast cancer associated-lung metastases and potential role of NLP for disease characterization and clinical research. (Support from ASCO Medical Student Rotation for Underrepresented Populations Award.)

HER2 alterations and prognostic implications in all subtypes of breast cancer.

1041 Background: Amplification or overexpression of human epidermal growth factor receptor 2 (HER2) oncogene is present in about 15-20% of breast cancers &amp; is a prognostic &amp; predictive biomarker. Additional ERBB2/HER2 alterations have become apparent on tumor next generation sequencing (NGS), including activating kinase domain mutations &amp; fusions. Methods: DNA NGS (592 gene panel or whole exome) data from 12,153 breast samples retrospectively reviewed for ERBB2 alterations with RNA whole-transcriptome sequencing (WTS) data available for 7289 (60%) samples. Gene fusions detected using the ArcherDx fusion assay or WTS. Clinicopathologic features were described including breast cancer subtype, age, &amp; biopsy site. HER2 status determined according to 2018 ASCO-CAP guideline. Overall survival obtained from insurance claims &amp; Kaplan-Meier estimates were calculated for defined patient (pt) cohorts. Statistical significance was determined using Chi-square &amp; Wilcoxon rank sum tests. Results: ERBB2 mutations ( ERBB2mts) were identified in 3.2% (n = 388) of tumors overall &amp; most common in liver metastases (113/1972, 5.7%). ERBB2mts were found more in breast lobular tumors compared to ductal tumors (10 vs 2.1%, p &lt; 0.001). HER2+ tumors had higher frequency of ERBB2mts compared to HER2- (4.3 vs 3%, p = 0.028). Tumors with score of 0 by immunohistochemistry demonstrated lower rate of ERBB2mts (0+ 2.2%, 1+ 3.5%, 2+ 4.5%, 3+ 3.45%, p &lt; 0.05). Among HER2- tumors, ERBB2mts were present in 3.6% of hormone receptor (HR)+/HER2- &amp; 1.9% of TNBC. Metastatic tumors had a higher rate of ERBB2mts compared to locoregional breast tumors (3.8 vs 2%, p &lt; 0.001), with increased rates of activating mutations S310F (0.1 vs 0.0%, p &lt; 0.05) &amp; D769H (0.3 vs 0.1%, p &lt; 0.05), &amp; the resistance mutation L755S (1.2 vs 0.6%, p &lt; 0.01). Compared to ERBB2-WT, ERRB2mts were associated with decreased ERBB2 transcripts levels in HER2+ samples (222 vs 441 transcripts per million [TPM], p &lt; 0.001) &amp; increased levels in HER2- samples (73 vs 35 TPM, p &lt; 0.001). High tumor mutational burden (≥ 10 mut/Mb) &amp; ERBB3 mutations were more common in ERBB2mts compared to ERRB2-WT (16.7 vs 7.7%, p &lt; 0.001; 10.6 vs 0.8%, p &lt; 0.001). ERBB2 fusions were rare (0.49%) with 97% occurring in HER2+ tumors. Of 8358 pts with outcome data, prognosis (HR 1.2, P = 0.06) &amp; response to chemotherapy (HR 1.1, P = 0.42) was similar between pts with HER2- ERBB2mt &amp; ERBB2-WT. Conclusions: ERBB2mts &amp; fusions were observed in all breast cancer subtypes - more commonly in HER2+, metastatic, &amp; lobular histology tumors - &amp; did not influence prognosis. These alterations may reflect response to treatment pressures in HER2+ disease to reactivate HER2-mediated growth pathways following anti-HER2 therapy &amp; may represent a targetable upregulated oncogenic pathway in HER2- disease. Ongoing identification of ERBB2 alterations may augment treatment options for breast cancer pts &amp; clinical outcomes from this approach are under investigation.

National Cancer Database trends in surgical resection of the breast primary for stage IV breast cancer

BackgroundSurvival benefit after resection of the breast primary for women with metastatic breast cancer reported in retrospective studies has not been uniformly confirmed by randomized controlled trials. To assess the need for dissemination of trial results by the ACS Cancer Research Program Dissemination and Implementation (ACS CRP D&I) committee, we analyzed trends and predictors of surgery and other therapies for stage IV breast cancer. MethodsThe National Cancer Database (NCDB) was queried to identify women diagnosed with clinical stage IV breast cancer of ductal, lobular, or metaplastic histology between 2004 and 2017. Trends in utilization of breast surgery and other treatments and possible predictors of breast surgery were examined in univariable and multivariable analyses. ResultsWe identified 87,331 cases meeting inclusion criteria. Rates of surgical resection rose until 2009, peaking at 37%, then declined to a rate of 18% in 2017. The largest decline was seen in the hormone receptor positive (HR+), HER2 negative (HER2-) subgroup with up to 70% of patients undergoing surgery in 2007, down to 15% in 2017. In 2004, the rate of systemic therapy alone was slightly more common than locoregional therapy (surgery and/or radiation) with or without systemic therapy (48% vs 37%). However, by 2017, systemic therapy alone was by far more common (69% vs 20%). ConclusionRates of surgical resection of the breast primary for stage IV breast cancer have been on the decline in recent years, suggesting that providers at Commission on Cancer accredited hospitals are becoming more selective about who will be offered surgical resection.

Abstract PD6-04: Mutational landscape and immune infiltration of breast cancer metastases to gynecologic and other organs

Abstract Introduction: Breast cancer metastases (BCM), which cause most breast cancer (BC)-associated mortality, have increased genetic complexity compared to early-stage disease. However, the contribution of genetic alterations to site of BCM is not well-understood. Different breast cancer subtypes have varying patterns of BCM, e.g., lobular carcinoma more frequently spreads to gynecologic (Gyn) organs and the GI tract, perhaps hinting at selection pressures wherein some organs are hospitable to tumors with certain genetic alterations. Methods: Relationships between BCM site and mutations detected by DNA next-generation sequencing (NGS; NextSeq 592 gene panels or NovaSeq whole exome sequencing) were investigated using 12,464 BC samples sequenced at Caris Life Sciences (sample sizes, Table 1). PD-L1 expression was tested through IHC (Clone SP-142 (cut-off ≥1, 1%)). Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (high ≥ 10 mutations per MB). Immune cell fractions were calculated by deconvolution of whole-transcriptome data (NovaSeq) using Quantiseq (reference). Statistical significance was determined using chi-square and Wilcoxon rank sum tests adjusted for multiple comparisons. Results: Compared to primary breast tumors, BCM had increased frequency of TMB-H (10.08% vs. 4.94%), decreased PD-L1 positivity (21.09% vs. 35.82%), and were enriched for PIK3CA (34.62% vs 30.53%) and ESR1 mutations (13.34% vs 2.17%) (all P&amp;lt;0.001). PD-L1 positivity was highest in BCM to lymph nodes (43.06%) and axilla (39.77%). BCM to Gyn organs had more lobular histology, the highest rate of hormone receptor (HR)+ tumors (77.17%), and rarely had high TMB (6.73%) or were PD-L1 positive (11.39%). Double dendrogram hierarchical clustering of BCM site by mutation frequency and pathway alterations revealed BCM to Gyn organs as a simplicifolious clade with a unique mutational pattern. Compared to BC in breast, BCM to Gyn organs had higher rates of mutations of PIK3CA, AKT1, and BRAF; more mutations in DNA repair (0.79% vs 0.06%), transcription factor (4.72% vs 0.93%), and Wnt signaling pathways (2.36% vs 1.47%); but no increase in BRCA mutations. BCM to brain had the most p53 pathway and homologous recombination (HR) pathway mutations (64.71% and 14.01%), while Gyn had the least (19.69% and 7.09%). Quantiseq RNA deconvolution revealed differences in tumor immune cell infiltrate by BCM site. Gyn metastases vs breast tumors had increased B cells (6.20% vs 5.40%), M2 macrophages (5.71% vs 4.07%), and NK cells (3.82% vs 3.18%) (all P&amp;lt;0.01) and a M2/M1 macrophage ratio of 22.8:1 vs 1.3:1. Conclusions: BCM to Gyn organs have a unique mutational and immune suppression profile. Integrating the profiling with clinical outcomes may extend this prognostic signature and set the stage for improved treatment strategies for these patients. Confirmation from matched or sequential specimens could clarify tumor evolution. Our data support repeat biopsy of Gyn site metastases since more targetable mutations might be revealed. Targeting mechanisms of immunosuppression in Gyn BCM could expand therapeutic options. Table 1.Breast Cancer TumorsTumor SiteTotalPredominant Breast Cancer SubtypeAll12464HR+/HER2- (51.6%)Breast5014HR+/HER2- (46.5%)Liver2003HR+/HER2- (63.3%)Bone1132HR+/HER2- (69.4%)Axilla1051HR+/HER2- (47.7%)Lung823HR+/HER2- (46.1%)Lymph Node647HR+/HER2- (43.4%)Chest/Chest Wall375HR+/HER2- (44.8%)Brain359TNBC (38.2%)Other315HR+/HER2- (57.1%)Skin282HR+/HER2- (50.7%)Connective Tissue193HR+/HER2- (51.8%)GI Organs143HR+/HER2- (69.9%)Gynecologic Organs127HR+/HER2- (76.4%) Citation Format: Anna D Louie, Rani Chudasama, Sharon Wu, Marzia Capelletti, Daniel Magee, W. Michael Korn, Virginia Kaklamani, Antoinette R Tan, Pavani Chalasani, Wafik S El-Deiry, Don Dizon, Stephanie L. Graff. Mutational landscape and immune infiltration of breast cancer metastases to gynecologic and other organs [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 PD6-04.

Abstract PD14-06: Does chemotherapy benefit patients with HR+/HER2- invasive lobular breast cancer?

Abstract Introduction Invasive lobular breast cancer (ILBC) is the second most common subtype of breast cancer. More evidence is emerging on the unique clinical features of ILBC. However, most systemic therapy guidelines for ILBC are derived from clinical trials with no specific focus on ILBC. Also, the benefit of chemotherapy for the treatment ILBC has been questioned. Using a large national registry, we aimed at comparing outcomes of various systemic therapy regimens in hormone receptor-positive (HR+) and HER2- ILBC. Methods We performed a year-stratified simple random sampling method to select 10% of ER+ or PR+ (HR+) and HER2- female patients with ILBC with AJCC stages I-III who underwent surgery from the National Cancer Database (NCDB) (2010-2017). Patients were grouped into four treatment cohorts: surgery only (S), chemotherapy alone (CT), endocrine therapy alone (ET), combined chemotherapy followed by endocrine therapy (CET). Overall survival (OS) among groups was first examined using the Kaplan-Meier method and Cox proportional hazard modeling. Focusing on ET and CET, propensity score (PS) match in logistic regression was performed to reduce selection biases due to demographical and clinical characteristics. OS between PS matched ET and CET pairs were evaluated again using the same methods. OS differences between ET and CET by lobular histology group and by disease stage were also examined. Results Approximately 90% of ILBC were HR+ and HER2+. N=17,789 patients were included in this analysis: 59.7% received ET, 26.2% CET, 2.3% CT and 11.9% S. 5-years OS was significantly better for patients who received ET (90.7%) or CET (90.4%) as compared to CT (79.4%) or S only (79.7%) (p&amp;lt;.001). Of interest, after adjusting for other demographic and clinical characteristics, 5-years OS was similar for both ET and CET (p=.064). Increased ET administration (52.6% to 67.4%, p for trend &amp;lt;.001) and decreased CET (30.4% to 20.2%, p for trend &amp;lt;0.001) were observed from 2010 to 2017. Among n=15,273 patients who underwent ET (n=10,616; 69.5%) or CET (n=4,657; 30.5%), both groups had similar histology findings (45.5% vs 47.7% lobular histology mixed with other features). However, significant demographic and clinical characteristics differences were identified between both cohorts. Patients in the CET group were younger (mean age 56.9±10.5 vs. 65.5±11.6) (p&amp;lt;.001), had a higher stage at diagnosis (34.8% stage III vs. 4.2%), more positive regional LN (67.5% vs. 13.7%), and received more radiation therapy (74.1% vs. 58.5%) as compared to those in the ET group. 5-years OS remained similar between ET and CET when adjusting for age, stage, LN involvement, histology, and radiation therapy (adjusted HR, 95% CI: 1.04, 0.89-1.20). Importantly, OS was similar between ET and ECT among patients with OncotypeDX (ODX) score &amp;lt; 26 (96.4% vs 97.5%) and ODX score ≥ 26 (5-year OS: 92.2% vs 91.4%). PS match yielded 3,002 pairs; 5-years OS remained similar between ET (92.6%) and CET (91.6%) (p=0.94). In addition, no significant difference was detected when stratifying by disease stage and histology. Conclusion In this large analysis , chemotherapy did not improve survival in patients with HR+ and HER2- lobular cancer treated with ET, regardless of stage or lymph node involvement, or ODX score. The majority of patients with early stage HR+/HER2- with ILBC in the US receive ET, and one-fourth receive CET. Research investigating de-escalated chemotherapy-free regimens for ILBC are warranted. Exploring biomarkers-based approach to identify subgroups who would benefit from chemotherapy would better define systemic treatment options for ILBC. Citation Format: Marita Yaghi, Iktej Jabbal, Nadeem Bilani, Maroun Bou Zerdan, Leah Elson, Hong Li, Diana Saravia, Elizabeth Stone, Zeina Nahleh. Does chemotherapy benefit patients with HR+/HER2- invasive lobular breast cancer? [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 PD14-06.

Abstract PD7-06: Trends in surgical resection for stage IV breast cancer: Less surgery more systemic treatment

Abstract Background: There is debate regarding the benefit of breast surgery in women with stage IV breast cancer, especially among those with oligometastatic disease and good response to systemic therapy. Although some retrospective studies have suggested that locoregional therapy may improve survival, this finding has not been universally replicated in randomized controlled trials (RCT) in India, Turkey, and recently the US. To assess need for dissemination of trial results by members of the Alliance/American College of Surgeons Clinical Research Program Dissemination and Implementation (ACS CRP D&amp;I) committee, we sought to determine trends in surgical resection and other therapies for stage IV breast cancer in response to these findings. Methods: The National Cancer Database (NCDB) was queried to identify women diagnosed with clinical stage IV breast cancer of ductal, lobular, or metaplastic histology between 2004-2017. Trends in the rate of women who underwent surgery with breast-conserving surgery (BCS) or mastectomy, radiation, and/or systemic treatments were compared. Possible predictors of breast surgery were examined in univariable and multivariable analysis. Results: We identified 87,331 cases meeting inclusion criteria and assessed demographics for surgery versus no surgery. Of the 87,331 cases, 7,718 (9%) underwent BCS and 17,625 (20%) underwent mastectomy. Rates of breast surgical resection for women with clinically diagnosed stage IV breast cancer rose until 2009, reaching a peak at 37%, followed by a decline to a rate of 18% in 2017 (Table). The largest decline was seen in the hormone receptor positive (HR+) and HER2- subgroup with 71% of patients undergoing surgery in 2007 down to 15% in 2017. Concurrently, the mean number of days between chemotherapy initiation and definitive surgery has been on the rise, ranging from 52 days in 2004 up to 94 days in 2017. In 2004, the rate of systemic therapy alone was slightly more common than locoregional therapy (surgery and/or radiation) with or without systemic therapy (48% vs 37%). By 2017, systemic therapy alone was by far more frequently utilized (69% vs 20%, p&amp;lt;0.001). On multivariable analysis, factors associated with reduced odds of receiving surgery were older age, black race, higher comorbidity index, being uninsured, smaller tumors, lower histologic grade, multiple sites of metastasis, and treatment with chemo-endocrine therapy (all group p values ≤0.001). Factors associated with increased odds of receiving surgery were metaplastic histology, TN subtype, and radiation therapy (all group p values ≤0.001). Conclusions: Rates of surgical resection of the breast primary for stage IV breast cancer have been on the decline in recent years, especially for HR+/HER2- disease, suggesting that providers are responding to the lack of benefit demonstrated in RCTs. Higher rates of surgery in patients with HR-/HER2+ disease and the concurrent rise in the time interval between initiation of systemic therapy and definitive surgical intervention suggest that providers may still be selecting surgery for patients with certain subtypes or those with a durable response to systemic therapy. These areas of continued clinical equipoise could be a target for future studies or de-implementation strategies. OverallHR+/HER2-HER2+TNUnknownSurgery/Total%Surgery/Total%Surgery/Total%Surgery/Total%Surgery/Total%20041189/351334-55-30-50-3420051202/353834-65-35-23-3420061268/375834-54-36-31-3420071571/433636-71-41-32-3620081992/54203754/925926/544820/41491892/52333620092194/592437172/3604883/1525556/106531883/53063520102318/6419361162/331835554/134841352/80144250/9522620112322/6921341220/378932532/144137384/91542186/7762420122238/7110311177/393830587/163536339/85340135/6842020132147/7579281173/423128534/172831334/92536106/6951520142013/8033251086/442825496/185227306/99831125/7551720151805/794323914/434321517/198126288/9962986/6231420161609/819420829/464018459/196823247/10122474/5741320171477/813618722/467815421/190522256/10372578/51615Percent of women with stage IV breast cancer undergoing surgery by year and receptor subtype. Rows containing any number &amp;lt;10 are not reported by subtype to maintain confidentiality, per NCDB guidelines. Citation Format: Sasha R Douglas, Ingrid Lizarraga, Judy C Boughey, Anna Weiss, Kelly Hunt, Diana Dickson-Witmer, Preeti D Subhedar, Ko Un Park, Beiqun Zhao, Sarah Blair. Trends in surgical resection for stage IV breast cancer: Less surgery more systemic treatment [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 PD7-06.

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% &amp;gt;12m, 9% &amp;lt;=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.