Citations

Abstract Background Molecular breast imaging (MBI) has shown utility as a supplement to mammography in women with dense breasts. Background parenchymal uptake (BPU), which describes the level of Tc-99m sestamibi in fibroglandular tissue on MBI, varies among women with similar density. Higher BPU is associated with greater breast cancer risk. The goal of this work is to investigate the histological correlations of BPU that may explain this association with risk. Methods We compared histologic features of prospectively collected benign breast tissue biopsies from healthy women who had a region of dense tissue on mammography exhibiting one of the extreme categories of BPU on MBI: either photopenic or marked. Tissue composition of specimens was assessed by measuring area of epithelium, stroma, and fat and counting lobules. Lobular involution status was assessed by an expert pathologist as either none, partial, or complete. Ki-67 index and estrogen receptor-alpha expression were also assessed. Results Biopsies were performed in 48 women (mean age 54.9 years [SD 11.1 years]), including 20 with marked BPU and 28 with photopenic BPU. Women with marked BPU were younger (mean age 49.9 vs. 58.4 years, p = 0.004), had higher body mass index ( p = 0.01), and were more likely premenopausal ( p = 0.005). Marked BPU specimens had a higher proportion of epithelium (14.5% vs. 2.2%, p < 0.001), lower stromal content (44.8% vs. 84.2%, p = 0.005), similar fat (18.9% vs. 12.9%, p = 0.41), and greater lobule counts (15.5 vs. 6.3, p < 0.001) compared to photopenic specimens. Complete lobular involution was less frequent in marked tissue than in photopenic tissue (10.5% vs. 76%, p < 0.001). Ki-67 index was higher in marked BPU tissues (5.4% vs. 1.6%, p = 0.006), though the difference was attenuated after adjustment for epithelial area (p = 0.26). Estrogen receptor-alpha expression did not differ between marked and photopenic groups (25.6% vs. 28.4%, p = 0.12). Conclusions Marked BPU on MBI is associated with greater epithelial content, less lobular involution, and higher proliferative activity—features characteristic of tissue at elevated risk for malignant transformation. These findings suggest that BPU provides functional information beyond mammographic density, supporting its role as an imaging biomarker for breast cancer risk in women with dense breasts. Trial Registration: NCT01240278 and NCT01588834

AbstractObjectiveTo compare perioperative costs and morbidity between open and robotic sacrocolpopexy after implementation of enhanced recovery after surgery (ERAS) pathway.MethodsThe present retrospective cohort study of patients undergoing open or robotic sacrocolpopexy (January 1, 2014, through November 30, 2017) used an ERAS protocol with liposomal bupivacaine infiltration of laparotomy incisions. Primary outcomes were costs associated with index surgery and hospitalization, determined with Medicare cost‐to‐charge ratios and reimbursement rates and adjusted for variables expected to impact costs. Secondary outcomes included narcotic use, length of stay (LOS), and complications from index hospitalization to postoperative day 30.ResultsFor the total of 231 patients (open cohort, 90; robotic cohort, 141), the adjusted mean cost of robotic surgery was $3239 higher compared with open sacrocolpopexy (95% confidence interval [CI] $1331–$5147; P < 0.001). Rates were not significantly different for intraoperative complications (robotic, 4.3% [6/141]; open, 5.6% [5/90]; P = 0.754), 30‐day postoperative complications (robotic, 11.4% [16/141]; open, 16.7% [15/90]; P = 0.322), or readmissions (robotic, 5.7% [8/141]; open, 3.3% [3/90]; P = 0.535). The percentage of patients dismissed on postoperative day 1 was greater in the robotic group (89.4% [126/141] vs. 48.9% [44/90], P < 0.001).ConclusionsDecreased LOS associated with ERAS provided significant cost savings with open sacrocolpopexy versus robotic sacrocolpopexy without adverse impacts on perioperative complications or readmissions.

Abstract Purpose Breast cancer risk is elevated in pathogenic germline BRCA 1/2 mutation carriers due to compromised DNA quality control and elevated mutagenic load. We hypothesized that if immunosurveillance promotes tumor suppression, then normal breast lobules from BRCA carriers may demonstrate higher immune cell densities. Methods We assessed immune cell composition in normal breast lobules from age-matched women with progressively increased breast cancer risk, including 1) 19 women who donated normal breast tissue to the Komen Tissue Bank (KTB) at Indiana University Simon Cancer Center, 2) 15 women with biopsy-identified benign breast disease (BBD), and 3) 19 prophylactic mastectomies from women with germline mutations in BRCA1/2 genes. We performed immunohistochemical stains and analysis to quantitate immune cell densities from digital images in up to 10 representative lobules per sample. Median cell counts per mm2 were compared between groups using Wilcoxon rank-sum tests. Results Compared to BBD tissues, normal breast lobules from BRCA carriers had significantly higher densities of CD8 + cells (median 354.4 vs 200.0 cells/mm2, p = 0.01). Compared to KTB normal donor breast tissues, normal breast lobules from BRCA carriers also had significantly higher densities of CD4+ (median 116.3 vs 17.7 cells/mm2), CD8+ (354.4 vs 150.9 cells/mm2), CD11c+ (3.5% vs 0.4% pixels positive), and CD68+ (237.5 vs 57.8 cells/mm2) immune cells (each p < 0.001). Conclusions These preliminary analyses show that normal/benign breast lobules of BRCA mutation carriers contain increased immune cells compared with BBD and normal donated tissues. Future studies will be helpful to define relationships of mutations and immune responses.

Abstract Introduction: The immune microenvironment of the breast is critical in the development and progression of breast cancer. By analyzing the immune components of breast tissues from patients at varying degrees of breast cancer risk, we may gain enhanced understanding of breast cancer risk and mechanisms of carcinogenesis. Methods: We compared the immune cell composition in breast lobules of age-matched patients with normal and benign breast disease (BBD) at progressively lower breast cancer risk: 1) 18 women with germline mutations in (BRCA1/2); 2) women at intermediate risk (BBD), and 3) women at normal risk (Komen Tissue Bank- (KTB)). We performed immunohistochemical stains for T lymphocytes (CD4, CD8); dendritic cells (CD11c); B lymphocytes (CD20) and macrophages (CD68) and quantitated immune cell densities in up to 10 representative lobules per sample. Results: The median age of all groups was 43.8 years (range: 34-67). BRCA carriers and BBD patients had a higher percentage of fibrocystic lobules (50% fibrocystic) compared to KTB samples (15% fibrocystic), p&lt;0.001. BRCA carriers had significantly higher densities of CD4, CD8, CD11c, and CD68 positive immune cells compared to KTB donor breast tissues, see Table. Compared with BBD patients, mutation carriers had higher densities of CD8+ cells and suggestively higher CD4+ cells, with similar results for other markers assessed. Conclusions: Preliminarily, these data showed that benign prophylactic breast tissues from BRCA mutation carriers contain increased numbers of several immune cell types versus tissues from patients at lower breast cancer risk, including BBD patients and research tissue donors. Further investigation is needed to confirm and expand these findings in relation to breast cancer risk. Table: Pairwise Wilcoxon rank-sum p-values comparing immune cell densities in breast lobules from women with BRCA germline mutations, vs BBD and KTB groups. All Lobules BRCA BBD KTB BRCA vs BBD BRCA vs KTB Median Median Median p-value p-value (IQR) (IQR) (IQR) CD4+, cells/mm2 116.3 63.8 17.7 0.08 &lt;0.001 (46.4-183.6) (25.0-121.1) (13.3-40.6) CD8+, cells/mm2 354.4 200 150.9 0.01 &lt;0.001 (285.5-473.2) (118.9-385) (110.1-225.0) CD11c+, % pp 3.5 3.4 0.4 0.66 &lt;0.001 (1.9-6.8) (1.6-4.7) (0-0.6) CD20+, cells/mm2 6.2 16.7 0 0.16 0.65 (0-25.4) (0-58.3) (0-20.8) CD68, cells/mm2 237.5 219 57.8 0.99 &lt;0.001 (122.9-281.8) (75.0-459.4) (29.2-100.0) IQR - Interquartile Range pp - pixel positive Citation Format: Joshua W. Ogony, Tanya L. Hoskin, Melody L. Stallings Mann, Stacey J. Winham, Rushin Brahmbhatt, Muhammad Asad Arshad, Alvaro Pena Jimenez, Teresa M. Allers, Mark E. Sherrman, Daniel W. Visscher, Derek C. Radisky, Amy C. Degnim. Immune biomarkers in breast tissues of patients with BRCA1/2 mutations, benign breast disease, and normal tissue donors [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 5947.

AbstractObjectiveTo assess the effect of Enhanced Recovery After Surgery (ERAS) with and without liposomal bupivacaine (LB) on opioid use, hospital length of stay (LOS), costs, and morbidity of women undergoing sacrocolpopexy.MethodsRetrospective cohort of women who underwent abdominal sacrocolpopexy between April 1, 2009 and November 30, 2017. Costs for relevant healthcare services were determined by assigning 2017 charges multiplied by 2017 Medicare Cost Report's cost to charge ratios. Outcomes were compared among periods with multivariable regression models adjusted for age, American Society of Anesthesiologists score, and concurrent hysterectomy and posterior repair.ResultsPatients were subdivided into pre‐ERAS (G1, n = 128), post‐ERAS (G2, n = 83), and post‐ERAS plus LB (G3, n = 91). The proportion of patients needing opioids during postoperative days 0–2 was significantly less for G3 (75.8%) compared with G1 (97.7%) and G2 (92.8%); P < 0.001). The median morphine equivalent units (MEU) with interquartile ranges, mean LOS, and adjusted mean standardized costs were significantly lower in G3 compared with the other two groups (35 [20–75] vs. 67 [31–109], and 60 [30–122] MEUs; 1.8 vs. 2.3 vs. 2.9 days; and $2391, $2975, and $3844, for G3, G2, and G1, respectively; P < 0.001).ConclusionImplementation of an ERAS pathway led to significant decreases in opioid use, LOS, and costs. Supplementation with LB further improved these measures.

Abstract Background: Partial breast irradiation (PBI) is an established option for selected patients with early stage breast cancer. The optimal technique, target volume and dose/fractionation for PBI has yet to be defined. The most studied regimen in North America (38.5 Gy in 10 fractions twice daily) has been associated with cosmetic deterioration. We hypothesized that condensing treatment and reducing the total administered dose could improve the therapeutic ratio in luminal breast cancer and DCIS based on emerging evidence that breast cancer is more sensitive than surrounding normal tissues to high dose fractions. Herein, we report cosmetic, tolerability, disease control, and patient reported outcomes of a novel ultra-accelerated PBI regimen. Methods: We conducted a single arm, three cohort trial of photon, proton, and brachytherapy PBI. Technique was selected at physician and patient discretion. Eligible women were age ≥ 50 years with estrogen receptor positive (ER+), sentinel lymph node negative invasive or in-situ breast cancer measuring ≤ 2.5 cm. The regimen was designed to have comparable biologically equivalent effect as 40 Gy in 15 fractions, assuming an α/β ratio of 3.5. Intracavitary brachytherapy target volume was lumpectomy cavity plus 1 cm and prescribed 21 Gy in 3 fractions. Photon and proton target volumes were post-operative tumor bed plus 1 cm and a 3 mm setup uncertainty margin, prescribed 21.9 Gy (RBE) in 3 fractions, and delivered with image guidance. The primary outcome was the percentage difference in patients with adverse cosmesis (defined as fair or poor cosmesis) at 3 years compared to baseline pre-PBI, as assessed by trained nurses using the 4-point Harvard breast cosmesis scale. Patients also completed quality of life surveys and self-reported cosmesis using the 4-point scale. Locoregional and distant recurrence-free survival was determined using the Kaplan-Meier method. Adverse events were assessed using CTCAE, v 4.0. Results: Between 2015 and 2017, 163 patients were treated: photons in 58, protons in 48, and brachytherapy in 57. Median patient age was 66 years. 129 (79%) patients had invasive breast cancer (all ER+) and 34 (21%) had DCIS (83% ER+). Median tumor size was 1.1 cm. Grade was 2-3 in 102 (63%). The median mean heart/ipsilateral lung doses were photons 0.1/1.6 Gy, protons &lt;0.001/0.1 Gy, and brachytherapy 0.5/0.9 Gy. Median follow-up was 4.1 years (IQR 3.9-5.0). The proportion of patients with adverse cosmesis (by RN assessment) was 14.3% at baseline and 3.8% at 3 years, with four patients (1 photon, 1 proton, 2 brachytherapy) experiencing cosmetic deterioration at 3 years from baseline. The proportion with adverse cosmesis by self-report at 3 years was 2.4%, with three patients (1 photon, 1 proton, 1 brachytherapy) reporting cosmetic deterioration. Four patients developed locoregional recurrence (1 photons, 2 protons, 1 brachytherapy); three were local only and one was local and distant. 4-year locoregional recurrence and distant metastasis-free survival were 97.9% and 97.4%, respectively. There were 2 treatment related ≥ grade 2 late events (grade 2 fibrosis and grade 2 seroma, both brachytherapy associated), and no evidence of deterioration in patient-reported pain, fatigue, breast related or overall quality of life, as assessed by the patient reported outcomes version of the CTCAE, 10-point linear analog scales, and the breast cancer treatment outcomes scale. Conclusions: Ultra-accelerated 3-fraction PBI exquisitely spared normal tissues and was associated with favorable cosmetic outcomes, disease control, and excellent long-term tolerability. This ‘precision-radiotherapy’ approach may optimize the therapeutic ratio over more aggressive radiotherapy options as well as radiotherapy omission, particularly in patients with long life expectancies. Citation Format: Robert Mutter, Tina Hieken, Todd DeWees, Arslan Afzal, Stephanie Kenison, Laura Vallow, Christopher Deufel, Nicholas Remmes, Kathryn Ruddy, Judy Boughey, Keith Furutani, Amy Degnim, James Jakub, Tamara Vern-Gross, Dean Shumway, William Wong, Samir Patel, Lisa McGee, Minetta Liu, Carlos Vargas, Daniel Visscher, Bradley Stish, Deanna Pafundi, Mark Waddle, Michael Golafshar, Michele Halyard, Kimberly Corbin, Sean Park. Ultra-accelerated photon, proton, and brachytherapy partial breast irradiation: Primary results of the Mayo 3-fraction trial [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 PD7-03.

The poly(ADP-ribose) binding protein CHFR regulates cellular responses to mitotic stress. The deubiquitinase UBC13, which regulates CHFR levels, has been associated with better overall survival in paclitaxel-treated ovarian cancer. Despite the extensive use of taxanes in the treatment of ovarian cancer, little is known about expression of CHFR itself in this disease. In the present study, tissue microarrays containing ovarian carcinoma samples from 417 women who underwent initial surgical debulking were stained with anti-CHFR antibody and scored in a blinded fashion. CHFR levels, expressed as a modified H-score, were examined for association with histology, grade, time to progression (TTP) and overall survival (OS). In addition, patient-derived xenografts from 69 ovarian carcinoma patients were examined for CHFR expression and sensitivity to paclitaxel monotherapy. In clinical ovarian cancer specimens, CHFR expression was positively associated with serous histology (p = 0.0048), higher grade (p = 0.000014) and higher stage (p = 0.016). After correction for stage and debulking, there was no significant association between CHFR staining and overall survival (p = 0.62) or time to progression (p = 0.91) in patients with high grade serous cancers treated with platinum/taxane chemotherapy (N = 249). Likewise, no association between CHFR expression and paclitaxel sensitivity was observed in ovarian cancer PDXs treated with paclitaxel monotherapy. Accordingly, differences in CHFR expression are unlikely to play a major role in paclitaxel sensitivity of high grade serous ovarian cancer.

548 Background: sTILs are a well-established prognostic and predictive biomarker in patients with operable TNBC receiving pre or postoperative systemic therapy. We1 and others2,3 have also shown that sTILs are prognostic in patients who did not receive adjuvant chemotherapy. Here, we detail the outcomes of systemically untreated patients with N0 TNBC according to sTIL score. We focused on the N0 subset as a group of patients who may be candidates for future prospective therapy de-escalation trials. Methods: From a clinically annotated cohort of 605 patients with centrally confirmed TNBC (ER/PR < 1% and HER2 negative) with long-term outcomes data, we identified 182 patients treated with locoregional therapy only (breast surgery +/- radiation therapy and no chemotherapy). The clinicopathological characteristics of this cohort have previously been published1. In this analysis, we report the 5- and 10-year invasive disease-free survival (iDFS) and overall survival (OS) rates of patients with N0 TNBC according to sTIL levels. IDFS and OS were defined as per the STEEP classification and estimated using the Kaplan–Meier method. Comparisons of the survival distributions between groups were assessed by the log-rank test. sTILs were assessed as a continuous parameter according to the International TIL Working Group guidelines. For comparisons of outcomes between groups, tumors were classified as lymphocyte-predominant TNBC (defined as containing ≥50% sTILs) vs non-lymphocyte-predominant ( < 50% sTILs). Results: Of 182 systemically untreated patients, 149 (82%) were N0 and most (78%) were post-menopausal. T stage distribution was T1: 68%, T2: 28%, T3/4: 4%. Among N0 patients, 31 (21%) had lymphocyte-predominant TNBC, and in this group the 5-year iDFS and OS were 89% (95% CI 76-100) and 96% (95% CI 89-100), while the 10-year iDFS and OS were 89% (95% CI 76-100) and 87% (95% CI 73-100), respectively. In contrast, outcomes for patients with non-lymphocyte predominant TNBC were significantly worse. For this group, 5-year iDFS and OS were 62% (95% CI 53-73) and 78% (95% CI 71-86) while the 10-year iDFS and OS were 45% (95% CI 36-58) and 66% (95% CI 68-76), respectively ( log-rank p = 0.02 for iDFS and log-rank p = 0.03 for OS). Conclusions: sTIL quantification identifies a subset of patients with early-stage N0 TNBC with an exceedingly good prognosis, even in the absence of adjuvant chemotherapy. These data provide support for the evaluation of sTILs as part of prospective investigation of systemic therapy de-escalation strategies in N0 TNBC. References:1Leon-Ferre et al, Breast Cancer Res Treat (2018) 167:89-99 2Park et al, Ann Oncol (2019) 12:1941-1949 3De Jong et al, ESMO 2020

Abstract Background: Women with benign breast disease (BBD) are at increased risk of breast cancer (BC). Classic studies based on film-based mammographic screening and pathology diagnosis of surgical biopsies conducted in the 1980s established a hierarchy of increasing BC risk: non-proliferative (NP) BBD, proliferative BBD without atypia (PDWA) and atypical hyperplasia (AH). Given changes in epidemiological BC risk factors and introduction of percutaneous core needle biopsy (CNB) in mid-1990s, and later, digital mammography, we hypothesized that the patient characteristics and relative frequency of BBD diagnoses have changed over time. Accordingly, we performed a longitudinal analysis of the frequency of patient characteristics and BBD diagnoses in the Mayo BBD cohort. Methods: Utilizing the Mayo Clinic Surgical and Pathology Indices, women ages 18 to 85 who had a BBD biopsy between 1/1/67 and 12/31/13 were identified. Breast pathologists reviewed biopsies masked to diagnoses of incident BC diagnosed in follow-up. Demographic characteristics and BC events were obtained by query of institutional data sources and participant surveys. Trends were evaluated for the following eras: 1: pre-mammogram (1967-1981), 2: pre-CNB (1982-1992), 3: CNB Transition (1993-2001), and 4: CNB (2002-2013). Demographics were formally compared across eras using chi-square tests for categorical variables and analyses of variance (ANOVAs) for continuous variables. Results: From 1967-2013, the cohort includes 19,582 unique women with BBD. The frequency of CNB increased from eras 1-4: 0.04%, 0.6%, 51.3 %, and 88.9%, respectively. Mean age at BBD diagnosis was younger in era 1 (48.0 years) vs eras 2-4 (53.2, 52.0, and 51.8, respectively, p&lt;0.001). The percentage of biopsies diagnosed as PDWA increased from era 1-4 (25.7%, 34.3%, 35.2%, 46.2%, p&lt;0.001), as did the percentage with AH (2.4%, 5.1%, 8.6%, 12.3%, p&lt;0.001). Over eras 1-4, the percentages of women with a strong family history of BC increased (9.9%, 12.7%, 17.1%, and 29.0%, p&lt;0.001) as did mean BMI (24.8, 26.4, 27.4, and 28.6, p&lt;0.001). With a median follow-up of 10.9 years, 1,719 breast cancers have developed, with increasing proportion of noninvasive (DCIS-only) disease across eras 1-4: 15.0%, 21.1%, 21.2%, and 33.2%, p&lt; 0.001. Conclusions: Analysis of this large, single institution BBD cohort for the 46 year period 1967-2013 demonstrates that BC risk factors among BBD patients has changed over time, with subjects demonstrating increasing age, BMI, and family history, and that the percentages of BBD classified as PDWA and AH have increased. Impact on BC risk will be further investigated. Citation Format: Amy Degnim, Karthik Ghosh, Jodi M Carter, Robert A Vierkant, Matthew R Jensen, Stacey J Winham, Tanya L Hoskin, Marlene Frost, Teresa M Allers, Denise L Gehling, Mindy J Kern, Laura M Pacheco-Spann, Celine M Vachon, Derek C Radisky, Daniel W Visscher, Mark E Sherman. Benign breast disease: Temporal trends from 1967 to 2013 [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 PS7-11.

Background: Periprosthetic joint infections (PJIs) following total hip arthroplasty (THA) and total knee arthroplasty (TKA) are associated with substantial morbidity. A better understanding of the costs of PJI treatment can inform prevention, treatment, and reimbursement strategies. The purpose of the present study was to describe direct inpatient medical costs associated with the treatment of hip and knee PJI. Methods: At a single tertiary care institution, 176 hips and 266 knees that underwent 2-stage revisions for the treatment of PJI from 2009 to 2015 were compared with 1,611 hips and 1,276 knees that underwent revisions for aseptic indications. In addition, 84 hips and 137 knees that underwent irrigation and debridement (I&D) with partial component exchange were compared with 39 hips and 138 knees that underwent partial component exchange for aseptic indications. Line-item details of services billed during hospitalization were retrieved, and standardized direct medical costs were calculated in 2018 inflation-adjusted dollars. Results: The mean direct medical cost of 2-stage revision THA performed for the treatment of PJI was significantly higher than that of aseptic revision THA ($58,369 compared with $22,846, p < 0.001). Similarly, the cost of 2-stage revision TKA performed for the treatment of PJI was significantly higher than that of aseptic revision TKA ($56,900 compared with $24,630, p < 0.001). Even when the total costs of aseptic revisions were doubled for a representative comparison with 2-stage procedures, the costs of PJI procedures were 15% to 28% higher than those of the doubled costs of aseptic revisions (p < 0.001). The mean direct medical cost of I&D procedures for PJI was about twofold higher than of partial component exchange for aseptic indications. Conclusions: The direct medical costs of operative treatment of PJI following THA and TKA are twofold higher than the costs of similar aseptic revisions. The high economic burden of PJI warrants efforts to reduce the incidence of PJI. Reimbursement schemes should account for the high costs of treating PJI in order to ensure sustainable patient care. Level of Evidence: Economic Level IV . See Instructions for Authors for a complete description of levels of evidence.