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Introduction: Young women with estrogen receptor (ER)-positive early-stage breast cancer (EBC) frequently present with larger, higher-grade, more aggressive tumors, with lower ER expression than older women. Post-hoc analyses within the MINDACT and TAILORx cohorts reported that women aged 40-50 with ER+ EBC exhibited a chemotherapy benefit independent of genomic risk compared to women aged > 50, possibly due to chemotherapy-induced ovarian suppression (CIOS). However, women < 40 years, who seldom develop CIOS, are under-represented in clinical trials. Therefore, it is important to distinguish the tumor biological profile within this younger age group. To understand the biological basis underlying why younger women have poorer outcomes than older women, this study aimed to identify genes that distinguish tumors in younger women from older women. Methods: EBC patients enrolled in the FLEX study (NCT03053193) undergo standard of care MammaPrint (MP) and BluePrint (BP) tests, and consent to clinically annotated whole transcriptome data collection. MP categorizes tumors as High Risk (HR) or Low Risk (LR) of recurrence. Together, MP and BP classify molecular subtype as Luminal A, Luminal B, HER2, or Basal. Whole transcriptome gene expression differences were compared among ER+ tumor specimens from three age groups: < 40 years old (n=283), 40-54 years old (n=1535), and ≥ 55 years old (n=4355). Differentially expressed genes (DEGs) were identified from 100 randomized iterations for each comparison; an equal number of LR and HR samples were analyzed in each group. DEGs found in > 20 iterations indicated gene stability within the age group. DEGs were also identified within each age group after correcting for BP subtype, and between pre-menopausal (n=1314) and post-menopausal (n=4859) women. Gene expression data were quantile normalized using R package ‘limma’. DEGs with an adjusted p 2-fold change. Conclusion: Tumors from women aged 40-54 had few DEGs, suggesting observed chemotherapy benefit represents differences in host biology rather than intrinsic tumor biology as compared with tumors from women < 40 or ≥ 55, where detected DEGs are associated with proliferation, receptor signaling, and metabolism. Fewer DEGs were observed by menopausal status than age, indicating age is a more relevant cutoff. Future studies will aim to further characterize this high risk young patient population. Citation Format: Shubhada Dhage, Mina Gendy, Nina D'Abreo, Ruth Oratz, Sami G. Diab, VK Gadi, Cathy Graham, Midas Kuilman, Shiyu Wang, Patricia Dauer, Andrea Menicucci, William Audeh, Douglas K. Marks. Deciphering the inferior prognosis of young women with estrogen receptor-positive early-stage breast cancer through full transcriptome analysis: A FLEX database sub-study [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 P5-07-05.

BACKGROUND: Immune checkpoint inhibitors in combination with chemotherapy have demonstrated an improvement of pathologic complete response (pCR) in patients with HR-HER2- and MammaPrint (MP) High Risk, HR+HER2- tumors in the I-SPY2 TRIAL. However, not all patients benefit from immune checkpoint blockade and these new agents come with additional financial burden and significant long-lasting side effects such as adrenal insufficiency. Thus, it is imperative to better understand who benefits. Response Predictive Subtypes (RPS) were developed in the I-SPY2 TRIAL using pre-treatment expression data from 987 MP High Risk patients; 39% of HR+HER2- tumors and 63% of HR-HER2- tumors were identified as immune sensitive. In I-SPY2.2, RPS tumor classification uses ImPrint, a 53-gene signature that has been independently validated to predict the likelihood of a pCR with PD1-PDL1 immune checkpoint inhibitors with high sensitivity and specificity. Using a real-world dataset of 10,000 patients enrolled in the FLEX trial, we identified immune sensitive (ImPrint+) patients within immunohistochemistry (IHC) subtypes and within MP and BluePrint (BP) subgroups. METHODS: FLEX (NCT03053193) is an ongoing registry trial with 97 sites open in the United States and 2 international sites. Patients enrolled in FLEX have early-stage breast cancer and receive standard of care MP testing with or without BP molecular subtyping and consent to clinically annotated full genome data collection. MP is a 70-gene risk of distant recurrence signature that classifies patients as Low Risk or High Risk. MP High Risk can be further stratified into High 1 and High 2, which have demonstrated differences in chemosensitivity and pCR rates in the I-SPY2 TRIAL (NCT01042379). BP, an 80-gene molecular subtyping signature, categorizes patients’ tumors as Luminal-, HER2- or Basal-Type. RESULTS: Of the 10,021 patients, 9.1% of the FLEX patient population are ImPrint+ and are predicted to have a meaningful pCR rate with immune checkpoint inhibitors. Younger (≤ 50 years) or pre/peri-menopausal patients, patients with larger or node-positive tumors, and patients of Black or Latin race/ethnicity independently had a higher likelihood of having ImPrint+ tumors (Table 1). ImPrint+ tumors were identified in all clinical subtypes by IHC. There is a higher likelihood of ImPrint+ tumors being MP High 2 or BP Basal-Type tumors. Within BP Basal tumors, 74.7% of HR+ and 66.0% of HR- tumors were ImPrint+. CONCLUSIONS: The focus of immune therapy trials has been on patients with HR-HER2-, MP High Risk patients. Indeed, most patients who are predicted to benefit have MP High 2 or BP Basal-Type tumors, including some HR+ patients, which is consistent with I-SPY2 results. Importantly, this large real-world dataset enables the identification of populations who may benefit from immune therapy outside of traditional clinical trial populations and supports the testing of checkpoint inhibitors in the immune-positive subtype. Younger women and patients of Black or Latin race/ethnicity who typically have more aggressive tumors also have higher proportions of ImPrint+ tumors. Thus, it is critical that these populations be included in clinical trials. This first look at immune sensitivity in over 10,000 FLEX patients with ImPrint generates preliminary data and hypotheses that will be explored in future FLEX substudies, including an analysis of lobular cancers and long-term outcomes in ImPrint+ patients across all races and ages. Table 1. Clinical characteristics of ImPrint+ and ImPrint- tumors. Citation Format: Adam M. Brufsky, Midas Kuilman, Rita Mukhtar, Denise M. Wolf, Christina Yau, Joyce O’Shaughnessy, Cathy Graham, Vijayakrishna K. Gadi, Pat Whitworth, Alexander Hindenburg, Ian Grady, Gordon Srkalovic, Kent Hoskins, Ajay Dhakal, Cynthia Ma, Natasha Hunter, Jennifer Crozier, Blanche Mavromatis, Lorenza Mittempergher, Christine Finn, Shraddha Modh, Erin B. Yoder, Patricia Dauer, Andrea Menicucci, Bas van der Baan, William Audeh, Laura J. Esserman. ImPrint immune signature in 10,000 early-stage breast cancer patients from the real-world FLEX database [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 PD9-08.

565 Background: Recent prospective clinical trials have demonstrated a differential chemotherapy effect based on age (≤ 50 vs. > 50 years) or menopausal status (pre- vs. post-) in a genomic low risk group. Whether this is a direct anti-tumor effect of chemotherapy or a secondary ovarian function suppression effect caused by chemotherapy is unclear. We aimed to compare the biological characteristics of breast cancer tumors from patients aged ≤ 50 years and from patients aged > 50 years using whole transcriptome analysis to provide insights into this differential chemotherapy response. Methods: The FLEX Registry (NCT03053193) enrolls stage I-III breast cancer patients who receive 70-gene signature (MammaPrint/MP) test with or without 80-gene signature (BluePrint/BP) test and consent to clinically annotated transcriptome data collection. 3868 patients with HR+HER2- tumors were evaluated, of whom 808 were aged ≤ 50 years and 3060 were aged > 50 years. Clinical risk was assessed based on the MINDACT algorithm. MP classified tumors as low risk (LR) or high risk (HR). HR was stratified to H1 or H2; H2 exhibits a greater chemotherapy response. BP and MP classified tumors as luminal A-, luminal B-, HER2-, or basal-type. Differences in MP, BP, and clinical features were assessed by chi-squared or t test. For gene expression analysis, older patients were randomly selected to obtain an equal sample size as younger patients. Differentially expressed genes (DEGs) were detected using limma and considered significant with FDR 50 were post-menopausal. A higher proportion of patients aged ≤ 50 had tumors of high clinical risk (54%) compared to patients aged > 50 (39%) (p < 0.001). Approximately 53% of patients aged ≤ 50 had a HR tumor, of whom 25% classified as H2, while patients aged > 50 had a lower frequency (44%) of HR tumors (p 50, and even fewer DEGs were detected when adjusting for MP risk and BP subtype group. Conclusions: Whole transcriptome analysis identified no substantial differences in gene expression between tumors, including Low Risk Luminal-type tumors, from women aged ≤ 50 (mostly pre or peri-menopausal) and women aged > 50 (mostly post-menopausal). These data support the likely explanation that the observed age-dependent difference in chemotherapy benefit in women ≤ 50 or >50 years of age is not due to intrinsic biological differences in breast cancers due to age, but rather to differences in the effect of chemotherapy on the host. Clinical trial information: NCT03053193.

Background: Triple negative breast cancers (TNBC) are more aggressive, have a worse prognosis, and few targeted therapies compared to other BC subtypes. TNBC is molecularly heterogeneous, with at least 4 distinct subtypes: basal-like immune-activated (BLIA), basal-like immunosuppressed (BLIS), luminal androgen receptor (LAR), and mesenchymal (MES). The molecular subtyping gene signature, BluePrint (BP), classifies breast tumors into Luminal, HER2, or Basal subtype based on the assessment of downstream signaling pathways and independently of IHC expression. Compared to IHC-defined TNBC, a higher frequency of BLIS or BLIA subtypes and fewer LAR or MES tumors were reported in BP-defined Basal tumors. To advance our understanding of TNBC heterogeneity, we evaluated the relationship between gene expression signatures, TNBC subtype and BluePrint, in IHC-defined TNBC. Methods: The FLEX registry (NCT03053193) is an ongoing, prospective study evaluating primary tumors from stage I-III BC patients who receive the risk of distant recurrence gene signature, MammaPrint (MP), and BP testing and consent to clinically annotated full transcriptome data collection. This analysis includes 204 IHC-defined TNBC patients. TNBC subtypes BLIA, BLIS, LAR, and MES were derived using an adjusted version of the Burstein centroid signature. BP classified patient samples into Luminal, HER2, and Basal subtypes. A proportion of tumors may exhibit a secondary but less pronounced activated pathway or BP subtype. Therefore, each BP subtype was divided into single activated or mixed subtype based on BP indices. Results: Of 204 TNBC tumors, 84% were classified as Basal by BP, most of which were BLIS (65%), followed by BLIA (22%), with a low frequency of MES (8%) and LAR (5%) subtypes (Table). Approximately 14% of TNBCs were reclassified as Luminal by BP, most of which were LAR (76%), whereas 24% were MES. Clustering analysis revealed similar gene expression profiles between Basal-BLIS and Basal-BLIA tumors. Interestingly, the transcriptional profile of Basal-MES and Basal-LAR tumors were similar to Luminal-MES and Luminal-LAR tumors. BP Basal indices distinguished between different TNBC subtypes. The Basal pathway was predominantly activated in 90% of BP Basals (single activated tumors), most of which were either BLIS or BLIA (96%), whereas 10% of BP Basals were mixed subtype and more likely to classify as LAR (53%) or MES (35%). Approximately 25% of the BP Basal gene signature overlapped with the TNBC subtype gene signature. Expression of 18 and 12 genes out of 28 genes that make up the BP basal signature were significantly different in Basal-BLIA/BLIS compared to LAR or MES, respectively (P < 0.05). PRR15 and CAPN13 were significantly differentially expressed between LAR and MES within Basals. Conclusion: BP reclassified a subgroup of TNBC tumors to Luminal, explaining the discrepancy in the distribution of TNBC subtypes between IHC-defined TNBC and BP Basal tumors. Furthermore, BP indices distinguished between single activated and mixed subtypes, which correlated with different TNBC subtypes. These data suggest that molecular classification by BP adds further precision in classifying TNBC patients and sheds new light on the heterogeneity of these tumors. These findings have clinical implications in stratifying patients and identifying successful targeted treatment options. Future studies are warranted to investigate treatment response and prognosis in these molecular subgroups. BasalLuminalHER2TotalBLIA370037BLIS11100111LAR1022335MES147021Total172 (84.3%)29 (14.2%)3 (1.5%)204 (100%) Citation Format: Virginia G. Kaklamani, Cathy Graham, Karen L. Tedesco, Abirami Sivapiragasam, Jennifer A. Crozier, Apurva N. Shah, Yuan Yuan, Josien Haan, Andrea Menicucci, Michelle L. Bolner, Shiyu Wang, Lorenza Mittempergher, Erin Yoder, William Audeh, FLEX Investigators' Group. Using blueprint to elucidate the molecular heterogeneity of triple negative breast cancers [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 PS18-05.

556 Background: Genomically basal-type breast cancer is a heterogenous subtype that occurs at higher frequencies in non-Caucasian patients. Triple negative breast cancer (TNBC) has been refined into distinct transcriptomic groups including the basal-like immunoactive (BLIA), basal-like immunosuppressed (BLIS), luminal androgen receptor (LAR), and mesenchymal (MES) subtypes. Here we report the distribution of triple negative subtypes in genomically basal cancers from Caucasian (CA), African American (AA), and Latin American (LA) patients and the association of clinical estrogen receptor (ER) status. Methods: The FLEX Registry (NCT03053193) is an ongoing, prospective study evaluating primary tumors from patients with stage I-III breast cancer who receive the 70-gene signature and 80-gene signature (80-GS) molecular testing and consent to clinically annotated full transcriptome data collection. This sub-analysis evaluated 143 80-GS Basal type tumors from patients with self-reported ethnicity (60 CA, 59 AA, 24 LA). TNBC subtypes BLIA, BLIS, LAR, and MES were derived using an adjusted version of the 80-gene centroid signature published by Burstein and colleagues (2015). Differences in clinical ER expression between ethnicities were assessed by Fisher’s exact test. Results: Basal indices from 80-GS were not influenced by patient ethnicity (one-way ANOVA, p = 0.182). The frequency of BLIA, BLIS, LAR, and MES subtypes did not vary significantly by ethnicity (Fisher’s exact test, p = 0.671). The majority of tumors in all ethnic groups were BLIS (67% CA, 75% AA, 63% LA), followed by BLIA (22% CA, 22% AA, 25% LA), with low frequency of LAR (5% CA, 1.7% AA, 8.3% LA) and MES (5% CA, 1.7% AA, 4.2% LA) subtypes. Nearly one third (31%) of Basal type tumors were defined by IHC as ER positive and were present in all TNBC subtypes (39% BLIA, 29% BLIS, 33% LAR, and 20% MES); ER receptor expression ranged from 1-90% and was not associated with specific basal subtype (p = 0.8) nor ethnicity (P = 0.76). Progesterone receptor expression ranged from 1-50%. Conclusions: This analysis demonstrated that genomic Basal type tumor classification by 80-GS encompasses all TNBC subtypes evaluated regardless of ethnicity. Additionally, we show that IHC ER positive tumors occur in all TNBC subtypes assessed. These findings confirm the heterogeneous nature of basal breast tumors in CA, AA, and LA patients and highlight the clinical need to delineate basal biology in the ER+ cohort to advance treatment for basal-like tumors. Clinical trial information: NCT03053193 .

Aiming to minimize overtreatment of high-risk breast lesions (HRLs), including atypical ductal hyperplasia, and small breast cancers, including ductal carcinoma in situ (DCIS), we investigated a minimally invasive (MI) approach to definitive diagnosis and management of these conditions. In the prospective Intact Percutaneous Excision registry study, women aged 31–86 years had removal of small invasive cancers, DCIS, or HRLs using image-guided 12–20 mm radiofrequency basket capture (MI excision). Second-pass 20 mm basket capture obtained shaved margins in cancer patients. Standard imaging (specimen, breast) and histologic criteria were applied. Patient data were registered in an Institutional Review Board approved, Health Insurance Portability and Accountability Act-compliant registry. Of 282 registered patients, 124 had DCIS (n = 52) or invasive cancer (n = 72) and 160 had HRLs. Among cancer patients, 101 (81%) had clear histologic margins [average lesion size was 11 mm for both invasive cancers (4–20 mm) and DCIS (1.5–20 mm)]; 29 patients had re-excision (six despite clear margins). Among 160 HRLs, two were upgraded to DCIS and had MI excision. Two other HRL patients had subsequent standard surgical excision (no cancer found). For diminutive HRLs, DCIS, and invasive cancers, MI excision can achieve the same procedure goals as standard surgical excision. Because MI excision removes less tissue with small incisions, it may reduce the discomfort and expense associated with standard treatment.

Narrative Reflective Process (Schwind, 2008) facilitates emergence of unanticipated discoveries of personal knowing. In nursing education, personal knowing is of an essence when interacting with learners. For that reason, five nurse-teachers from Ontario, Canada, undertook a year-long commitment to engage in a guided narrative reflective process, using the metaphor self-as-instrument-of-care. Narrative reflective process, which grows out of narrative inquiry, engenders such creative reflective tools as storytelling, metaphors, writing, drawing and conversations. When this reflective process is undertaken by a group of practitioners, the emergent relational knowing deepens, becomes more complex, revealing new patterns of being, doing and becoming. These five nurse-teachers became aware of developing patterns, thus expanding consciousness of how they are in teaching-learning relationships with their learners, as well as their colleagues. They learned how increased self-knowing and awareness of who they are ...

In trials of 3D conformal external beam partial breast radiotherapy (PBRT), the dosimetrist must balance the priorities of achieving high conformity to the target versus minimizing low-dose exposure to the normal structures. This study highlights the caveat that in the absence of a low-dose lung restriction, the use of relatively en-face fields may meet trial-defined requirements but expose the ipsilateral lung to unnecessary low-dose radiation. Adding a low-dose restriction that ≤20% of the ipsilateral lung should receive 10% of the prescribed dose resulted in successful plans in 88% of cases. This low-dose lung limit should be used in PBRT planning.

Objective This paper reports the experience with a two-stage approach to surgical correction of the complete cleft palate, wherein timing of the second stage is dependent on the judgment of the speech pathologist and the orthodontist together with the surgeon. Patients Of a total of 35 patients having complete unilateral clefts a sample of 22 were available for postsurgical assessment. The first-stage repair of the palate was carried out at an average age of 10.7 months (range 6 to 17 months), and the second-stage repair of the residual cleft was completed at an average age of 32.7 months (range 26 to 34 months). Interventions The first-stage repair of the soft palate defect involved mobilizing two short posteriorly based flaps, which extend onto the posterior quarter of the hard palate thus including up to 1 cm of mucoperiosteum. Careful freeing of the muscle is followed by an intravelar veloplasty. The later closure of the residual cleft involved turnover hinge flaps and small mucoperiosteal flaps. Results Eighty-seven percent of the sample had good to excellent speech as assessed by the Great Ormond Street screening method. Only two patients showed evidence of recessive maxillae with Class III malocclusions. Conclusions A two-stage surgical closure of the palate using this procedure would appear to confer several valuable advantages to the patient. These include favorable outcomes for speech in the large majority of cases and minimal adverse effects on the growth of the midface region.

This article describes an innovation in baccalaureate nursing education that is intended to assist in the preparation of nursing students for careers in which evidence-informed practice is an imperative. The innovation involves the combination of central aspects of the internationally recognized Registered Nurses’ Association of Ontario Best Practice Guidelines Program with existing curricular goals and themes in a baccalaureate nursing program at a small university in southern Ontario in Canada. [ J Nurs Educ . 2014;53(3, Suppl.):S55–S58.]