For individuals at high risk of developing breast cancer, interventions to mitigate this risk include surgical removal of their breasts and ovaries or five years treatment with the anti-estrogen tamoxifen or aromatase inhibitors. We hypothesized that a silicone based anti-estrogen-eluting implant placed within the breast would provide the risk reduction benefit of hormonal therapy, but without the adverse effects that limit compliance. To this end, we demonstrate that when placed adjacent to mammary tissue in the 7,12-dimethylbenz[a]anthracene-induced rat breast cancer model a fulvestrant-eluting implant delays breast cancer with minimal systemic exposure. Using adult female sheep, surgical placement of fulvestrant-eluting implants was safe and did not elicit significant breast tissue pathology when placed at the base of the udder for directed elution into the mammary tissue. At 30 days of elution, fulvestrant was found to penetrate mammary tissue forming a concentration gradient beyond 15 mm from the implant. Consistent with the small animal rat study, minimal systemic fulvestrant biodistribution was found. Together, these studies provide the proof of principle that a breast indwelling fulvestrant-eluting implant can reduce the risk of breast cancer and limit systemic exposure, while penetrating and distributing through breast tissue.

Hormone-receptor positive (HR +) and human epidermal growth factor receptor 2 (HER2) negative early breast cancer (eBC) is a heterogeneous disease with several contributing factors for increased risk of recurrence, including tumor features, individual biomarkers, and genomic risk. The current standard approach in the management of HR + /HER2neg eBC includes chemotherapy and endocrine therapy (ET), and additional therapies based on risk profile, menopausal status, and genetics are sometimes appropriate. The risk of recurrence is more pronounced in patients with high-risk eBC including large tumor size, nodal involvement, high proliferative index, and genetic predisposition. In premenopausal patients with high-risk eBC, ovarian function suppression in combination with adjuvant ET improves survival. In postmenopausal patients, extended aromatase inhibitor (AI) therapy can be considered. Recent trials have identified novel treatment approaches to reduce the risk of recurrence in high-risk HR + /HER2neg eBC including the addition of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to adjuvant ET. For patients with germline BRCA1/BRCA2 mutations, adjuvant poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have been shown to improve overall survival (OS). However, despite these recent advances, the risk of recurrence remains substantial, highlighting an area of unmet need. There are several ongoing clinical trials further investigating the role of CDK 4/6 inhibitors and immunotherapy in high-risk HR + /HER2neg eBC.

Novel agents have expanded the traditional HER2 definitions to include HER2-Low (HER2L) Breast Cancer (BC). We sought to evaluate the distinct molecular characteristics of HER2L BC to understand potential clinical/biologic factors driving resistance and clinical outcomes. Retrospective analysis was performed on 13,613 BC samples, tested at Caris Life Sciences via NextGen DNA/RNA Sequencing. BC subtypes were defined by IHC/ISH. CODEai database was used to access clinical outcomes from insurance claims data. Overall, mutational landscape was similar between HER2L and classical subsets of HR+and HRneg cohorts. TP53 mutations were significantly higher in HRneg/HER2L group vs. HR+/HER2L tumors (p<0.001). A higher mutation rate of PIK3CA was observed in HRneg/HER2L tumors compared to TNBC subtype (p=0.016). PD-L1 positivity was elevated in HRneg/HER2L tumors compared to HR+/HER2L tumors, all p<0.01. Patients with HR+/HER2L tumors treated with CDK4/6 inhibitors had similar OS compared to pts with HR+/HER2-0 (HR=0.89, p=0.012). 27.2

Breast cancers, both early and advanced, are heterogeneous causing differential responses to targeted therapy. Explosion in targeted treatment choices requires real time assessment of tumor characteristics in patients initially and over time. A dynamic detection system, not a static pathology specimen, is required for continuous profiling while treatment changes; hence, the interest in circulating tumor cells (CTCs). Our novel QCDx br™ system analyzes all nucleated cells from a blood sample aliquot, morphologically intact and immobilized in hydrogel, after multiplex, immunofluorescent (IF) staining. We characterize increased numbers of CTCs (nucleated, CD45-negative cells) as single cells, in clusters and in connection with circulating inflammatory cells, stained with two, separate IF marker cocktails, denoting (1) epithelial (EpCAM, Cytokeratin CK), mesenchymal (Vimentin VIM) phenotypes and (2) therapeutic HER2, ER and TROP2 targets which are the basis for targeted therapy in breast cancer. In the ongoing, prospective CLINBREAC trial, we enrolled to date 9 neoadjuvant (early stage, ES) and 21 metastatic (late stage, LS) breast cancer patients, collecting 7.5 ml of blood at 3-month intervals or at change of therapy. We are now out over 2 years with the earliest ES and LS patients showing changes in CTCs with disease progression and in response to treatment, often pre-dating changes seen in follow up biopsies. Detection of HER2+ CTCs was of particular interest in patients with HER2 low cancers¬ (1+ or 2+). Results presented here, contain the more complete datasets from 8 ES and 11 LS patients. QCDx br™ detected CTCs in all 19 Stage I-IV patients that could exceed 100 CTCs/2500 nucleated cells in LS and 50 CTCs/2500 nucleated cells in ES patients. The table shows count averages of CTCs/2500 nucleated cells detected by different IF markers. Of note, CTCs showed combinations of IF markers (hybrid cells). For example, CTCs expressed both VIM and CK indicating epithelial to mesenchymal transition (EMT) phenotype, which may signify higher metastatic potential. ER+ CTC were seen in LS, not ES patients. All ES patients including those with HER2 low tumors, showed HER2+ CTCs. Of note, not included in the table are two, triple-positive patients with oligo-metastatic disease now 4 and 10 years out from diagnosis without evidence of disease and on maintenance HER2 and ER-directed therapy. No CTCs are seen at their first data point. We were unable to detect CTCs in 13 healthy volunteers. In ES patients, CTC numbers did not associate with tumor size, nodal involvement, ER or HER2 status. For example, one TNBC patient with a T3 tumor and positive nodes had some of the lowest numbers of CTCs. The more complete quantification of the LS patients is in process. As development of QCDx br™ continues, multiplex IF staining of 12+ markers per CTC and identification of single CTC mutational changes is expected. This powerful technology enables targeted treatment decisions with specific drugs resulting in maximal responses. Average CTC counts/2500 nucleated cells detected by phenotypic and therapeutic IF cocktails Citation Format: Susan Tannenbaum, Emily Hsu, jasmin Hundal, Amber Wilkes, Austin Fergusson, Fahmy Mamuya, Triantafyllos Tafas. Targeting treatment to tumor response: demonstration of response monitoring with subsequent impact on treatment choices in real time utilizing a novel technology [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 P1-05-09.

For individuals at high risk of developing breast cancer, interventions to mitigate this risk include surgical removal of their breasts and ovaries or five years treatment with the anti-estrogen tamoxifen or aromatase inhibitors. We hypothesized that a silicone based anti-estrogen-eluting implant placed within the breast would provide the risk reduction benefit of hormonal therapy, but without the adverse effects that limit compliance. To this end, we demonstrate that when placed adjacent to mammary tissue in the DMBA-induced rat breast cancer model a fulvestrant-eluting implant delays breast cancer with minimal systemic exposure. Using adult female sheep, fulvestrant-eluting implants were found to be safe and non-toxic when placed at the base of the udder for directed elution into the mammary tissue. At 30 days of elution, fulvestrant was found to penetrate mammary tissue forming a concentration gradient beyond 15 mm from the implant. Consistent with the small animal rat study, minimal systemic fulvestrant biodistribution was found. Together, these studies provide the proof of principle that a breast indwelling fulvestrant-eluting implant can reduce the risk of breast cancer and limit systemic exposure, while penetrating and distributing through breast tissue.

Primary results from the phase 3 RESONATE-2 study demonstrated superior efficacy and tolerability with ibrutinib versus chlorambucil in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Here, we describe characteristics and outcomes of patients who received ibrutinib treatment for ≥5 years in RESONATE-2. Patients aged ≥65 years with previously untreated CLL/SLL, without del(17p), were randomly assigned 1:1 to once-daily ibrutinib 420 mg until disease progression/unacceptable toxicity (n = 136) or chlorambucil 0.5−0.8 mg/kg for ≤12 cycles (n = 133). Baseline characteristics in ibrutinib-randomized patients (n = 136) were generally similar between patients on ibrutinib treatment for ≥5 years (n = 79) versus those on treatment for <5 years (n = 57). In patients on ibrutinib treatment for ≥5 years, complete response rates improved over time, reaching 42% by 5 years. Estimated 7-year progression-free survival and overall survival rates were 82% and 94%, respectively. Adverse events (AEs) led to dose reductions in 16/79 patients (20%); these AEs were resolved for 13/16 patients (81%). AEs led to dose holds (≥7 days) in 45/79 patients (57%); these AEs were resolved for 43/45 patients (96%). More than half (58%) of ibrutinib-randomized patients benefitted from ibrutinib treatment for ≥5 years regardless of baseline characteristics. Dose modification resolved AEs for most patients, thereby facilitating continued treatment.

6536 Background: Racial/ethnic minority and immigrant groups individually experience lower rates of cervical cancer (CC) screening. Although immigrants represent large proportions of racial/ethnic minorities, few studies have explored the interacting health consequences of these social categories. Intersectionality is a theoretical framework which recognizes that studying social categories independently cannot capture their cumulative effects on health. In the context of CC screening, only one study took this approach but did not analyze several important barriers to care. This study aims to analyze the joint influence of race/ethnicity and immigrant status on screening and identify barriers unique to each intersectional group. Methods: Data from the National Health Interview Survey years 2005, 2010 and 2015 were drawn from IPUMS. Analyses were restricted to those eligible for CC screening (n=17,941). Multivariable logistic regression was used to model the interactional effect of race/ethnicity and immigrant status on screening up to date (UTD) status adjusting for confounders. Variables reflecting socioeconomic status (SES), access to care, acculturation and language were separately included to see whether they explained identified disparities. Finally, amongst women not UTD on screening, reasons for this were analyzed. All analyses were adjusted for complex survey design. Results: US born Non-Hispanic Black women had higher odds of being UTD on screening (OR 1.63, 95% CI [1.23, 2.18]) while immigrant Non-Hispanic White (OR 0.45 [0.29, 0.7]), immigrant Asian (OR 0.29 [0.2, 0.42]) and immigrant Hispanic/Latinx women (OR 0.51 [0.39, 0.67]) had lower odds compared to US born Non-Hispanic White women. Adjusting for SES (OR 0.87 [0.65, 1.16]) and access (OR 1 [0.74, 1.36]) attenuated the ORs for immigrant Hispanic/Latinx women but not immigrant Asian and White women. Adjusting for acculturation attenuated the ORs for immigrant Hispanic/Latinx (OR 0.84 [0.58, 1.22]) and White women (OR 0.68 [0.42, 1.12]) only. Adjusting for language increased but did not attenuate the ORs for all immigrant groups. Analyses of reasons for not screening showed immigrant Non-Hispanic White, Black and Asian women had greater proportions selecting “Didn’t need or know needed this test” versus other groups (10-12% vs. 5.4-8.4%). Conclusions: Immigrant status continues to explain much of the CC screening disparities previously attributed to race/ethnicity. SES and access to care remain important barriers for immigrant Hispanic/Latinx women but less so for other immigrant groups. This study reveals that acculturation is an important barrier for immigrant Non-Hispanic White and Hispanic/Latinx women, possibly representing disparities in knowledge. Language barriers may also contribute in all immigrant women. Further intersectional studies are needed to identify remaining barriers.

Book Citations: Authors, Title, HemaSphere, 2023;7(S3):pages. The individual abstract DOIs can be found at https://journals.lww.com/hemasphere/pages/default.aspx. Disclaimer: Articles published in the journal HemaSphere exclusively reflect the opinions of the authors. The authors are responsible for all content in their abstracts including accuracy of the facts, statements, citing resources, etc. 1160 Dose reduction for cardiac AEs may enable patients to continue to benefit from long-term ibrutinib and mitigate the risk of cardiac AE recurrence or worsening. HemaSphere | 2023;7(S3) EHA2023 Hybrid Congress Copyright Information: (Online) ISSN: 2572-9241 © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association. This is an open access Abstract Book distributed under the Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) which allows third parties to download the articles and share them with others as long as they credit the author and the Abstract Book, but they cannot change the content in any way or use them commercially. Abstract Book Citations: Authors, Title, HemaSphere, 2023;7(S3):pages. The individual abstract DOIs can be found at https://journals.lww.com/hemasphere/pages/default.aspx.Book Citations: Authors, Title, HemaSphere, 2023;7(S3):pages. The individual abstract DOIs can be found at https://journals.lww.com/hemasphere/pages/default.aspx. Disclaimer: Articles published in the journal HemaSphere exclusively reflect the opinions of the authors. The authors are responsible for all content in their abstracts including accuracy of the facts, statements, citing resources, etc. 1161

7538 Background: Continuous therapy with once-daily ibrutinib (Ibr) is associated with long-term PFS in pts with B-cell malignancies. Dose reduction is a potential AE management approach that may optimize treatment outcomes. We evaluated outcomes with dose reductions in Ibr-treated pts with cardiac AEs. Methods: Data were pooled for Ibr-treated pts from 10 studies of CLL (n=781), mantle cell lymphoma (MCL; n=250), marginal zone lymphoma (MZL; n=63) or Waldenström macroglobulinemia (WM; n=169). Cardiac AEs, initial and recurrent, were identified by preferred terms within the cardiac disorders system organ class. Recurrence was defined as an AE of same or worse grade, and was measured up to 30 days after last dose of ibrutinib or start of next-line therapy, whichever occurred earlier. Results: Overall, 234/1263 pts (19%) had cardiac AEs of any grade. Twelve pts were excluded from the analysis: 9 who had a dose reduction prior to a cardiac AE (0.7%) and 3 who had a fatal cardiac AE with no prior cardiac AE (0.2%). Of the remaining 222 pts with grade 1-4 cardiac AEs, 22 (10%) had Ibr dose reduction to 420 mg (n=3), 280 mg (n=10), or 140 mg (n=9) after a cardiac AE. These pts (n=22) tended to be older (≥75 y: 45% vs 29%), less heavily pretreated (≥1 prior therapy: 45% vs 73%), and with a lower Ibr discontinuation rate (23% vs 48%) than those without dose reduction (n=200). Recurrence of the same cardiac AEs at the same or worse severity was less frequent in pts with dose reductions, both overall (14% vs 18%) and as serious AEs (5% vs 10%). No pt died due to cardiac AE recurrence. Among pts with cardiac AEs who started with the 420 mg Ibr dose (177/222; excludes 45 patients with MCL or MZL who per label start with 560 mg dose), no cardiac AE recurred at same or worse severity in the subset with dose reductions (Table). PFS was not negatively impacted by dose reduction, both overall (n=22; median PFS not reached [NR], 24-mo PFS: 91%), and in those who started with the 420 mg dose (n=18; median PFS NR; 24-mo PFS, 94%). Conclusions: Dose reduction for cardiac AEs may enable pts to continue to benefit from long-term Ibr and mitigate the risk of cardiac AE recurrence or worsening. Clinical trial information: NCT01105247 , NCT01236391 , NCT01578707 , NCT01722487 , NCT01611090 . [Table: see text]

WHAT IS THIS SUMMARY ABOUT?:This is a plain language summary of a publication describing long-term results from the RESONATE-2 study with up to 8 years of follow-up. The original paper was published in Blood Advances in June 2022. WHAT WERE THE RESULTS?:Researchers looked at 269 adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had not received any treatment for their CLL/SLL. Study participants were randomly divided into two groups: 136 participants received treatment with a drug called ibrutinib, and 133 participants received treatment with a drug called chlorambucil. Participants in the study were treated and followed for up to 8 years, with results showing that more participants who took ibrutinib (59%) were alive without worsening of their disease at 7 years after starting treatment than participants who took chlorambucil (9%). Almost half of the participants (42%) were able to stay on ibrutinib treatment for up to 8 years. WHAT DO THE RESULTS OF THE STUDY MEAN?:In people with CLL or SLL, more participants who were taking ibrutinib were alive without worsening of their disease after 7 years compared with participants who took chlorambucil. Clinical Trial Registration: NCT01722487 (ClinicalTrials.gov) Clinical Trial Registration: NCT01724346 (ClinicalTrials.gov).

Importance:Cytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation. Objective:To determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer. Design, Setting, and Participants:This registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings. Exposures:Immunosuppression due to therapy; systemic anticancer therapy (IO or non-IO). Main Outcomes and Measures:The primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm. Results:The median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79). Conclusions and Relevance:This cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm. Trial Registration:ClinicalTrials.gov Identifier: NCT04354701.

100 Background: Decentralized clinical trials (DCT) aim to bring a trial’s activities to the patient. However, to date there is little practical experience about conducting them in the therapeutic arena. Due to the COVID-19 pandemic, and in partnership with Bristol Myers Squibb (BMS), we modified our Investigator-Initiated study, BrUOG354 (ClinicalTrials.gov ID: NCT03355976), a phase II trial on the role of Nivolumab and Ipilimumab in extra-renal clear cell carcinoma. This allowed for the shipment of investigational product (IP) to the patient for local administration without trial site activation. Here we report the experience and lessons learned. Methods: The administrative process to facilitate decentralization on BrUOG-354 required FDA guidance, BMS agreement, and Lifespan IRB approval. Brown University Oncology Group (BrUOG) databases were mined for all communications with local sites and providers. We report on enrollment figures per quarter pre- and during/post-pandemic, the number of off-study sites approached, and agreements reached. The reasons for not moving forward at the local site were characterized by two authors (DD, RW). Results: This study was initiated at two Providence health systems initially and activated a third site at the University of Illinois at Chicago in 2021. In total, 46 volunteers were consented to this trial between April 2018 and April 2023, with 16 (34.8%) registered prior to the lockdown in March 2020 and 30 (65.2%) after. Among 34 patients treated at the PI’s institution, seven travelled from out of state for treatment. Two who started treatment pre-lockdown were successfully transitioned so that protocol therapy was administer locally, and both remain on study. Five people were registered during the pandemic and six institutions were approached; three accommodated the request. Reasons provided for not allowing local administration of IP including: unavailability of a research pharmacy (1), blanket institutional prohibition (1) and lack of indemnification language (1). Conclusions: The experience with BrUOG354 exemplifies the potential of DCTs in an oncological setting while simultaneously highlighting barriers to implementation. Therapeutic DCTs are feasible and heightened capacity for future patient-centric trial designs is an exciting prospect. For these to succeed, the ability to conduct study visits by telehealth, especially for out of state residents, is critical. While not originally designed to be decentralized, adopting this approach enabled us to complete enrollment in a rare tumor during the pandemic. By shifting to a patient-centric model, DCTs may improve patient access and options for clinical trials in particular for less common malignancies, while preserving quality of life, addressing financial toxicity, and foster a more diverse trial population. Clinical trial information: NCT03355976 .

Introduction: Breast cancer has pioneered precision medicine with prognostic and predictive subtypes, defined by immunohistochemistry (IHC). Novel therapeutic strategies have led to the emergence of HER2-Low (H2L) as a new entity, defined as tumors with HER2 IHC score of 1+ (>10% cell stained), as well as those with 2+ (>10% cell stained) with paired negative in-situ hybridization (ISH) assay. H2L has been reported to represent up to half of all breast cancer. Further investigation into the mutational landscape of H2L compared to historical subtypes is needed to understand the clinical and biologic factors driving mechanisms of resistance and to consider post-progression treatment options within H2L populations. Methods: The Caris Life Sciences database was used to identify H2L breast tumors by IHC and CISH and evaluated for mutations detected by DNA next-generation sequencing (NextSeq 592-gene panel or NovaSeq whole exome panel). PD-L1 expression was tested by IHC (SP142 IC ≥ 1%). Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (high ≥ 10 mutations per Mb). Statistical significance was determined using Fisher’s-Exact/Mann Whitney/X2 test with Benjamini-Hochberg-correction-adjusted p value (q value) of <0.05. Results: A total of 19789 breast tumors were included in this study. Using standard definitions, 12480 were defined as hormone receptor positive (HR+), 7309 hormone receptors negative (HRneg), 5564 were TNBC, and 1784 HER2 positive (HER2pos). 4349 cases were also identified as H2L, which included 3403 HR+H2L and 946 HRneg H2L. H2L was 22% (4349/19789) of total population; 27% (3403/12480) of the HR+ population and 12.9% (946/7309) of the HRneg population. Within the H2L tumors, when stratified by HR status, we observed in the HR+H2L tumors an increased frequency of amplifications in CCND1 (15.6% vs 5.0%), FGF3 (13.3% vs 4.7%), FGF4 (13.3% vs 4.2%), FGF19 (14.4% vs 4.7%), ZNF703 (15.6% vs 4.4 %), NSD3 (12.9% vs 5.2%), ADGRA2 (13.1% vs 5.3%), FGFR1 (11.7% vs 3.6%) and EMSY (5.2% vs 1.4%) compared to the HRnegH2L tumors. TP53 mutations were strikingly higher in the HRnegH2L group (74.4% vs 25.0%) compared to HR+H2L tumors. Markers of IO response also showed elevated positivity in PD-L1 (39.6% vs 19.5%) however, no difference was detected in TMB-H status in HRnegH2L tumors compared to HR+H2L tumors, all q<0.05. The genomic landscape differed when comparing HR+HER2pos tumors to HR+H2L tumors. Significantly more prevalent alterations in HR+HER2pos included amplifications in RNF43 (4.4% vs 1.4%), RARA (13.6% vs 0.1%), MLLT6 (19% vs 0.0%), MYC (6.1% vs 2.7%), DDX5 (10.1% vs 2.0%), CLTC (10.4% vs 3.3%) as well as TP53 (64.0% vs 25.0%) mutations and PD-L1 expression (26.6% vs 19.5%). Furthermore, mutations in PTEN (2.5% vs 7.8%), MAP3K1 (2.8% vs 7.1%), ESR1 (4.4% vs 14.3%), CDH1 (5.2% vs 16.4%), AKT1 (0.0% vs 4.3%) were elevated in the HR+H2L tumors compared to the HR+HER2pos tumors, all q<0.05. Interestingly, when the HRnegH2L tumors were compared to TNBC subtype differences were seen in the mutation rate of PIK3CA (33.5% vs 16.7%; q<0.0001), a master regulator of cell growth, and tumor suppressor gene TP53 (74% vs 86%). Conclusions: With some exceptions, H2L breast cancer shared genomic features with its more classically defined subset of either HR+ or HRneg disease. Notable differences in PIK3CA (an actionable mutation) and TP53 (a prognostic alteration) warrant additional assessment, as do amplifications variable between HR+H2L and HR+Her2pos groups. Our findings add tremendously to the current understanding of the molecular profile of the H2L subgroup and comparison to the classically defined breast cancer subgroups. Genomic risk assessments after progression on novel therapeutics will be needed to better define implications for mechanisms of resistance. Citation Format: Rani Bansal, Julie McGrath, Phil Walker, Matias A. Bustos, Estelamari Rodriguez, Sarah L. Sammons, Melissa K. Accordino, Jane Meisel, Margaret Gatti-Mays, Emily Hsu, Kate I. Lathrop, Virginia Kaklamani, Matthew Oberley, W. Michael Korn, Stephanie L. Graff. HER2-12 Genomic and Transcriptomic Landscape of HER2-Low Breast Cancer [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 HER2-12.

Supplementary figures S1-S11

PURPOSE Virtual medicine (VM) use increased during the COVID-19 pandemic as it represented a safe alternative to traditional face-to-face health care delivery. This prospective cross-sectional study aimed to characterize preferences and perceived barriers to VM on the basis of language and specific sociodemographic variables while also identifying particular subpopulations at risk of dissatisfaction regarding VM. METHODS An institutional review board-approved, 23-item questionnaire was offered in English and Spanish. Examined variables included demographic information, preferences, and perceived barriers regarding VM. Multivariable analysis was performed to determine the association between demographic variables and participants' preferences and perceived barriers. RESULTS Fewer Hispanic and underserved patients (N = 241) had received oncological care through VM (28.9% v 30.8%) despite comparable preferences and levels of satisfaction regarding the incorporation of VM in health care delivery (21.6% v 25.4%; 68.7% v 82.1%), respectively, with no significant difference by age, level of education, marital status, or Hispanic ethnicity, although Spanish as primary language was statistically significant (P = .001). Although Hispanic and underserved rely more on social media to receive health information (26.5% v 24.7%), they have more technical barriers. They were up to 2.9 times more likely not to have a phone/iPad/similar or access broadband connectivity. CONCLUSION Given the shift toward outpatient and home-based care, an aging population, and cultural appropriations, VM excitedly allows the reincorporation of family/caregiver in medical engagement. Hispanic patients are equally interested and satisfied in receiving oncological care through VM, but fewer are currently using it. Barriers are predominantly technical and targetable with appropriate policies to help overcome technological barriers on the basis of language, ethnic, locoregional, and sociodemographic variables.

iLLUMINATE is a randomized, open-label phase III study of ibrutinib plus obinutuzumab (n=113) versus chlorambucil plus obinutuzumab (n=116) as first-line therapy for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. Eligible patients were aged ≥65 years, or <65 years with coexisting conditions. Patients received oral ibrutinib 420 mg once daily until disease progression or unacceptable toxicity or six cycles of oral chlorambucil, each in combination with six cycles of intravenous obinutuzumab. After a median follow-up of 45 months (range, 0.2-52), median progression-free survival continued to be significantly longer in the ibrutinib plus obinutuzumab arm than in the chlorambucil plus obinutuzumab arm (median not reached versus 22 months; hazard ratio=0.25; 95% confidence interval: 0.16-0.39; P<0.0001). The best overall rate of undetectable minimal residual disease (<0.01% by flow cytometry) remained higher with ibrutinib plus obinutuzumab (38%) than with chlorambucil plus obinutuzumab (25%). With a median treatment duration of 42 months, 13 months longer than the primary analysis, no new safety signals were identified for ibrutinib. As is typical for ibrutinib-based regimens, common grade ≥3 adverse events were most prevalent in the first 6 months of ibrutinib plus obinutuzumab treatment and generally decreased over time, except for hypertension. In this final analysis with up to 52 months of follow-up (median 45 months), ibrutinib plus obinutuzumab showed sustained clinical benefit, in terms of progression- free survival, in first-line treatment of chronic lymphocytic leukemia, including in patients with high-risk features. ClinicalTrials.gov identifier: NCT02264574.

Across patient subgroups, more than half (58%) of ibrutinib-randomized patients benefitted from long-term ibrutinib treatment for ≥5 years. Responses deepened over time through 5 years. Dose modification was effective in resolving AEs for the majority of patients, thereby allowing patients to remain on treatment.

Background It is widely expected that circulating tumor cells (CTCs) in cancer patients shall turn out to be good prognosticators for outcomes. However, enumeration and monitoring of CTCs continues to pose serious hurdles. Current methods to assess CTCs utilize various approaches to enrich for CTCs. The only FDA-approved system detects CTCs via enrichment for EpCAM. Cancer heterogeneity requires an enrichment-free characterization of all CTCs to better identify this ever-changing landscape for biologic understanding and clinical management. Methods CLINBREAC is a single site, prospective, longitudinal trial for detecting and characterizing all CTCs in breast cancer patients. We present results from 8 metastatic and 2 neoadjuvant patients followed over time. Collection of 18ml blood samples occurred at enrollment and at change of treatment, or at 3-month intervals. Using the RareScope™ Fluorescence Light Sheet Microscope (QCDx LLC, Farmington CT), an aliquot of all morphologically intact, un-enriched nucleated cells placed in immobilized suspensions were analyzed. All cells were stained with immunofluorescent markers against CD45, Vimentin (Vim), EpCAM and Cytokeratin (CK) for characterization of epithelial or mesenchymal CTC phenotypes and trophoblast surface antigen 2 (TROP-2), ER-α and HER2 for treatment-specific characterization. Results No CTCs were observed in blood samples from 13 healthy volunteers. All patient samples contained CTCs collected over all time-points from 10 patients. In all, 1261 CTCs were identified, range, 18-85 CTCs per 1.7K to 2.7K nucleated cells analyzed. Each sample had a unique pattern of epithelial and mesenchymal markers that changed with time and treatment and mirrored clinical course. Of the CTC populations seen, 239 (19%) stained EpCAM+. Of the remaining CTCs, 798 CK+ (63%) and 842 Vim+ (67%) . An example: Patient 1: progression of metastatic triple negative breast cancer on nab-paclitaxel and atezolizumab after which anti-TROP-2 directed therapy with sacituzumab govitecan was initiated. In 39 CTCs present in sample 1, EpCAM-5%, CK-36%, and Vim-92% alone and co-expressed with EpCAM and CK. In subsequent samples, CTCs decreased from 39 to 23 to 6 consistent with response to treatment. TROP2+ CTCs decreased from 14/25 cells to 1/10 with treatment. CTCs co-expressed TROP2, HER2 and ER-α. As TROP2+ CTCs decreased from Sample 1 to 3 (56 to 10%) HER2+ CTCs increased (12 to 70%). The correlation of CTCs with clinical course of disease was observed in all 8 metastatic patients. Phenotypic changes occurred in all patients’ CTCs followed over time. Conclusions RareScope technology, utilized here, is a novel CTC-detection methodology that does not rely on prior enrichment of blood for CTCs. In patients analyzed here, all samples contained CTCs in higher numbers than described previously; a minority of CTCs contain EpCAM+ CTCs and may account for lower numbers in prior studies. Continuing refinement of this technology with addition of multiplex testing on single cells with a larger panel of antibodies will enhance targeted analysis and shall be useful in detection and detailed characterization of CTCs with un-precedented resolution and in real time. Citation Format: Susan Tannenbaum, Emily Hsu, Ashwanth Reddy, Spencer Keilich, Triantafyllos Tafas. Unbiased liquid biopsy in breast cancer patients utilizing novel light sheet microscopy of circulating tumor cells. Proof of concept in 10 patients and 13 controls [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 P2-02-07.

Genomic abnormalities, including del(17p)/TP53 mutation, del(11q), unmutated IGHV, and mutations in BIRC3, NOTCH1, SF3B1, and XPO1 predict poor outcomes with chemoimmunotherapy in chronic lymphocytic leukemia. To better understand the impact of these high-risk genomic features on outcomes with first-line ibrutinib-based therapy, we performed pooled analysis of two phase 3 studies with 498 patients randomized to receive ibrutinib- or chlorambucil-based therapy with median follow-up of 49.1 months. Ibrutinib-based therapy improved overall response rates (ORRs), complete response rates, and progression-free survival (PFS) versus chlorambucil-based therapy across all subgroups. In ibrutinib-randomized patients with versus without specified genomic features, ORR and PFS were comparable across subgroups. PFS hazard ratio (95% CI) for del(17p)/TP53 mutated/BIRC3 mutated: 1.05 (0.54-2.04); del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV: 1.11 (0.69-1.77); unmutated IGHV: 1.79 (0.99-3.24); and NOTCH1 mutated 1.05 (0.65-1.69). This integrated analysis demonstrated efficacy of first-line ibrutinib-based treatment irrespective of cytogenetic and mutational risk features. Registered at ClinicalTrials.gov (NCT01722487 and NCT02264574).