IntroductionExperts suggest doxorubicin clearance is decreased in women with a body mass index (BMI) of ≥35 kg/m2. However, few data support this recommendation.MethodsWomen receiving doxorubicin for breast cancer in three BMI groups were recruited (n = 15). Doxorubicin dosing was determined by body surface area and was administered by 30-min intravenous infusion. Blood samples were obtained at 0 h (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 5, 12-24, and 24-72 h following the beginning of infusion. Concentrations of doxorubicin and its metabolite, doxorubicinol, were assayed by LC-MS/MS. Non-compartment analysis was done using PKanalix2021R2 for pharmacokinetic (PK) analyses.ResultsThe median [range] BMI and age were 30.3 [23.5-57] kg/m2 and 53 [31-69] years. Thirteen of the 15 women had samples available for analysis. Four of the 13 had a BMI ≥ 35.0 kg/m2. PK parameters ranged from 37.8% (AUC0-inf) to 91.0% (Vd). Doxorubicinol PK parameters ranged from 37.8% (Cmax) to 67.6% (AUC0-inf). The average doxorubicinol:doxorubicin AUClasts ratio was 0.26 (range: 0.04-0.88). A t-test didn't suggest a significant difference in individual PK parameters (BMI < 35 kg/m2 vs. ≥35.0 kg/m2). The two highest clearances (380 L/h and 250 L/h) had a BMI ≥ 35.0 kg/m2; also, the highest clearance (1114 L/h) for doxorubicinol was ≥35.0 kg/m2.ConclusionsLarge interindividual variabilities in doxorubicin PK were observed in women up to a BMI of 57 kg/m2 and a total body weight of 141.5 kg. Women with a BMI ≥ 35.0 kg/m2 and breast cancer did not appear to have lower clearances of doxorubicin.ClinicalTrials.gov IDNCT01537029.

Supplementary Fig. S1. Early stages CRC patients expressed very low DC-HIL expression on MDSCs. Supplementary Fig. S2. No effect of anti-CD14 mAb on T cell suppressor function of MDSCs. Supplementary Fig. S3. DC-HILneg MC38 and CT26 mouse colon cancer cell lines exhibit high response to anti-DC-HIL treatment. Supplementary Fig. S4. MDSCs in spleen and draining lymph nodes did not express DC-HIL. Supplementary Fig. S5. Combination treatment of anti-DC-HIL/anti-PDL1 mAb did not produce synergistic anti-tumor effects to MC38 colon cancer. Supplementary Fig. S6. Changes in health conditions of mice treated with anti-DC-HIL mAb. Supplementary Fig. S7. Representative FACS data showing frequency of immune cells in the tumor microenvironment of mice treated with mAb. Supplementary Fig. S8. Blood granulocytic MDSC of CRC patients expressed low-levels of DC-HIL and were not immunosuppressive in ex vivo cultures.

Supplementary Table S1. Summary of MDSC analysis of metastatic cancer patents. aAll cancer patients are diagnosed as stage III or IV. Supplementary Table S2. Correlation of variables and expansion of DC-HIL+ MDSCs among colorectal cancer patients. Supplementary Table S3. % DC-HIL+ MDSC/PBMC in subgroups with vs. without radiotherapy. Supplementary Table S4. Reversing effects of anti-DC-HIL vs. anti-PDL1 mAb on MDSC suppressor function between two different treatments. Supplementary Table S5. DC-HIL and PDL1 expression in colorectal cancer tissues.

Importance There has been little consideration of genomic risk of recurrence by breast cancer subtype despite evidence of racial disparities in breast cancer outcomes. Objective To evaluate associations between clinical trial end points, namely pathologic complete response (pCR) and distant recurrence–free survival (DRFS), and race and examine whether gene expression signatures are associated with outcomes by race. Design, Setting, and Participants This retrospective cohort study used data from the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2 (I-SPY 2) multicenter clinical trial of neoadjuvant chemotherapy with novel agents and combinations for patients with previously untreated stage II/III breast cancer. Analyses were conducted of associations between race and short- and long-term outcomes, overall and by receptor subtypes, and their association with 28 expression biomarkers. The trial enrolled 990 female patients between March 30, 2010, and November 5, 2016, with a primary tumor size of 2.5 cm or greater and clinical or molecular high risk based on MammaPrint or hormone receptor (HR)-negative/ ERBB2 (formerly HER2 or HER2 / neu )–positive subtyping across 9 arms. This data analysis was performed between June 10, 2021, and October 20, 2022. Exposure Race, tumor receptor subtypes, and genomic biomarker expression of early breast cancer. Main Outcomes and Measures The primary outcomes were pCR and DRFS assessed by race, overall, and by tumor subtype using logistic regression and Cox proportional hazards regression models. The interaction between 28 expression biomarkers and race, considering pCR and DRFS overall and within subtypes, was also evaluated. Results The analytic sample included 974 participants (excluding 16 self-reporting as American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or multiple races due to small sample sizes), including 68 Asian (7%), 120 Black (12%), and 786 White (81%) patients. Median (range) age at diagnosis was 47 (25-71) years for Asian, 49 (25-77) for Black, and 49 (23-73) years for White patients. The pCR rates were 32% (n = 22) for Asian, 30% for Black (n = 36), and 32% for White (n = 255) patients ( P = .87). Black patients with HR-positive/ ERBB2 -negative tumors not achieving pCR had significantly worse DRFS than their White counterparts (hazard ratio, 2.28; 95% CI, 1.24-4.21; P = .01), with 5-year DRFS rates of 55% (n = 32) and 77% (n = 247), respectively. Black patients with HR-positive/ ERBB2 -negative tumors, compared with White patients, had higher expression of an interferon signature (mean [SD], 0.39 [0.87] and −0.10 [0.99]; P = .007) and, compared with Asian patients, had a higher mitotic score (mean [SD], 0.07 [1.08] and −0.69 [1.06]; P = .01) and lower estrogen receptor/progesterone receptor signature (mean [SD], 0.31 [0.90] and 1.08 [0.95]; P = .008). A transforming growth factor β signature had a significant association with race relative to pCR and DRFS, with a higher signature associated with lower pCR and worse DRFS outcomes among Black patients only. Conclusions and Relevance The findings show that women with early high-risk breast cancer who achieve pCR have similarly good outcomes regardless of race, but Black women with HR-positive/ ERBB2 -negative tumors without pCR may have worse DRFS than White women, highlighting the need to develop and test novel biomarker-informed therapies in diverse populations.

HSP90 inhibitors destabilize oncoproteins associated with cell cycle, angiogenesis, RAS-MAPK activity, histone modification, kinases and growth factors. We evaluated the HSP90-inhibitor ganetespib in combination with standard chemotherapy in patients with high-risk early-stage breast cancer. I-SPY2 is a multicenter, phase II adaptively randomized neoadjuvant (NAC) clinical trial enrolling patients with stage II-III breast cancer with tumors 2.5 cm or larger on the basis of hormone receptors (HR), HER2 and Mammaprint status. Multiple novel investigational agents plus standard chemotherapy are evaluated in parallel for the primary endpoint of pathologic complete response (pCR). Patients with HER2-negative breast cancer were eligible for randomization to ganetespib from October 2014 to October 2015. Of 233 women included in the final analysis, 140 were randomized to the standard NAC control; 93 were randomized to receive 150 mg/m 2 ganetespib every 3 weeks with weekly paclitaxel over 12 weeks, followed by AC. Arms were balanced for hormone receptor status (51–52% HR-positive). Ganetespib did not graduate in any of the biomarker signatures studied before reaching maximum enrollment. Final estimated pCR rates were 26% vs. 18% HER2-negative, 38% vs. 22% HR-negative/HER2-negative, and 15% vs. 14% HR-positive/HER2-negative for ganetespib vs control, respectively. The predicted probability of success in phase 3 testing was 47% HER2-negative, 72% HR-negative/HER2-negative, and 19% HR-positive/HER2-negative. Ganetespib added to standard therapy is unlikely to yield substantially higher pCR rates in HER2-negative breast cancer compared to standard NAC, and neither HSP90 pathway nor replicative stress expression markers predicted response. HSP90 inhibitors remain of limited clinical interest in breast cancer, potentially in other clinical settings such as HER2-positive disease or in combination with anti-PD1 neoadjuvant chemotherapy in triple negative breast cancer. Trial registration: www.clinicaltrials.gov/ct2/show/NCT01042379

Breast cancer survivors have reduced peak aerobic capacity (VO2peak) which may be related to latent or lingering chemotherapy induced cardiac damage. Nine, older (67 ± 3 years), long-term survivors (9.8 years) of anthracycline based chemotherapy and age- and sex-matched healthy controls were recruited and tested to determine whether: i) VO2peak remains reduced in long-term survivorship; and ii) reductions in VO2peak are due to cardiac dysfunction. VO2peak was significantly reduced in breast cancer survivors relative to healthy controls (15.9 ± 2.0 vs 19.9 ± 3.1 ml/kg/min, p = 0.006), however the heart rate and stroke volume responses to exercise were normal (heart rate reserve; 88 ± 9 vs 85 ± 10 bpm, p = 0.62: stroke volume reserve; 13 ± 6 vs 13 ± 9 ml,p = 0.94). These findings indicate low-normal ventricular size in long-term breast cancer survivors, but normal reserve function.

Background Transcriptomic immune-related gene signatures have been associated with achievement of pathologic complete response (pCR) and prognosis in the neoadjuvant setting. I-SPY 2 is a multicenter, phase 2 platform trial using response-adaptive randomization within subtypes defined by receptor status (HR/HER2) and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk breast cancer. Given racial disparities in mortality from breast cancer and the paucity of racial demographic data from clinical trials, we aimed to evaluate the association between racial groups and baseline characteristics, including expression-based subtypes and immune signatures, treatment response, and prognosis of patients enrolled in the I-SPY 2 TRIAL. Methods Our study population included 990 I-SPY 2 patients. 15 patients identified as part of a racial group with <10 patients enrolled in the trial and were excluded from analysis. Pre-treatment expression data was available for 971 patients. Follow-up data was available for 907 patients; median follow-up time of 4.4 yrs. Chi-square test was used to assess associations between racial groups and pre-treatment SBR grade, HR/HER2 defined subtypes, intrinsic subtype (defined by BluePrint 80-gene molecular subtyping) and residual cancer burden (RCB) class. Logistic regression was used to evaluate race association with pCR. Cox proportional hazard modeling was used to assess the association between racial groups and event free survival (EFS) in a univariate setting, adjusting for pCR status. Association between racial groups and 28 expression signatures related to immune, proliferation, ER and HER2 pathway was analyzed using ANOVA with post-hoc Tukey test in the overall population and in each receptor subtype. Results Of 975 patients included in our analysis, 787 (81%) were White, 68 (7%) were Asian, and 120 (12%) were Black or African American. No significant associations between race and pre-treatment SBR grade (p=0.49), HR/HER2 defined subtypes (p=0.09), or expression-based subtypes (p=0.25) were observed. pCR rates do not significantly differ by racial groups (Odds ratio of pCR relative to White: 1.00 for Asian and 0.89 for Black or African American); and no significant differences in RCB class distribution by race was observed (p=0.88). Event free survival was not associated with patient racial group in a univariate Cox model (Hazard ratio relative to White: 1.10, p=0.73 for Asian and 1.37, p=0.13 for Black or African American). Among the 28 expression signatures evaluated, four were differentially expressed among racial groups within the overall population (F-test p<0.05): IFN module, B cell signature, Dendritic cell signature, and Mitotic score. Pairwise comparisons between racial groups with post-hoc Tukey test identified significant differences in IFN module expression between Black or African American vs. White (p=0.019) and Dendritic cell signature expression between Asian vs White (p=0.047). Among patients in the TNBC subtype, three signatures (dendritic cell signature, macrophage signature and ERBB2 module) were differentially expressed between Black or African American and White patients (p=0.002, 0.016 and 0.007). Conclusion Our analysis demonstrates that among women with high risk breast cancer, race does not affect subtype specific response rates nor event free survival. Distribution of subtypes previously shown to be associated with pCR in the I-SPY2 trial did not significantly differ among racial groups indicating race is less likely than tumor biology to predict response. The decreased expression of immune signatures observed in Black or African American women with TNBC suggests possible differential sensitivity to immunotherapy plus combination chemotherapy. Tumor immune multiplex studies are underway to further investigate. Citation Format: Beverly Kyalwazi, Christina Yau, Olufunmilayo Olopade, A. Jo Chien, Anne Wallace, Andres Forero-Torres, Lajos Pusztai, Erin Ellis, Kathy Albain, Anne Blaes, Barbara Haley, Judy Boughey, Anthony Elias, Amy Clark, Claudine Isaacs, Rita Nanda, Hyo Han, Rachel Yung, Debu Tripathy, Kristen Edmiston, Rebecca Viscusi, Donald Northfelt, Qamar Khan, Ashish Sanil, Scott Berry, Smita Asare, Amy Wilson, Gillian Hirst, Nola Hylton, Michelle Melisko, Jane Perlmutter, Hope Rugo, Fraser Symmans, Laura van ‘t Veer, Donald Berry, Laura Esserman. Analysis of clinical outcomes and expression-based immune signatures by race in the I-SPY 2 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 GS4-02.

Abstract Background: HER2 mutations are oncogenic drivers in a subset of metastatic breast cancers (MBC). Neratinib (N) is an oral, irreversible pan-HER tyrosine kinase inhibitor with preclinical and clinical activity against HER2 mutations. Genomic analyses from paired biopsies following N ± fulvestrant (F) suggest that resistance to N may occur via amplification of the mutant allele or by acquisition of secondary HER2 mutations. Addition of trastuzumab (T) to N+F showed encouraging clinical activity with durable responses in the SUMMIT trial in hormone receptor-positive (HR+), HER2-mutant MBC, including patients (pts) who had previously received cyclin-dependent kinase 4 & 6 inhibitors (CDK4/6i) [Jhaveri et al. SABCS 2020]. On the basis of these findings, and in order to better understand the contribution of N to the activity of the N+F+T combination, SUMMIT has recently been expanded to include a randomized Simon 2-stage comparison of N+F+T vs. F+T vs. F in pts with HR+, HER2-mutated, HER2-negative MBC who were exposed to CDK4/6i. Enrollment for stage 1 is now complete (N+F+T, n=7; F+T, n=7; F, n=7), and results will be forthcoming once the data are mature. Here we report updated findings from the breast cancer cohorts of the SUMMIT trial for which data are currently available. Methods: The phase 2 SUMMIT trial (NCT01953926) enrolled pts with HR+, HER2-negative MBC whose tumors harbored activating HER2 mutation(s) identified by genomic sequencing. Prior to starting the randomized portion of the trial, these patients were enrolled in a non-randomized cohort and received N+F+T (oral N 240 mg/d, i.m. F 500 mg d1&15 of cycle 1 then q4w, i.v. T 8 mg/kg initially then 6 mg/kg q3w). Following initiation of the randomized portion of the trial, these pts received N+F+T, F+T or F (1:1:1 ratio; dose schedules as above). Pts with HER2-mutant triple-negative breast cancer (TNBC) were enrolled in a non-randomized cohort and received N+T (dose schedules as above). Loperamide prophylaxis was mandatory during the first 2 treatment cycles. There was no restriction on the number of prior lines of systemic therapy for MBC. Efficacy endpoints: investigator-assessed objective response rate and clinical benefit rate (RECIST v1.1 or other defined criteria); duration of response; best overall response. Results: Prior to enrolling the randomized cohort, 24 pts with HR+, HER2-mutated MBC who had previously received CDK4/6i were enrolled in the non-randomized cohort and received N+F+T, and 17 pts with HER2-mutant TNBC were enrolled and received N+T, as of 18-Jun-2021. Data for randomized pts are not yet mature. HER2 allelic variants across both cohorts (pts may have >1 mutation): kinase domain hotspots (n=26); exon-20 insertion (n=9); extracellular domain hotspot (n=4); exon-19 deletion (n=1); transmembrane domain missense (n=1); kinase domain non-hotspot (n=2). Efficacy findings are reported in the Table. Diarrhea was the most commonly reported adverse event: N+F+T (non-randomized cohort), 96%; N+T (TNBC cohort), 94%. No grade 4 diarrhea was reported. Conclusions: N+F+T is a promising combination for pts with HR+, HER2-mutated MBC with prior exposure to CDK4/6 inhibitors. N+T also showed encouraging activity in HER2-mutated TNBC. The first results from the randomized comparison of N+F+T vs. F+T vs. F in pts with HR+, HER2-mutated MBC (Simon stage 1 analysis) will be presented at the meeting. Table: Efficacy findingsHR+, HER2-mutated, HER2-non-amplified MBCHER2-mutant TNBCN+F+T (n=24)N+T (n=17)Confirmed objective response,a n (%)11 (46)5 (29)CR0 (0)1 (6)PR11 (46)4 (24)ORR, % (95% CI)46 (26–67)29 (10–56)Best overall response, n (%)13 (54)7 (41)CR0 (0)1 (6)PR13 (54)6 (35)Best overall response rate, % (95% CI)54 (33–74)41 (18–67)Medianb DOR, months (95% CI)14.4 (6.4–NR)NRClinical benefit, n (%)14 (58)6 (35)CR or PR11 (46)5 (29)SD ≥24 weeks3 (13)1 (6)CBR,b % (95% CI)58 (37–78)35 (14–62)aORR defined as either a CR or PR confirmed no less than 4 weeks after the response criteria are met; bCBR defined as confirmed CR or PR or SD for ≥24 weeks. Note: Tumor response is based on investigator tumor assessments per RECIST v1.1 for HR+, HER2-mutated cohort, and RECIST v1.1 or modified PERCIST for HER2-mutated TNBC cohort. CBR, clinical benefit rate; CI, confidence interval; CR, complete response; DOR, duration of response; F, fulvestrant; HR+, hormone receptor-positive; MBC, metastatic breast cancer; N, neratinib; NR, not reached; ORR, objective response rate; PERCIST, Positron Emission Tomography Response Criteria in Solid Tumors; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; T, trastuzumab, TNBC, triple-negative breast cancer. Citation Format: Komal Jhaveri, Haeseong Park, James Waisman, Jonathan W Goldman, Angel Guerrero-Zotano, Valentina Boni, Barbara Haley, Ingrid A Mayer, Adam Brufsky, Eddy S Yang, José A García-Sáenz, François-Clement Bidard, John Crown, Bo Zhang, Aimee Frazier, Irmina Diala, Lisa D Eli, Brian Barnett, Hans Wildiers. Neratinib + fulvestrant + trastuzumab for hormone receptor-positive, HER2-mutant metastatic breast cancer and neratinib + trastuzumab for triple-negative disease: Latest updates from the SUMMIT 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 GS4-10.

First, we agree with the GEC-ESTRO group that, at the inception of this phase 1 trial, intraoperative radiation (IORT) was not felt to be an ideal form of APBI, given the increased rates of local recurrence reported by the ELIOT 1 Veronesi U Orecchia R Maisonneuve P et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): A randomised controlled equivalence trial. Lancet Oncol. 2013; 14: 1269-1277 Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar and TARGIT-A trials 3 Vaidya JS Wenz F Bulsara M et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet. 2014; 383: 603-613 Abstract Full Text Full Text PDF PubMed Scopus (612) Google Scholar at that time. However, recently, with long-term follow-up of the TARGIT-A trial, the investigators have reported evidence of noninferiority between the TARGIT-IORT modality and whole breast radiation in properly selected patients. 4 Vaidya JS Bulsara M Baum M et al. Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial. BMJ. 2020; 370: m2836 Crossref PubMed Scopus (77) Google Scholar Still, as Hannoun-Levi et al point out, about 20% of patients receiving TARGIT-IORT still required adjuvant external beam radiation, given adverse pathologic features found after surgical pathology was finalized, which is not ideal. This, therefore, spurred our interest to investigate neo-adjuvant single-fraction approaches with longer intervals before surgery, allowing radiation related tissue changes to affect pathology findings that might better inform the need for subsequent external beam radiation therapy. Furthermore, we recognize that local recurrences for hormone positive cancers typically can occur after 5 years, making it difficult to make definitive recommendations with limited follow up, as in the multicatheter interstitial brachytherapy (MCIB) approach reported by Hannoun-Levi and colleagues. 5 Hannoun-Lévi JM Lam Cham Kee D Gal J et al. Accelerated partial breast irradiation in the elderly: 5-Year results of the single fraction elderly breast irradiation (SiFEBI) phase I/II trial. Brachytherapy. 2020; 19: 90-96 Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Like the MCIB technique, S-PBI, as investigated in this trial, is another promising adjuvant modality for single-episode treatment APBI and one that will improve access to care, particularly for patients at centers where interstitial brachytherapy is not available.

A comparative analysis of clinical and pathologic characteristics of HER2 positive breast cancer patients treated with adjuvant versus neoadjuvant antiHer2 therapy: an analysis of 397 cases. Introduction: Currently there are several anti-HER2 therapy options for patients with HER2 positive breast cancer. Surgery as an initial treatment is usually performed in patients with smaller, node negative tumors. Neoadjuvant therapy (NAT) is the treatment of choice for patients with higher stage disease. Detailed analysis of clinical and pathologic characteristics of patients who received adjuvant versus NAT anti-HER2 therapy has not been well elucidated. Objectives: A comparative analysis of clinical and pathologic findings including biomarker expression (ER, PR, HER2 and Ki67) was performed to determine if there were differences in tumor characteristics and clinical outcome in the two groups.Methods:We retrospectively analyzed data on HER2+ breast cancer patients treated with adjuvant and NAT anti-HER2 therapy from 2011 to 2017. Clinical and pathologic parameters including biomarker expression prior to the start of therapy were obtained from the electronic database after IRB approval. In the adjuvant group, patients were treated with initial surgery followed by anti-HER2 therapy plus chemotherapy. In the NAT group, anti-HER2 therapy plus chemotherapy was administered prior to definitive surgery. Types of anti-HER2 therapies and follow-up information were obtained from the electronic medical record. Results:We identified 258 (64.9%) patients who received NAT and 139 (35.0%) received adjuvant anti-HER2 therapy. Table 1.VariablesNeoadjuvant groupAdjuvant groupp-valueAgeBelow 40 years42 (16.2%)11(7.9%)0.02940 years and above Total216 (83.7%) 258128 (92.0%) 139Menopausal statusPremenopausalPostmenopausal Total113 (45.3%)136 (54.6%) 24935 (25.1%)104 (74.8%) 139<0.001Nodal status on biopsyNegativePositive Total31 (18.1%)140 (81.8%) 17117 (53.1%)15 (46.8%) 32<0.001Tumor size by imaging (cm)Mean + SD3.87+2.832.24+1.76<0.001Tumor grade123 Total5 (2%)78 (31.3%167 (66.8%) 2507 (5.3%)49 (37.6%)74 (56.9%) 1300.068HER2 by IHC0 and 1+ (FISH +)2+ (FISH+)3+ Total11 (4.2%)61 (23.8%)184 (71.8%) 2564 (3.5%)41 (36.6%)67 (59.8%) 1120.042HER2 FISH copy no.Mean +SD15.44 ± 8.2512.64 ± 6.470.007HER2 ratioMean SD6.35 ± 3.445.57 ± 3.560.046ER statusNegativePositive Total113 (43.9%)144 (56.0%) 25745 (35.1%)83 (64.8%) 1280.122Percent positive71.38 ± 33.3778.74 ± 29.040.042ER intensity1+2+3+ Total24 (16.9%)38 (26.7%)80 (56.3%) 1422 (2.6%)26 (34.2%)48 (63.1%) 760.001PR statusNegative Positive Total147 (57.1%)110 (42.8%) 25766 (51.9%)61 (48.0%) 1270.389Percent positive42.33 ± 34.5444.72 ± 32.890.645PR intensity1+2+3+ Total20 (18.5%)41 (37.9%)47 (43.5%) 10810 (17.5%)30 (52.6%)17 (29.8%) 570.012KI67 indexPercent positive49.44 ± 22.6638.56 ± 22.36<0.001Anti-HER2 therapyHerceptinHerceptin+ Perjeta Total72 (31.0)160 (68.9%) 23291 (89.2%)11 (10.7%) 102<0.001SurgeryTotal Partial BilateralModified radicalOther Total SurvivalAlive. Dead116 (44.95)75 (29.0%)25 (9.6%)38 (14.7%)04 (1.5%) 258 239 (92.6%) 19 (7.3%)55 (40.4%)56 (41.1%)18 (13.2%)5 (3.6%)02 (1.4%) 136 125 (89.9%) 14 (10.0%)0.002 0.458Conclusions:Patients who received NAT were significantly younger, premenopausal with more aggressive tumor biology (higher Ki67, HER2 expression). Recent advances in anti-HER2 therapy has improved the outcome of these patients despite having higher stage disease. Breast conserving surgery was higher in the adjuvant group since the tumors were smaller in size. There was no significant difference in overall survival when compared to the adjuvant group (p=0.458) Citation Format: Venetia Sarode, Tricia Rood, Yulun Liu, Yisheng Fang, Sunati Sahoo, Yan Peng, Helena Hwang, Marilyn Leitch, Barbara Haley. A comparative analysis of clinical and pathologic characteristics of patients with HER2 positive breast cancer treated with neoadjuvant versus adjuvant anti-HER2 therapy: Analysis of 397 cases [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 P1-02-14.

Purpose: H3B-6545, a novel Selective ERα Covalent Antagonist (SERCA), inactivates both and wild-type and mutant ERα by targeting cysteine 530 and enforcing antagonist conformation. H3B-6545 demonstrated preclinical high activity in breast cancer models with constitutively active ESR1 mutations (Furman C, SABCS 2020) and clinical activity in pretreated women with ER+ breast cancer (Hamilton EP, ASCO 2021). Patients and Methods: The primary objective of the phase II is to estimate the objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and secondary objectives include safety. Results: 94 pts were treated with 450 mg daily, the recommended phase II dose: 11 in the phase I and 83 in the phase II parts of the trial. Patients and tumor characteristics were presented previously (Hamilton EP, ASCO, 2021). As of March 31, 2021, grade (gr) 2 or higher adverse events (AE) reported in ≥10% were anemia (19%), nausea (17%), fatigue (16%), and diarrhea (12%). Laboratory gr 2 or higher abnormalities reported in ≥10% pts were creatinine clearance decrease (39%), hemoglobin decrease (38%), Lymphocytes decrease (37%), ALT increase (14%), AST increase (13%), bilirubin increase (12%), and creatinine increase (12%). AE of gr 1 sinus bradycardia (asymptomatic) was reported in 35% and gr 2 (symptomatic, no intervention needed) was reported in 5%. Gr 2 and 3 QTcF prolongation were reported in 2 and 3 pts, respectively. There were no treatment-related deaths. Efficacy estimates are presented in Table 1. CI: Confidence interval. N: total number of pts in full analysis set, used in PFS analysis. n: number of response-evaluable pts, used in ORR and CBR analysis. Efficacy estimates were consistent across the various subgroups. Responses were demonstrated in heavily pretreated pts, pts with visceral metastases, pts with constitutionally active ESR1 Y537S mutations, and in pts who received chemotherapy in the metastatic setting. Numerically higher response rate and longer PFS were observed in pts with ESR1 Y537s. Conclusions: H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients. Clinical activity was consistent across the various subgroups. Tumors harboring the constitutionally active ESR1 Y537S mutation may present higher ERα activity, and consequently enrich for luminal A traits and demonstrate greater lineage dependence on ERα. Table 1.Consistency of H3B-6545 activity across the key subgroupsEfficacyClinical CharacteristicORR % (95% CI)CBR % (95% CI)Median PFS mo (95% CI)Overall population (N=94, n=72)16.7 (8.9, 27.3)40.3 (28.9, 52.5)5.1 (3.2, 6.2)Liver and/or lung metastases (N=76, n=62)17.7 (9.2, 29.5)41.9 (29.5, 55.2)5.4 (1.8, 7.2)≥3 prior regimens (N=49, n=39)20.5 (9.3, 36.5)48.7 (32.4, 65.2)5.4 (3.5, 7.3)Prior chemotherapy (N=47, n=35)17.1 (6.6, 33.6)51.4 (34.0, 68.6)5.5 (3.6, 7.3)PgR+ (N=38, n=32)15.6 (5.3, 32.8)50.0 (31.9, 68.1)5.4 (2.0, 8.8)ESR1 clonal Y537S (N=10, n=10)30.0 (6.7, 65.2)60.0 (26.2, 87.8)7.3 (0.8, 11.2)ESR1 clonal D538G (N=19, n=17)0.0 (0.0, 19.5)35.3 (14.2, 61.7)5.4 (1.7, 7.2) Citation Format: Erika P Hamilton, Judy S Wang, Timothy Pluard, Aki Morikawa, E Claire Dees, Robert H Jones, Barbara Haley, Anne Armstrong, Adam L Cohen, Pamela Munster, Gail S Wright, Fadi Kayali, Lisa Cantagallo, Manav Korpal, Jenny Long, Jianjun Xiao, Benoit Destenaves, Lei Gao, Tarek Sahmoud, Antonio Gualberto, Dejan Juric. H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer - A phase II 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 P1-17-10.

HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2 + breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms ‘graduate’ in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2 + tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome.

Importance Residual cancer burden (RCB) distributions may improve the interpretation of efficacy in neoadjuvant breast cancer trials. Objective To compare RCB distributions between randomized control and investigational treatments within subtypes of breast cancer and explore the relationship with survival. Design, Setting, and Participants The I-SPY2 is a multicenter, platform adaptive, randomized clinical trial in the US that compares, by subtype, investigational agents in combination with chemotherapy vs chemotherapy alone in adult women with stage 2/3 breast cancer at high risk of early recurrence. Investigational treatments graduated in a prespecified subtype if there was 85% or greater predicted probability of higher rate of pathologic complete response (pCR) in a confirmatory, 300-patient, 1:1 randomized, neoadjuvant trial in that subtype. Evaluation of a secondary end point was reported from the 10 investigational agents tested in the I-SPY2 trial from March 200 through 2016, and analyzed as of September 9, 2020. The analysis plan included modeling of RCB within subtypes defined by hormone receptor (HR) andERBB2 status and compared control treatments with investigational treatments that graduated and those that did not graduate. Interventions Neoadjuvant paclitaxel plus/minus 1 of several investigational agents for 12 weeks, then 12 weeks of cyclophosphamide/doxorubicin chemotherapy followed by surgery. Main Outcomes and Measures Residual cancer burden (pathological measure of residual disease) and event-free survival (EFS). Results A total of 938 women (mean [SD] age, 49 [11] years; 66 [7%] Asian, 103 [11%] Black, and 750 [80%] White individuals) from the first 10 investigational agents were included, with a median follow-up of 52 months (IQR, 29 months). Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (HR-positive/ERBB2-negative: hazard ratio [HZR], 1.75; 95% CI, 1.45-2.16; HR-positive/ERBB2-positive: HZR, 1.55; 95% CI, 1.18-2.05; HR-negative/ERBB2-positive: HZR, 2.39; 95% CI, 1.64-3.49; HR-negative/ERBB2-negative: HZR, 1.99; 95% CI, 1.71-2.31). Prognostic information from RCB was similar from treatments that graduated (HZR, 2.00; 95% CI, 1.57-2.55; 254 [27%]), did not graduate (HZR, 1.87; 95% CI, 1.61-2.17; 486 [52%]), or were control (HZR, 1.79; 95% CI, 1.42-2.26; 198 [21%]). Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) andERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis. Conclusions and Relevance In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy. Trial Registration ClinicalTrials.gov Identifier:NCT01042379

Abstract Background: The development of central nervous system (CNS) metastases presents a considerable challenge in metastatic breast cancer (MBC) due to the limited availability of evidence-based treatments. Up to 50% of patients with HER2-positive (HER2+) MBC develop CNS metastases during the course of their disease. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated activity against CNS metastases in HER2+ MBC in two phase 2 studies (NEfERT-T, TBCRC 022) and one phase 3 study (NALA); significant benefits for predefined CNS endpoints were reported in NEfERT-T and confirmed in NALA. Here we present an exploratory analysis of patients from NALA with CNS involvement at enrollment. Methods: NALA was an international, randomized, open-label, active-controlled, phase 3 study in patients with HER2+ MBC who had received ≥2 lines of HER2-directed therapy in the metastatic setting (ClinicalTrials.gov: NCT01808573). Patients with asymptomatic metastatic brain disease managed with stable doses of corticosteroids for ≥14 days prior to randomization were eligible, whereas patients with symptomatic or unstable brain metastases were excluded. Patients were randomized (1:1 ratio) to neratinib (N; 240 mg qd po) + capecitabine (C; 750 mg/m2 bid po) or lapatinib (L; 1250 mg qd po) + C (1000 mg/m2 bid po). Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Intervention for symptomatic metastatic CNS disease was a secondary endpoint. CNS disease at baseline was defined as patients with treated or untreated disease in the ‘brain’ assessed by investigator at enrollment. CNS imaging was not mandatory at screening. Results: Of the 621 patients enrolled in NALA, 101 (16%) had documented baseline CNS disease and 520 (74%) had no CNS disease at baseline. Patients with CNS disease had a lower performance status and were more likely to have hormone receptor-negative disease than those with no CNS disease; no major imbalances of baseline characteristics were noted between treatment arms. Overall, 78 (77%) patients had previously received CNS radiation [whole brain, n=59 (58%); stereotactic, n=17 (17%); unknown, n=2 (2%)], and 5 (5%) patients had undergone CNS surgery. Median treatment duration was 5.7 (IQR 2.8-8.5) months for N, and 3.5 (IQR 2.1-6.9) months for L. PFS, OS, and cumulative incidence of interventions for symptomatic CNS disease are summarized in the table. No new safety signals were detected. Conclusions: Regardless of the status of CNS metastases at baseline, patients appeared to have better outcomes in the N+C arm compared with the L+C arm. Table. Efficacy outcomes in patients with and without CNS disease at baselineIntention-to-treat (n=621)CNS metastases at baseline – Yes (n=101)CNS metastases at baseline – No (n=520)N+C (n=307)L+C (n=314)N+C (n=51)L+C (n=50)N+C (n=256)L+C (n=264)PFSaHazard ratio (95% CI)0.76 (0.63–0.93)0.66 (0.41–1.05)0.76 (0.62–0.94)P-value0.00590.07410.0099Restricted mean PFSb, months8.86.67.85.59.06.9Difference, months2.22.32.1OSHazard ratio (95% CI)0.88 (0.72–1.07)0.90 (0.59–1.38)0.85 (0.68–1.06)P-value0.20860.63520.1517Restricted mean OSb, months24.022.216.415.425.623.6Difference, months1.71.02.0Incidence of CNS interventionOverall cumulative incidencec, %22.7629.1940.1347.7919.1624.65P-value0.0430.4300.067aCentrally confirmed; bRestriction prespecified as 24 months for PFS, and 48 months for OS; c % requiring intervention for CNS disease (competing risk model) Citation Format: Cristina Saura, Larisa Ryvo, Sara Hurvitz, William Gradishar, Beverly Moy, Suzette Delaloge, Sung-Bae Kim, Mafalda Oliveira, Maureen Trudeau, Ming-Shen Dai, Barbara Haley, Ron Bose, Luciana Landeiro, Judith Bebchuk, Aimee Frazier, Kiana Keyvanjah, Richard Bryce, Adam Brufsky. Impact of neratinib on outcomes in HER2-positive metastatic breast cancer patients with central nervous system disease at baseline: Findings from the phase 3 NALA trial [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 PD13-09.

9068 Background: The phase 2 SUMMIT basket trial (NCT01953926) demonstrated efficacy of neratinib in patients with EGFR exon 18-mutant NSCLC [Boni et al. WCLC 2020]. Neratinib also has documented activity in HER2+ metastatic breast cancer with CNS metastases [Saura et al. SABCS 2020 & J Clin Oncol 2020]. Here we report neratinib efficacy in a subgroup of patients with EGFR exon 18-mutant NSCLC and CNS involvement from SUMMIT. Methods: Patients with EGFR exon 18-mutant NSCLC were treated with single-agent neratinib (240 mg po daily). Prior EGFR tyrosine kinase inhibitors (TKIs), chemotherapy, and checkpoint inhibitors (IO) were allowed. Patients with stable, asymptomatic CNS metastasis were enrolled. Study endpoints: objective response rate (ORR) at week 8 (±1 week); ORR (RECIST 1.1 confirmed); duration of response (DOR); clinical benefit rate (CBR); progression-free survival (PFS); safety; biomarkers. Results: Baseline characteristics of 11 patients with EGFR exon 18-mutant NSCLC: median age 67 (range 56–83) years; ECOG PS 0/1 (45%/55%). Prior lines of therapies: 2 (range 1–3): EGFR TKIs (91%); chemotherapy (55%); IO (27%). 3/11 patients had baseline CNS metastasis and received radiation 8–22 months prior to study enrollment. Best CNS response in these 3 patients was stable disease with overall individual PFS of 1.9 (censored), 6.9 and 9.1 months and OS of 2.6 (censored), 17.7 (censored), and 17.9 months. Efficacy is summarized in Table. Efficacy summary: TKI-pretreated EGFR exon 18-mutant NSCLC cohort receiving neratinib monotherapy. Conclusions: Activity of single-agent neratinib was observed in prior TKI-exposed patients with EGFR exon 18-mutant NSCLC. Despite the small sample size of only 3 patients with baseline CNS metastases, findings suggest a potential role for neratinib as a systemic treatment option for patients with NSCLC and difficult-to-treat uncommon mutations with CNS involvement. The SUMMIT trial continues to enroll patients with EGFR exon 18-mutant NSCLC. Clinical trial information: NCT01953926. [Table: see text]