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Systemic therapy for both early-stage and metastatic human epidermal growth factor receptor-2-positive (HER2+) breast cancer has seen significant evolution over the last 20 or more years. Innovative trials leveraging the prognostic and predictive information that neoadjuvant chemotherapy provides has led to preoperative systemic therapy becoming the overwhelmingly favored sequencing in the early-stage setting. However, deintensification of therapy is important to consider for patients with good-risk disease or significant comorbidities. Finally, with the abundance of newly approved agents, drug sequencing in the second-line setting has become an important and individualized decision for patients with metastatic disease.

Supplementary Figure 1: Trial Enrollment Schema Supplementary Figure 2: Kaplan Meier Curve Among Patients Receiving Palbociclib and Paclitaxel

KM Curves

Purpose:The CDK 4/6 inhibitor palbociclib rapidly and reversibly inhibits the cell cycle. The goal of this study was to exploit the cell cycle through intermittent, alternating dosing with palbociclib/paclitaxel to enhance efficacy. We determined the combination dose-limiting toxicity (DLT) in patients with Rb protein–expressing, advanced breast cancer.Patients and Methods:This open-label, phase I trial (NCT01320592) enrolled patients to sequential cohorts of palbociclib orally dosed intermittently between days 1 and 19 of a 28-day cycle alternating with weekly paclitaxel. Dose escalation proceeded in a standard 3 + 3 design. Ten additional patients received the combination at the recommended phase II dose (RP2D). Those who reached response plateau ≥6 cycles could continue on palbociclib alone on a 3 week on/1 week off schedule at one dose level above their combination dose.Results:Twenty-seven patients enrolled. Although there was only 1 DLT (grade 3 alanine aminotransferase/aspartate aminotransferase at 125 mg), neutropenia (NTP) requiring dose modification in cycle 1 (C1) resulted in an RP2D of 75 mg palbociclib/80 mg/m2 paclitaxel. During C1, the most common adverse event was NTP, occurring in 15 patients (55.6%); grade 1 or 2 nausea and peripheral neuropathy were also observed in 8 patients each (29.6%). The clinical benefit rate was 55% at the RP2D; benefit was observed across all receptor subtypes.Conclusions:Alternating sequential palbociclib/paclitaxel in patients with Rb+ advanced breast cancer is feasible and safe, without evidence of additive toxicity. This represents a new application for CDK 4/6 inhibitors in Rb+ breast cancer regardless of subtype; efficacy trials are warranted.

Dose Cohort Scema

Background Although patients with clinical response of hormone receptor-positive (HR+)/HER2-negative breast cancer (BC) frequently respond to neoadjuvant therapy, fewer than 10% of patients achieve a pathologic complete response (pCR) with standard chemotherapy or endocrine therapy, even in combination with targeted agents such as CDK4/6 inhibitors. Thus, finding more effective therapies for this disease remains an area of unmet need. HER2 amplification is a known driver of endocrine resistance and HER2 may be expressed at a low level (IHC 1+ or 2+) in up to 60% of HR+ BC. Trastuzumab deruxtecan (DS-8201a, T-DXd) is a novel HER2-targeting antibody drug conjugate (ADC) that is FDA approved for HER2-positive metastatic BC and has demonstrated promising clinical efficacy in HER2-low BC with an objective response rate of ~37%. The aim of TALENT (TRIO-US B-12) is to evaluate the clinical activity and toxicity of neoadjuvant T-DXd either alone or in combination with endocrine therapy in patients with HR+/HER2-low early BC. Methods TRIO-US B-12 TALENT (NCT04553770) is an ongoing randomized, multicenter, open-label, two-stage, phase II neoadjuvant trial for participants with early stage, HR+, HER2-low expressing (1+ or 2+ by IHC) BC. Eligible participants include men and women with previously untreated, operable invasive BC greater than 2.0 cm (cT2) in size. Pts with recurrent or metastatic BC, or inflammatory BC are excluded. Pts are randomized 1:1 to receive six cycles of T-DXd (5.4 mg/kg IV q21 days) either alone or in combination with anastrozole AI (1 mg PO QD). Men and pre/peri menopausal women randomized to the AI arm also receive standard of care GnRH agonist. Stratification factors include HER2 expression (1+ or 2+) and menopausal status (men stratified as post-menopausal). Tumor tissue is taken at baseline, cycle 1 day 17-21, and at surgery. Blood samples are taken at four time points for biomarker analysis. The primary endpoint is pCR rate (breast and lymph node) at definitive surgery. In stage I, 58 participants will be randomized (29/arm). If ≥2 participants in an arm achieve pCR, that arm will expand (stage II) to enroll an additional 15 participants (total of 44/arm). A pCR rate of >10% (5/44) would be considered favorable, warranting further evaluation of the treatment in a larger trial. Other endpoints include safety, changes in Ki67 expression, Residual Cancer Burden index, biomarker analysis (including serial cfDNA analysis), and health-related quality of life. As of June 2021, sixteen participants have enrolled. Conclusions To our knowledge this is the first and only ongoing study evaluating T-DXd with or without endocrine therapy for HR+, HER2-low breast cancer in the neoadjuvant setting. The study will shed light on clinical activity and biomarkers, which may guide larger confirmatory studies for patients with HR+, HER2-low early breast cancer. Citation Format: Sara Hurvitz, Aditya Bardia, Merry L. Tetef, Nicholas P. McAndrew, Steven Applebaum, Aashini K. Master, Maggie L. DiNome, Minna K. Lee, Evangelia Kirimis, David D. Kim, Lisa S. Wang, Kyle Greene, Vu Phan, Nihal Abdulla, David Chan, Laura M. Spring, Christine Kivork, James Chauv. Phase II neoadjuvant trial evaluating trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early stage breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-12-05.

To highlight recent practice changing clinical trials, focusing on those leading to new drug approvals, in human epidermal growth factor receptor 2-positive (HER2+) breast cancer.The improved disease-free survival of adjuvant trastuzumab emtansine (T-DM1) over trastuzumab in patients with residual disease has made neoadjuvant sequencing of therapy standard for most patients with early stage disease. In patients with metastatic HER2+ breast cancer, trastuzumab deruxtecan has recently shown dramatically improved efficacy over T-DM1. Tucatinib is an oral tyrosine kinase inhibitor with best in class blood-brain barrier penetration. Margetuximab, a novel HER2-targeted chimeric monoclonal antibody with an engineered Fc receptor designed to activate local immune response, was recently approved in heavily pretreated patients based on modest but significant improvement in progression-free survival.Patients with HER2+ breast cancer have a variety of therapeutic options in the early stage and metastatic setting. Optimal sequencing of therapy will depend on patient-specific factors such as site of tumor progression and underlying comorbidities. De-escalation of the first-line metastatic regimen may be considered in select patients with hormone positive/HER2+ breast cancer, by using endocrine therapy instead of chemotherapy in combination with HER2-targeted therapy, which may improve side effects without sacrificing efficacy.

Background: Although patients (pts) with hormone receptor-positive (HR+)/HER2-negative breast cancer (BC) frequently experience disease response to neoadjuvant therapy, fewer than 10% achieve a pathologic complete response (pCR) with standard chemotherapy or endocrine therapy, even in combination with CDK4/6 inhibitors. Thus, finding more effective therapies for this disease remains an unmet need. HER2 is expressed at a low level (IHC 1+ or 2+) in approximately 60-70% of HR+ BC. Trastuzumab deruxtecan (DS-8201a, T-DXd) is a novel HER2-targeting antibody drug conjugate (ADC) that is FDA approved in the US for HER2-positive and HER2-low metastatic BC (with boxed warnings for interstitial lung disease). However, the efficacy of T-DXd in the neoadjuvant setting is not known. The primary objective of TALENT (TRIO-US B-12, NCT04553770) is to evaluate the clinical activity and safety of neoadjuvant T-DXd alone or in combination with endocrine therapy in pts with HR+/HER2-low early BC. Methods: Men and women with previously untreated, operable invasive early stage, non-recurrent, HR+, HER2-low (IHC 1+ or 2+/ISH- by local or central review) BC measuring > 2 cm were eligible. In stage 1 of clinical trial, participants were randomized 1:1 to receive T-DXd (5.4 mg/kg IV q21 days) alone, Arm A, or in combination with anastrozole AI (1 mg PO QD), Arm B. Originally 6 cycles (cy) were given but in 02/2022, an amendment increased the number of treatment cy from 6 to 8 for newly enrolled pts, or those who had not yet had surgery. Men and pre/peri-menopausal women randomized to Arm B also received a GnRH agonist. Stratification factors were HER2 expression (1+ vs. 2+) and menopausal status (men as postmenopausal). Tumor tissue collected at baseline, cy 1 day 17-21, and at surgery. Breast imaging performed at baseline, cy 2 and pre-surgery/EOT. Primary endpoint is pCR rate (ypT0/is ypN0) at surgery. In stage 1, intent was to randomize 58 pts (if at least 2 pCR occurred in an arm, arm progresses to Stage 2 and an additional 15 pts to be enrolled). Other endpoints include safety, objective response rate (ORR), changes in Ki67 expression, Residual Cancer Burden index, exploratory biomarker analysis, and health-related quality of life. Here we present results from stage 1 of the trial. Results: From 09/21/2020 to 10/13/2022, 58 pts were enrolled and treated (29 Arm A, 29 Arm B) in stage 1 of trial. Five pts came off study before completing study therapy (2 after cy 1, 2 after cy 2, 1 after cy 3). As of data cut-off (10/05/2022), 33 pts completed study treatment and have had surgery (17 Arm A, 16 Arm B), 13 are on treatment and 7 are pending surgery; 27 pts completed 6 cy and 13 completed 8 cy. Baseline characteristics were balanced between arms. 19/58 pts were Stage IIA, 26/58 Stage IIB, 12/58 Stage IIIA, and 1/58 Stage IIIB at baseline. 46/58 pts had baseline HER2 expression (from central review) of 1+, 4/58 were 0, 6/58 were 2+, 1/58 had multicentric lesion 1+ and 2+, and 1/58 had a single lesion with 1+ and 2+. In Arm A, 1/17 pt had pCR after 8 cy, 2/17 pts had RCB-I after 6 cy (17.6% RCB 0/1). In Arm B, 1/16 pt had RCB-I after 8 cy (6.3%). The ORR for response-evaluable pts in Arm A was 75% (12/16, 1 CR, 11 PR) and in Arm B was 63.2% (12/19, 2 CR, 10 PR); 1 patient (Arm B) had PD. ILD occurred in 1 pt (1.7%), Gr 2 and resolved 11 days after stopping therapy. Most common treatment-related Grade ≥ 3 AEs in Arms A and B, respectively, include hypokalemia (1.7%, 5.2%), diarrhea (3.4%, 3.4%), neutropenia (3.4%, 1.7%), fatigue (1.7%, 3.4%), headache (3.4%, 1.7%), vomiting (3.4%, 1.7%), dehydration (1.7%, 1.7%) and nausea (3.4%, 0%). Conclusions: This is the first report of a trial evaluating neoadjuvant T-DXd in HER2 low breast cancer. T-DXd +/- endocrine therapy demonstrates promising clinical activity for pts with HR+ BC. Updated study results will be provided at the time of presentation. Citation Format: Aditya Bardia, Sara Hurvitz, Michael F. Press, Lisa S. Wang, Nicholas P. McAndrew, David Chan, Vu Phan, Deborah Villa, Merry L. Tetef, Erin Chamberlain, Nihal Abdulla, Thomas Lomis, Laura M. Spring, Steven Applebaum, Shaker Dakhil, Brian DiCarlo, David D. Kim, Evangelia Kirimis, William E. Lawler, Aashini K. Master, Kelly McCann, Edwin Hayashi, Christine Kivork, James Chauv. GS2-03 TRIO-US B-12 TALENT: Neoadjuvant trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early stage 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 GS2-03.

Background: Cardiotoxicity associated with use of trastuzumab (T) in breast cancer has been assessed in multiple studies with short-term follow up. However, long-term risk of clinical heart failure (CHF) with the use of T, either with or without anthracyclines (A), is poorly understood. Since the approval of T for use in early-stage breast cancer (ESBC) in 2006, long-term follow up data is now available in the SEER-Medicare database. Methods: We performed a retrospective cohort study in patients (pts) with ESBC identified in the SEER-Medicare database, diagnosed between 2005-2016, excluding pts with in-situ or metastatic disease at time of diagnosis or a history of CHF prior to diagnosis. Primary exposure variables were identified using HCPCS codes and included receipt of T or A. The reference baseline population used for univariate logistic regression of the primary exposure variables was pts with ESBC who received neither T nor A. For multivariate analyses, to avoid co-linearity in the final model, the exposure variables were categorized as either having or not having the exposure (i.e. with or without T, with or without A). The primary outcome variable was CHF, identified using codes 428.0-9, 402.11, 402.91 (ICD9) and I50.0-9, I110 (ICD10). Covariates used in multivariate logistic regression (MLR) included hypertension (HTN), valve disease, hyperthyroidism, diabetes (DM), emphysema, coronary artery disease (CAD), left sided radiation, age, and race. MLR models were constructed using a stepwise-up approach and confirmed using the stepwise-down method with a cutoff of p< 0.05 for inclusion in the final model. Results: A total of 244,129 pts were identified with a median follow up of 6.7 years (7.7 years in the T cohort). Median age was 68. Other demographics are listed in Table 1. Of these, 10,603 were HER2-positive (HER2+) pts who all received T and all of whom also received some form of chemotherapy. Of the HER2+ pts, 19.1% (2,026) also received A in addition to T as part of their treatment regimen. Pts who received T had significantly higher baseline rates of HTN, valve disease, hyperthyroidism, DM, emphysema, and CAD as compared to pts who did not receive T. Compared to pts who received T without A, pts who received T with A had significantly higher baseline rates of HTN, valve disease, hyperthyroidism, emphysema, and CAD with no difference in baseline rate of DM. Risk of CHF with exposure variables are summarized in Table 2. The overall rate of CHF for the entire 244,129 population was 21.3% with a rate of 20.8% in pts who did not receive any T or A (the baseline population). The rate of CHF in pts who received T without A was 19.1% (OR 0.90, 95% CI 0.85-0.95), and 29.0% for those who received T with A (OR 1.55, 95% CI 1.41-1.71). Associations of covariates of interest with risk of CHF as well as MLR models are summarized in Table 3. After adjusting for all baseline cardiac comorbidities as well as other covariates, receipt of T was associated with a reduced risk of CHF (OR 0.74, 95% CI 0.70-0.79, p< 0.001), and receipt of A remained associated with an increased risk of CHF (OR 1.19, 95% CI 1.15-1.24, p< 0.001). Conclusions: With long-term follow up, the addition of A to T significantly increased the risk of CHF over T without A (from 19.1% to 29.0%) in pts with ESBC. Additionally, pts who received T without A had a similar risk of CHF compared to the baseline population who received neither T nor A. After adjusting for potential confounders in the MLR model, T was associated with a slightly decreased overall risk of CHF, while A remained associated with an increased risk of CHF. Possible explanations for these findings include potential increased cardiac monitoring in the T population which may have led to optimization of cardiac comorbidities, which were higher in the T population at baseline. Taken together, these data indicate concern with use of T plus A in ESBC regarding the long-term development of clinical CHF; especially when non-A regimens with similar efficacy are available. Table 1: Demographics Table 2: Risk of Heart Failure with Primary Exposure Variables Table 3: Univariate and Multivariate Analyses Citation Format: Nicholas P. McAndrew, Karissa Britten, Xiaoyan Wang, Eric Yang, Sara Hurvitz, Dennis Slamon. Long-term heart failure risk of trastuzumab with or without anthracyclines in early stage breast cancer: A SEER-Medicare Database Analysis [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 P3-03-13.

Background: Patients with HER2 positive (+) breast cancer and central nervous system (CNS) metastases often have poor prognoses. DZD1516 is designed as a reversible and selective HER2 tyrosine kinase inhibitor (TKI) with full blood-brain barrier (BBB) penetration. Methods: DZD1516 is being developed in a phase 1 study (NCT04509596) in patients with HER2+ advanced or metastatic breast cancer relapsed from the standard of care. Key overall eligibility criteria were previously presented. DZD1516 was given orally twice daily (BID) in a continuous 21-day cycle (except Cycle 0). The primary objective is to evaluate the safety and tolerability of DZD1516 monotherapy and define the maximum tolerated dose (MTD). Results: As of June 23, 2022, twenty-three patients with HER2+ MBC from the USA and China were enrolled and dosed with DZD1516 monotherapy (25 mg ~ 300 mg, BID). Fifteen patients (65.2%) had baseline CNS metastases. Patients were heavily pre-treated, with a median of 7 lines of prior systemic treatment. All patients had been treated with HER2 large molecules, and 82.6% of patients also received prior HER2 TKI treatment. DZD1516 was well tolerated at doses up to 250 mg BID. Two dose-limiting toxicities were reported in the 300 mg cohort. As a result, 250 mg was defined as the MTD. Treatment-emergent adverse events (TEAEs) were reported in 91.3% of patients. Grade 3 drug-related TEAEs were reported in two patients. No grade 4 or 5 TEAEs were reported. The most common TEAEs included headache, vomiting, and hemoglobin decreased. The majority of the TEAEs could be managed and were reversible. The longest treatment duration was > 3 months. Following single oral dosing, DZD1516 was eliminated with a mean half-life of 13.4 – 22.5 hrs. After twice-daily dosing for 15 days, moderate accumulation of DZD1516 systemic exposure was observed at doses ≤ 200 mg BID and negligible accumulation at 250 mg BID. The combined molar exposure of DZD1516 and its active metabolite DZ2678 increased with dose between 50 mg to 250 mg dose range. In patients (n = 6), mean Kpuu,CSF was 2.1 for DZD1516 and 0.76 for DZ2678 across the dose range, indicating full penetration of DZD1516 and DZ2678 into human CNS. Nineteen patients (82.6%) had at least one post-treatment RECIST assessment. With a median of 7 lines of prior systemic treatment, the best antitumor efficacy in intracranial, extracranial, and overall lesions was stable disease. Conclusion: DZD1516 is a full BBB-penetrant HER2 inhibitor. Consistent with its high selectivity, no wild-type EGFR-related AEs have been reported. The updated data will be presented at the meeting. Citation Format: Nicholas P. McAndrew, Xichun Hu, Jian Zhang, Xiaojia Wang, Wenlei Yu, Xiaomei Pan. Updated data from the phase 1 trial of DZD1516, a BBB-penetrant selective HER2 inhibitor, in patients with HER2 positive metastatic 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 P4-01-23.

There are over 2 million cases a year of breast cancer, leading to over 600,000 deaths globally [1]. Despite these large numbers, increasingly more women are being cured with early stage disease and women with advanced disease are living longer [2]. The appreciation for molecular subtypes of the disease has led to significant therapeutic advances and estrogen receptor positive (ER+) breast cancer represents the largest of these subgroups. An appreciation for the importance of estrogen signaling in ER+ dates back to 1896 when Dr. George Thomas Beatson observed impressive disease responses after performing bilateral oophorectomy in 3 women at Glasgow Cancer Hospital [3]. The evolution of treatment for advanced disease from progestins, to the selective estrogen receptor modulator tamoxifen, and subsequently the aromatase inhibitors and the selective estrogen receptor degrader fulvestrant, has been accompanied by improved efficacy and decreased side effects. While the use of these drugs has changed the natural history of both early and advanced disease, it has been long recognized that many patients will develop resistance to this approach. After many years of trying to improve on single-agent endocrine treatment, since 2012 there has been an explosion of new drugs that have shown improved efficacy in combination with endocrine approaches. The first of these to receive FDA approval was the mTOR inhibitor everolimus (2012) [4], followed by the approval of 3 cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors [palbociclib (2015) [5], ribociclib (2018) [6], and abemaciclib (2018) [7]], and more recently the PI3-kinase inhibitor alpelisib (2019) [8]. In addition, chemotherapy is still used frequently when endocrine manipulations have been exhausted. Like other incurable malignancies, the goal in advanced ER+ breast cancer is to prolong survival and maintain quality of life. Currently, we have more tools available to achieve this than ever before and we will review the efficacy and side effect data with these agents that are driving physician choices for individual patients.

Background Palbociclib is highly active in oestrogen-receptor positive (ER+) metastatic breast cancer, but neutropenia is dose limiting. The goal of this study was to determine whether early neutropenia is associated with disease response to single-agent palbociclib. Methods Blood count and disease-response data were analysed from two Phase 2 clinical trials at different institutions using single-agent palbociclib: advanced solid tumours positive for retinoblastoma protein and advanced liposarcoma. The primary endpoint was PFS. The primary exposure variable was the nadir absolute neutrophil count (ANC) during the first two cycles of treatment. Results One hundred and ninety-six patients (61 breast, 135 non-breast) were evaluated between the two trials. Development of any grade neutropenia was significantly associated with longer median PFS in both the breast cancer (HR 0.29, 95% CI 0.11–0.74, p = 0.010) and non-breast cancer (HR 0.57, 95% CI 0.38–0.85, p = 0.006) cohorts. Grade 3–4 neutropenia was significantly associated with prolonged PFS in the non-breast cohort (HR 0.57, 95% CI 0.38–0.85, p = 0.006) but not in the breast cohort (HR 0.87, 95% CI 0.51–1.47, p = 0.596). Multivariate analysis yielded similar results. Conclusions Treatment-related neutropenia in the first two cycles was significantly and independently associated with prolonged PFS, suggesting that neutropenia may be a useful pharmacodynamic marker to guide individualised palbociclib dosing. Clinical trials registration information Basket Trial: NCT01037790; Sarcoma Trial: NCT01209598.

It has been over three decades since anthracyclines took their place as the standard chemotherapy backbone for breast cancer in the curative setting. Though the efficacy of anthracycline chemotherapy is not debatable, potentially life-threatening and long-term risks accompany this class of agents, leading some to question their widespread use, especially when newer agents with improved therapeutic indices have become available. Critically assessing when to incorporate an anthracycline is made more relevant in an era where molecular classification is enabling not only the development of biologically targeted therapeutics but also is improving the ability to better select those who would benefit from cytotoxic agents. This comprehensive analysis will present the problem of overtreatment in early-stage breast cancer, review evidence supporting the use of anthracyclines in the pre-taxane era, analyze comparative trials evaluating taxanes with or without anthracyclines in biologically unselected and selected patient populations, and explore published work aimed at defining anthracycline-sensitive tumor types.

While the outcomes for patients diagnosed with hormone receptor positive (HR+) and/or human epidermal growth factor receptor 2-positive (HER2+) breast cancers have continued to improve with the development of targeted therapies, the same cannot be said yet for those affected with triple-negative breast cancer (TNBC). Currently, the mainstay of treatment for the 10-15% of patients diagnosed with TNBC remains cytotoxic chemotherapy, but it is hoped that through an enhanced characterization of TNBC biology, this disease will be molecularly delineated into subgroups with targetable oncogenic drivers. This review will focus on recent therapeutic innovations for TNBC, including poly-ADP-ribosyl polymerase (PARP) inhibitors, phosphoinositide 3-kinase (PI3K) pathway inhibitors, immune checkpoint inhibitors, and cyclin-dependent kinase (CDK) inhibitors.

Chronic inflammation has been a proposed mechanism of resistance to aromatase inhibitors in breast cancer. Stratifying by HER2 status, a matched case-control study from the Wellness After Breast Cancer-II cohort was performed to assess whether or not elevated serum inflammatory biomarkers (C-Reactive protein [CRP], interleukin-6 [IL-6], and serum amyloid A [SAA]) and/or the presence of a high-risk IL-6 promoter genotype were associated with recurrence of hormone receptor positive (HR+) early breast cancer. Estrogen levels were also measured and correlated with biomarkers and disease outcomes. CRP and SAA were significantly associated with an increased risk of recurrence in the HR+/HER2− group, but not the HR+/HER2+ group. Mean serum estrogen levels were non-significantly elevated in patients who relapsed vs. non-relapsed patients. Surprisingly, high-risk IL-6 promoter polymorphisms were strongly associated with HER2+ breast cancer relapse, which has potential therapeutic implications, as elevated intracellular IL-6 has been associated with trastuzumab resistance in pre-clinical models.

Background:Cyclin dependent kinase 4/6 inhibitors (CDK 4/6i) are standard of care for hormone receptor positive, HER2 negative metastatic breast cancer (MBC), alone or in combination with endocrine therapy. Combination with paclitaxel (P) is possible with an intermittent, alternating dosing schedule in order to synchronize (sync) the cell cycle (cc) with a short burst of CDKi. To optimize this strategy, we measured cc biomarkers before, during and after a 4 day run in of ribociclib (R) in patients (pts) receiving R with P in a phase I clinical trial (NCT02599363). Methods:Eligible pts with Rb-positive MBC of any subtype and measurable disease were treated with 200, 400 or 600 mg of R on Days (D) 2-5, 9-12 and 16-19, and P 80mg/m2 on D1, 8, 15 and 22 in 28-day cycles (C). Skin biopsies, blood samples and FLT-PET CT were assessed at baseline (pre- R burst), D-3 (post R burst) and C1D1 P (after cc re-entry). Skin biopsies were analyzed for Ki-67 (Dako Santa Clara, CA), phospho-Rb (Ser807/811; Cell Signaling, Danvers, MA) and Rb (clone 1F8, Thermo Scientific, Waltham, MA) by IHC. Serum and plasma were analyzed for thymidine kinase (TK, Biovica, Sweden) and R pharmacokinetics (PK, WuXi, China) respectively.P-Rb and Rb results were binned for intensity and pattern of staining.Intensity was defined as None (0), Weak (W, 1+), Moderate (M, 2+), Strong (S, 3+). Pattern was defined as: Rare (R, 50%). SUV max was averaged over the 5 brightest lesions.Results:13 pts enrolled to the Phase I trial. Nine pts had at least 1 skin biopsy; 8 had ≥2. Five pts had at least one FLT-PET. Biomarker results are summarized in table. Ki-67 (skin) and TK and FLT (tumor) drop after 4 days of R treatment, when R PK levels are highest. Decreases in P-Rb, were less consistent, observed in 4/8 (50%) pts. While R PK levels drop after 2 days off treatment, only 2/8 (25%) subjects had higher cell cycle measurements on C1D1 compared to baseline.Conclusions:CC synchronization with intermittent dosing is possible, and allows safe administration of P. More time off R is needed for cc re-entry. Future trials should give more time off of R before P delivery. Pt ID (Dose(mg))TKi-67 (%)P-RbIntensity- PatternRbIntensity- PatternR PKR PKTK (Du/L)FLT(SUV*)LEE011(ng/mL)LEQ803(ng/mL)002 (200)B22M-FM-D002045n/a004 (200)B8M-RM-D00190311.6D-34NM-D69.612.01459.55.2C1D15M-RM-D16.96.5165310005 (200)B11M-RW-F0083212.4D-32M-RW-D83.013.8122.55.1C1D161M-FM-F17.56.18234.514.8006 (200)Bn/an/an/a009030.512.3D-3n/an/an/a15412.37429.59.6013 (200)B19M-FM-D008566.0D-33M-FW-F15815.8767.55.2007 (400)B8M-FM-D003070.5n/aD-31NM-D33230.82009.5n/a010 (400)B23M-FM-D001964.7D-30.5NM-F35929.322.74.1C1D14M-RM-D78.516.4 Citation Format: Amy Clark, Azadeh Elmi, Nicholas P. McAndrew, Paul Wileyto, Natalie Shih, Michael Feldman, Mark Rosen, Jessica Savage, Robin Holmes, Nancy Dinubile, Theresa Berger, Erin Schubert, Alice Matthai, Melissa Volpe, Payal Shah, Susan Domchek, David Mankoff, Angela DeMichele. Cell cycle synchronization: Biomarker analysis in a phase I trial of alternating ribociclib and paclitaxel in advanced breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB052.

TPS603 Background: Although patients with hormone receptor-positive (HR+)/HER2-negative breast cancer (BC) frequently respond clinically to neoadjuvant treatment, fewer than 10% achieve a pathologic complete response (pCR) with standard chemotherapy or endocrine therapy, even in combination with targeted agents such as CDK4/6 inhibitors. Thus, finding more effective therapies for this disease remains an area of unmet need. HER2 amplification is a known driver of endocrine resistance and HER2 protein may be expressed at a low level (IHC 1+ or 2+) in up to 60% of HR+ BC. Trastuzumab deruxtecan (DS-8201a, T-DXd) is a novel HER2-targeting antibody drug conjugate (ADC) that is FDA approved for HER2-positive metastatic BC and has demonstrated promising clinical efficacy in HER2-low BC with an objective response rate of ̃37%. The aim of TALENT (TRIO-US B-12) is to evaluate the clinical activity and toxicity of neoadjuvant T-DXd either alone or in combination with endocrine therapy in patients with HR+/HER2-low early BC. Methods: TRIO-US B-12 TALENT (NCT04553770) is an ongoing randomized, multicenter, open-label, two-stage, phase II neoadjuvant trial for participants with early stage, HR+, HER2-low expressing (1+ or 2+ by IHC) BC. Eligible participants include men and women with previously untreated, operable invasive BC greater than 2.0 cm (cT2) in size. Pts with recurrent or metastatic BC, or inflammatory BC are excluded. Pts are randomized 1:1 to receive six cycles of T-DXd (5.4 mg/kg IV q21 days) either alone or in combination with anastrozole (1 mg PO QD). Men and pre/peri menopausal women randomized to the anastrozole arm also receive standard of care GnRH agonist. Stratification factors include HER2 expression (1+ or 2+) and menopausal status. Tumor tissue is taken at baseline, cycle 1 day 17-21, and at surgery. Blood samples are taken at four time points for biomarker analysis. The primary endpoint is pCR rate (breast and lymph node) at definitive surgery. In stage I, 58 participants will be randomized (29/arm). If >2 participants in an arm achieve pCR, that arm will expand (stage II) to enroll an additional 15 participants (total of 44/arm). A pCR rate of >10% (5/44) would be considered favorable, warranting further evaluation of the treatment in a larger trial. Other endpoints include safety, changes in Ki67 expression, Residual Cancer Burden index, biomarker analysis (including serial cfDNA analysis), and health-related quality of life. As of January 2021, four participants have enrolled. Conclusions: To our knowledge this is the only ongoing study evaluating T-DXd with or without endocrine therapy for HR+, HER2-low breast cancer in the neoadjuvant setting. The study will shed light on clinical activity and biomarkers, which may guide larger confirmatory studies for patients with HR+, HER2-low early breast cancer. Clinical trial information: NCT04553770.

Purpose: The CDK 4/6 inhibitor palbociclib rapidly and reversibly inhibits the cell cycle. The goal of this study was to exploit the cell cycle through intermittent, alternating dosing with palbociclib/paclitaxel to enhance efficacy. We determined the combination dose-limiting toxicity (DLT) in patients with Rb protein–expressing, advanced breast cancer. Patients and Methods: This open-label, phase I trial (NCT01320592) enrolled patients to sequential cohorts of palbociclib orally dosed intermittently between days 1 and 19 of a 28-day cycle alternating with weekly paclitaxel. Dose escalation proceeded in a standard 3 + 3 design. Ten additional patients received the combination at the recommended phase II dose (RP2D). Those who reached response plateau ≥6 cycles could continue on palbociclib alone on a 3 week on/1 week off schedule at one dose level above their combination dose. Results: Twenty-seven patients enrolled. Although there was only 1 DLT (grade 3 alanine aminotransferase/aspartate aminotransferase at 125 mg), neutropenia (NTP) requiring dose modification in cycle 1 (C1) resulted in an RP2D of 75 mg palbociclib/80 mg/m2 paclitaxel. During C1, the most common adverse event was NTP, occurring in 15 patients (55.6%); grade 1 or 2 nausea and peripheral neuropathy were also observed in 8 patients each (29.6%). The clinical benefit rate was 55% at the RP2D; benefit was observed across all receptor subtypes. Conclusions: Alternating sequential palbociclib/paclitaxel in patients with Rb+ advanced breast cancer is feasible and safe, without evidence of additive toxicity. This represents a new application for CDK 4/6 inhibitors in Rb+ breast cancer regardless of subtype; efficacy trials are warranted.

e12049 Background: Triple-negative breast cancer (TNBC) is associated with a poor prognosis when compared to hormone receptor positive breast cancers. Anthracycline-based regimens (ABRs) are mainstays of treatment for non-metastatic TNBC. However, anthracyclines are associated with an increased risk of potentially life-threatening adverse effects. We sought to compare survival outcomes in patients with early TNBC treated with ABRs versus those treated with anthracycline-sparing regimens (ASRs). Methods: All patients treated for stage I-III TNBC who had undergone curative-intent surgery at a large academic medical center between January 2013-May 2018 were included in the study. Event-free survival (EFS) and disease-free survival (DFS) were the primary endpoints, with overall survival (OS) as a secondary endpoint and were defined as per standardized STEEP criteria. Kaplan-Meier, multivariable Cox regression, and log-rank tests were used to define key survival and treatment related differences between subjects treated with ABRs vs ASRs. Results: 137 patients met inclusion criteria with a median follow-up of 39 months. 21 patients (15%) recurred and 16 (12%) died. Patients treated with ABRs (n = 26, 19%) compared with ASRs (n = 111, 81%) had significantly shorter median EFS (38 months vs not-yet-reached, NYR, p < 0.001), DFS (37 months vs NYR, p < 0.001), and OS (50 months vs NYR, p < 0.001). Though patients in the ABR vs the ASR group were more likely to be node-positive (Odds Radio 3.46, p = 0.006), shorter survival estimates in the ABR group were observed after adjusting for nodal status. 27% of patients (7/26) had an anthracycline added after suboptimal response to an ASR. After adjusting for these patients, the survival findings were similar. 43 patients (31%) received a platinum containing ASR. In the platinum subgroup, ASRs were associated with longer EFS and DFS compared to ABRs, but this effect was not statistically significant in the node-positive group. No cardiac or secondary leukemic events were observed in either group. Conclusions: ABRs were associated with shorter EFS, DFS and OS, even after adjusting for certain high-risk clinical features. Larger studies are needed to identify the role of platinum containing ASRs in patients with early TNBC.

1043Background: CDK 4/6 inhibitors have been practice-changing in the treatment of metastatic breast cancer. Their activity against retinoblastoma protein positive (Rb+) breast cancer cells is medi...

Primary and recurrent retroperitoneal tumors can involve the aortoiliac vasculature. They are often considered inoperable or incurable because of the locally advanced nature of the disease or the technical aspects involved in safely resecting the lesion. Safe resection of these lesions requires experience and extensive preoperative planning for success. A retrospective database review of 76 patients with retroperitoneal tumors identified tumors involving major vascular structures in the abdomen and pelvis undergoing resection of tumor en bloc with the aortoiliac vasculature. Preoperative planning and intraoperative technical maneuvers are reviewed. Patients were followed until time of this report. Four patients with retroperitoneal tumors involving the aortoiliac vessels underwent surgery: two patients with sarcoma (one primary and one recurrent), one with metastatic renal cell carcinoma, and one with a paraganglioma. All patients had resection of the aorta and vena cava or the iliac artery and vein. Arterial reconstruction (anatomic or extra-anatomic) was performed in all cases. The patient with renal cell carcinoma also required venous reconstruction to support a renal autotransplant. Veno-venous bypass was required in one patient. Local control was achieved in 3 of 4 cases. Surgery for retroperitoneal tumors involving major vascular structures is technically feasible with appropriate planning and technique. Multiple disciplines are required, including general surgical oncology, vascular surgery, and possibly, cardiothoracic surgery.

Approximately 15-30% of breast cancers over-express the HER2/neu receptor. Historically, over-expression of HER2/neu has been identified using IHC or FISH, both of which are invasive approaches requiring tissue samples. Recent evidence has shown that some tumors identified as "negative" using these methods can respond to HER2/neu targeted therapy. Shedding of the extracellular domain (ECD) of the receptor into the circulation has led to the development of a serum test of HER2 ECD as an additional approach to probe HER2/neu overexpression. The serum test will be able to monitor the dynamic changes of HER2 status over the course of disease progression. Some studies further suggest that the serum HER2 ECD level and its change may serve as a biomarker to reflect patients' response to therapy. Yet more than 10years after the first serum HER2 ECD test was approved by the FDA, serum HER2 testing has yet to be widely used in clinical practice. In this article we will review the progress of the serum HER2 ECD test and discuss some obstacles impeding its incorporation into broad clinical practice. We will also discuss recent improvements in the sensitivity and specificity of the assay that offer some hope for the future of serum HER2 test.

Primary and recurrent retroperitoneal tumors can involve the aortoiliac vasculature. They are often considered inoperable or incurable because of the locally advanced nature of the disease or the technical aspects involved in safely resecting the lesion. Safe resection of these lesions requires experience and extensive preoperative planning for success. A retrospective database review of 76 patients with retroperitoneal tumors identified tumors involving major vascular structures in the abdomen and pelvis undergoing resection of tumor en bloc with the aortoiliac vasculature. Preoperative planning and intraoperative technical maneuvers are reviewed. Patients were followed until time of this report. Four patients with retroperitoneal tumors involving the aortoiliac vessels underwent surgery: two patients with sarcoma (one primary and one recurrent), one with metastatic renal cell carcinoma, and one with a paraganglioma. All patients had resection of the aorta and vena cava or the iliac artery and vein. Arterial reconstruction (anatomic or extra-anatomic) was performed in all cases. The patient with renal cell carcinoma also required venous reconstruction to support a renal autotransplant. Veno-venous bypass was required in one patient. Local control was achieved in 3 of 4 cases. Surgery for retroperitoneal tumors involving major vascular structures is technically feasible with appropriate planning and technique. Multiple disciplines are required, including general surgical oncology, vascular surgery, and possibly, cardiothoracic surgery.

541 Background: The Oncotype DX score is widely used to evaluate recurrence risk and potential benefit of chemotherapy in stage 1, estrogen receptor (ER) positive, Her2 negative tumors. Oncotype DX...