Citations

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer address all aspects of management for breast cancer. The treatment landscape of metastatic breast cancer is evolving constantly. The therapeutic strategy takes into consideration tumor biology, biomarkers, and other clinical factors. Due to the growing number of treatment options, if one option fails, there is usually another line of therapy available, providing meaningful improvements in survival. This NCCN Guidelines Insights report focuses on recent updates specific to systemic therapy recommendations for patients with stage IV (M1) disease.

LBA520 Background: I-SPY 2 is a multicenter trial using response-adaptive randomization within biomarker subtypes including MammaPrint (MP) risk to evaluate novel neoadjuvant agents in high-risk breast cancer. Oral paclitaxel and encequidar (OPE) is an oral combination of paclitaxel (P) with a p-glycoprotein pump inhibitor, encequidar, to enhance gastrointestinal (GI) absorption. Dostarlimab (D) is an anti-PD-1 monoclonal antibody. Methods: Women with tumors ≥ 2.5cm and MP high-risk cancers were screened and treated starting Oct 5, 2020. Treatment included Oral Paclitaxel 205mg/m2 and encequidar 12.9 mg on days 1-3, Carboplatin (Cb) AUC 1.5 on day 1 weekly x 12, and Dostarlimab (D) 500 mg every 3 weeks x 4, followed by doxorubicin/ cyclophosphamide (AC) every 2-3 weeks x 4. The control arm was IV P weekly x 12 followed by AC every 2-3 weeks x 4. For patients with HER2+ disease, weekly Trastuzumab (T) was administered during the first 12 weeks. The arm was eligible for graduation [> 85% chance of success in a 300-person phase 3 neoadjuvant trial with a pathologic complete response (pCR) endpoint] in 10 predefined signatures. Results: 106 patients (44 HR+HER2-, 56 HR-HER2- (TN), 6 HER2+) received OPE/Cb/D ± T. The control arm included 388 historical controls (201 HR+HER2-, 156 TN, 31 HER2+). 22 patients (20 HR+, 2 HR-) in OPE/Cb/D were MP1 (MP high) and 84 patients (29 HR+, 55 HR-) were MP2 (MP ultra-high). OPE/Cb/D graduated in the TN signature and accrual was stopped. Conclusions: OPE/Cb/D graduated in the TN signature with a higher predicted pCR rate compared to control. OPE and D have been, individually, shown to have efficacy in other settings. The lower-than-expected pCR rate and lower irAEs with triplet therapy (taxane, platinum, immune checkpoint inhibitor [ICI]) in TN compared to prior IV chemo + ICI arms on I-SPY 2 suggests a possible interference of OPE with ICI. Changes in gut microbiome is being investigated as an explanation. Clinical trial information: NCT01042379 . [Table: see text]

Abstract Background: The ATEMPT trial primary analysis found that one year of adjuvant trastuzumab emtansine (T-DM1) achieved a 3-year iDFS of 97.8% for patients with stage I HER2+ breast cancer, but was not associated with fewer clinically relevant toxicities (CRTs) compared with paclitaxel and trastuzumab (TH). In this end-of-study analysis, we report 5-year survival outcomes and correlative analyses from the trial. Methods: Patients with stage I centrally confirmed HER2+ breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for one year or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or paclitaxel 80 mg/m2 IV with weekly trastuzumab IV followed by trastuzumab for 9 months. The co-primary objectives were to compare the incidence of CRTs between the 2 arms and to evaluate iDFS in patients receiving T-DM1. To investigate proteomic correlates of recurrence, spatial proteomic analyses were performed on samples from 13 patients experiencing iDFS events (cases) and 24 matched controls using the NanoString GeoMx Digital Spatial Profiler. The impact of HER2 heterogeneity on outcomes was investigated among 17 cases and 51 matched controls by fluorescence in-situ hybridization (FISH). HER2 genetic heterogeneity was assessed by scrutinizing the whole tumor area and defined as the occurrence of HER2 gene amplification in >5% but < 50% invasive tumor cells. The risk of recurrence was evaluated centrally with the HER2DX genomic assay from 225 primary tumor samples. Germline whole genome sequencing (WGS) was conducted among 55 patients experiencing T-DM1-induced thrombocytopenia and/or bleeding and 55 matched controls to identify genomic correlates for this side effect. Results: A total of 497 patients who initiated protocol therapy were included in this analysis (383 T-DM1 and 114 TH). After a median follow up 5.8 years, among patients receiving T-DM1 there were a total of 11 iDFS events, with 3 distant recurrences. The 5-year iDFS for T-DM1 was 97.0% (95% CI, 95.3-98.8%), the 5-year recurrence-free interval (RFI) was 98.6% (95% CI: 97.4-99.8%) and the 5-year overall survival (OS) for T-DM1 was 97.8 % (95% CI, 96.3-99.3%). Although the study was not powered to evaluate the efficacy of TH, among the 114 patients receiving TH, a total of 9 iDFS events were observed, including 2 distant events; the 5-year iDFS with TH was 91.3% (95% CI: 86.0-96.9%), 5-year RFI was 93.3% (95% CI: 88.6-98.2%) and 5-year OS was 97.9% (95% CI: 95.2-100%). A total of 56 samples were evaluable for heterogeneity analyses, among which 14% (n=8) harbored HER2 genetic heterogeneity. Spatial proteomic analyses found that NF1 (adjusted p=0.72 × 10-6) and CTLA-4 (adjusted p=0.15 × 10-3) were significantly upregulated in primary samples from cases, while cleaved caspase 9, CD25, GITR, ICOS, p53 and PD-L2 were significantly upregulated in controls (all with adjusted p< 0.05). Germline WGS found that the top gene associations with thrombocytopenia and thrombocytopenia or bleeding were ALMS1 (p=0,19 × 10-3) and APBA3 (p=0,23 × 10-3), respectively, although none reaching the threshold for genome wide significance. rs62143195 and rs114169776 were the top single nucleotide polymorphisms associated with thrombocytopenia and thrombocytopenia or bleeding, respectively. Data on the impact of HER2 heterogeneity and of HER2DX score on survival outcomes will be presented. Conclusion: With longer follow-up, adjuvant T-DM1 confirmed outstanding long-term outcomes among patients with stage I HER2+ breast cancer, demonstrating a 5-year RFI of 98.6%. Spatial proteomic analyses identified a potential association between NF1 and CTLA-4 expression with recurrence. Details on the impact of HER2 heterogeneity and HER2DX assay on prognosis will be presented. Citation Format: Paolo Tarantino, Nabihah Tayob, Chau T Dang, Denise Yardley, Steven J. Isakoff, Vicente Valero, Meredith Faggen, Therese Mulvey, Ron Bose, Douglas Weckstein, Antonio C. Wolff, Katherine Reeder-Hayes, Hope Rugo, Bhuvaneswari Ramaswamy, Dan Zuckerman, Lowell Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit Cheng, Audrey Merrill Garrett, Paul K. Marcom, Kathy S. Albain, Patricia DeFusco, Nadine Tung, Blair Ardman, Rita Nanda, Rachel C. Jankowitz, Mothaffar Rimawi, Vandana Abramson, Paula R. Pohlmann, Catherine Van Poznak, Andres Forero-Torres, Minetta C. Liu, Kathryn Ruddy, Yue Zheng, Romualdo Barroso-Sousa, Adrienne Waks, Michelle K. DeMeo, Molly K. DiLullo, Giuseppe Curigliano, Harold Burstein, Ann Partridge, Eric Winer, Giuseppe Viale, Winnie Hui, Elizabeth A. Mittendorf, Bryan P. Schneider, Aleix Prat, Ian Krop, Sara Tolaney. Adjuvant Trastuzumab Emtansine Versus Paclitaxel plus Trastuzumab for Stage I HER2+ Breast Cancer: 5-year results and correlative analyses from ATEMPT (TBCRC033) [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 PD18-01.

Abstract Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR). Cemiplimab (Cemi) is a PD-1 inhibitor approved for the treatment of NSCLC, cutaneous basal, and squamous cell cancer. Here, we report current efficacy rates of Cemi in combination with paclitaxel followed by AC. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment; HR positive (HR+) patients had to be MP high risk. Treatment included paclitaxel 80 mg/m2 IV weekly x 12 and Cemi 350 mg IV given q3weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. All patients undergo serial MRI imaging; and imaging response (at 3 weeks, 12 weeks and prior to surgery) were used along with accumulating pCR data to continuously update and estimate pCR rates for trial arms. Analysis was modified intent to treat. Patients who switched to non-protocol therapy count as non-pCR. The goal is to identify (graduate) regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 neoadjuvant trial with a pCR endpoint within responsive signatures. Cemi was eligible to graduate in 3 pre-defined signatures: HER2-, HR-HER2-, and HR+HER2-. To adapt to changing standard of care, we constructed “dynamic controls” comprising ‘best’ alternative therapies using I-SPY 2 and external data and estimated the probability of Cemi being superior to the dynamic control. Results: 60 HER2- patients (28 HR+ and 32 HR-) received Cemi arm treatment. The control group included 357 patients with HER2- tumors (201 HR+ and 156 HR-) enrolled since March 2010. Cemi graduated in HR-/HER2- signature. Estimated pCR rates (as of June 2022) are summarized in the table. Immune-related endocrine disorders include: hypothyroid (14.5%), adrenal insufficiency (10%), hyperthyroid (4.8%),) and thyroiditis (3.2%). Only one grade 3 adrenal insufficiency was observed. All immune related AE’s were manageable. Additional biomarker analyses are ongoing and will be presented at the meeting. Response predictive subtypes (Immune+ vs Immune-) and additional predictive biomarkers were assessed. Associations with pCR will be presented at SABCS. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial. Anti-PD-1 therapy with Cemi resulted in a higher predicted pCR rate in HR-/HER2- 55 rate% disease compared to control at 29%. Immune-mediated AE’s were observed. This data is consistent with previously published data using check point inhibitors in early-stage HR-/HER2- breast cancer. Estimated pCR rates Citation Format: Erica Stringer-Reasor, Rebecca A. Shatsky, Jo Chien, Anne Wallace, Judy C. Boughey, Kathy S. Albain, Hyo S. Han, Rita Nanda, Claudine Isaacs, Kevin Kalinsky, Zahi Mitri, Amy S. Clark, Christos Vaklavas, Alexandra Thomas, Meghna S. Trivedi, Janice Lu, Smita Asare, Ruixiao Lu, Maria Pitsouni, Amy Wilson, Jane Perlmutter, Hope Rugo, Richard Schwab, W. Fraser Symmans, Nola M. Hylton, Laura Van ’t Veer, Douglas Yee, Angela DeMichele, Donald Berry, Laura J. Esserman, I-SPY Investigators. PD11-01 Evaluation of the PD-1 Inhibitor Cemiplimab in early-stage, high-risk HER2-negative breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL [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 PD11-01.

Abstract Background. Patient-reported outcomes (PROs) are increasingly recognized as a valuable component to understand treatment tolerability and toxicity among patients on clinical trials. We have implemented a system for monitoring patient reported outcomes (PROs), symptoms, and quality of life (QOL) using electronic PRO (ePRO) instruments for patients enrolled in the I-SPY2 trial. I-SPY2 is a phase II multi-site clinical trial evaluating the effect of novel neoadjuvant therapies for locally advanced breast cancer. We correlated patient demographic factors with symptoms, investigated the trajectory of symptoms throughout treatment, and sought to characterize symptoms associated with decline in physical function (PF). Methods. Our study population included 259 I-SPY2 patients that completed surveys on one of 9 study arms (including novel oral taxane/immunotherapy combinations, IV paclitaxel, checkpoint inhibitor+/- LAG3 inhibitor, and control IV paclitaxel +/- trastuzumab/pertuzumab). After the 12 week period of investigational agents, most patients received standard adriamycin and cyclophosphamide (AC). Symptom severity, frequency, and interference was assessed weekly using 33 items from the PRO-CTCAE item bank. PF was assessed using the NIH PROMIS instrument and was evaluated at baseline, inter-regimen (after 12 weeks of treatment), pre-surgery, and 1 and 6 months at follow-up. An odds ratio was used to assess univariate associations between age and race, and symptoms. Regularized multi-variate regression was used to evaluate early symptoms (prior to week 6) predictive of a clinically significant (>5 point T-score) decline in PF from baseline to post-treatment follow-up among all races and age groups. Results. Of 259 patients (mean age (SD) = 46.8 (13.6)), 160 (58%) were White, 13 (5%) were Asian, 26 (10%) were African American (AA), 25 (9.3%) were Hispanic, and 35 (13.5%) self-reported “Other”. At baseline, AA patients had a higher severity of joint pain than White patients (OR = 14.9, P < 0.05). During study treatment with paclitaxel and/or novel agent within the first 12 weeks of treatment, AA patients and non-white (NW) patients were more likely to report severe vomiting than White patients (OR =13.22 and 12.72, P< 0.05 and P< 0.03 respectively). During treatment with AC, NW patients were more likely to report higher severity of neuropathy than White patients (OR = 5.43, P< 0.03). Among all patients, in analysis of early symptoms predictive of a clinically significant decline in PF between baseline and 1 month post treatment, predictors included high frequency of diarrhea, severity of itching, and severity of joint pain. Further analysis of symptom trajectories revealed that frequency of diarrhea reported rose sharply between baseline and Cycle 2 with 9 patients (7%) reporting occasional or frequent diarrhea to 39 patients (28%) reporting occasional to almost constant diarrhea and remained stable at that proportion for the remainder of treatment. Frequency of diarrhea declined slightly during AC (17%) and dropped to baseline levels by follow-up. In contrast, severity of joint pain persisted post-treatment, rising consistently from baseline through follow- up with 3 patients (2%) reporting moderate to severe joint pain at baseline to 18 patients (35%) reporting moderate to severe joint pain at follow-up. Conclusion. Among I-SPY2 participants, when higher grade of diarrhea is persistent (or uncontrolled), it impacts physical function even after end of therapy. In some cases, race was also a determinant in symptom trajectory, although a higher enrollment of AA and NW patients will enable more robust estimates to be computed. While some of these early symptom predictors are transient and resolve by the time of follow-up, others persist long-term and contribute more directly towards impaired physical function at follow-up. Citation Format: Amrita Basu, Saumya Umashankar, Kaylee Blevins, Anna Northrop, Anika Christofferson, Ebunoluwa Olunuga, Jaeyoon Cha, Ananya Mittal, Julissa Molina-Vega, Laura Sit, Thelma Brown, Bev Parker, Diane Heditsian, Susie Brain, Carol Simmons, Alessandra Taboada, Tina J. Hieken, Kathryn Ruddy, Carolina Salvador, Candace Mainor, Anosheh Afghahi, Sarah Tevis, Anne Blaes, Irene M. Kang, Jane Perlmutter, Hope Rugo, Sai Kanaparthi, Garry Peterson, Lisa T. Weiss, Adam Asare, Laura J. Esserman, Michelle Melisko, Dawn Hershman. The Association Between Symptom Severity and Physical Function among Participants in I-SPY2 [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 P5-07-03.

Abstract Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR). Cemiplimab is an anti-PD-1 inhibitor approved for the treatment of NSCLC and cutaneous basal and squamous cell CA. Lymphocyte activation gene 3 (LAG-3) binds MHC class II leading to inhibition of T-cell proliferation and activation and is often co-expressed with PD-1. REGN3767 is a fully humanized mAb that binds to LAG-3 and blocks inhibitory T-cell signaling. Concurrent blockade of LAG-3 with an anti-PD-1 may enhance efficacy of an anti-PD-1. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment; HR positive (HR+) patients had to be MP high risk. Treatment included Paclitaxel 80 mg/m2 IV weekly x 12 and Cemiplimab 350 mg and REGN3767 1600 mg both given q3weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. Cemiplimab/REGN3767 was eligible to graduate in 3 of 10 pre-defined signatures: HER2-, HR-HER2-, and HR+HER2-. The statistical methods for evaluating I-SPY 2 agents has been previously described. To adapt to changing standard of care, we constructed “dynamic controls” comprising ‘best’ alternative therapies using I-SPY 2 and external data and estimated the probability of Cemiplimab/REGN3767 being superior to the dynamic control. Response predictive subtypes (Immune+ vs Immune-) were assessed using pre-treatment gene expression data and the ImPrint signature. Results: 73 HER2- patients (40 HR+ and 33 HR-) received Cemiplimab/REGN3767 treatment. The control group included [357 patients with HER2- tumors (201 HR+ and 156 HR-) enrolled since March 2010. Cemiplimab/REGN3767 graduated in both HR-/HER2- and HR+/HER2- groups; estimated pCR rates (as of June 2022) are summarized in the table. Safety events of note for Cemiplimab/REGN3767 include hypothyroidism 30.8%, adrenal insufficiency (AI) 19.2%, hyperthyroidism 14.1%, pneumonitis 1.3%, and hepatitis 3.8%. All were G1/2 except for 6 (7.7%) G3 AI and 3 (3.8%) G3 colitis. Rash occurred in 62.8%, 9% G3 and 2 pts (2.6%) had pulmonary embolism. X% of adrenal insufficiency cases required replacement therapy. 40 patients (11 HR+ and 29 HR-) in Cemiplimab/REGN3767 were predicted Immune+; 32 (29 HR+ and 3 HR-) were predicted Immune-. In the HR+ group pCR was achieved in 10/11 (91%) patients with Immune+ subtype compared with 8/29 (28%) with Immune- subtype. Additional biomarker analyses are ongoing and will be presented at the meeting. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial. Dual immune blockade with a LAG-3 inhibitor and anti-PD1 therapy resulted in a high predicted pCR rate both in HR-/HER2- (60%) and HR+/HER2- (37%) disease. The novel Imprint signature identified a group of HR+ patients most likely to benefit from this active regimen. Table 1: Estimated pCR rates Citation Format: Claudine Isaacs, Rita Nanda, Jo Chien, Meghna S. Trivedi, Erica Stringer-Reasor, Christos Vaklavas, Judy C. Boughey, Amy Sanford, Anne Wallace, Amy S. Clark, Alexandra Thomas, Kathy S. Albain, Laura C. Kennedy, Tara B. Sanft, Kevin Kalinsky, Hyo S. Han, Nicole Williams, Mili Arora, Anthony Elias, Carla Falkson, Smita Asare, Ruixiao Lu, Maria Pitsouni, Amy Wilson, Jane Perlmutter, Hope Rugo, Richard Schwab, W. Fraser Symmans, Nola M. Hylton, Laura Van’t Veer, Douglas Yee, Angela DeMichele, Donald Berry, Laura J. Esserman, I-SPY Investigators. Evaluation of anti-PD-1 Cemiplimab plus anti-LAG-3 REGN3767 in early-stage, high-risk HER2-negative breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL [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 GS5-03.

Abstract Background Adjuvant abemaciclib (a CDK4 and 6 inhibitor) combined with ET resulted in significant and clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in patients (pts) with HR+, HER2-, node-positive, high risk EBC in the monarchE trial, and is an approved adjuvant therapy for these patients. Here we present efficacy results from a pre-specified overall survival interim analysis (OS IA2) which was planned to occur 2 years (yrs) after the primary outcome analysis. Methods Pts were randomized (1:1) to receive ET for up to 10 yrs +/- abemaciclib for 2 yrs (study treatment period). High-risk EBC was defined as either ≥4 positive axillary lymph nodes (ALN), or 1-3 ALN with either Grade 3 disease and/or tumor ≥5 cm (Cohort 1). While the proliferation biomarker Ki-67 was centrally assessed in all pts with available tissue sample, an additional smaller group of pts with 1-3+ ALN and central Ki-67 ≥20% as the only high-risk feature were included (Cohort 2). The intent-to-treat (ITT) population consisted of both Cohort 1 (5120 pts) and Cohort 2 (517 pts). Hazard ratios (HR) were estimated using Cox proportional hazard model. Results At a median follow-up of 42 months, all pts were off abemaciclib. IDFS and DRFS data illustrate a sustained benefit beyond the treatment period. In the ITT population, the HR for IDFS was 0.664 (95% CI: 0.578, 0.762) and DRFS was 0.659 (95% CI: 0.567, 0.767). At 4 yrs, this reflected an improvement in IDFS rates from 79.4% to 85.8% (absolute difference 6.4%), and in DRFS rates from 82.5% to 88.4% (absolute difference 5.9%). The continued separation of the curves was associated with an increase in absolute benefit in IDFS 4-year rates compared to 2-and 3-year IDFS rates (absolute difference 2.8% and 4.8% respectively). While OS remained immature, there was a lower number of deaths observed in the abemaciclib plus ET arm compared to the ET alone arm (157 [5.6%] vs 173 [6.1%], HR 0.929 [95% CI: 0.748, 1.153], p = 0.503), suggesting that the robust benefit in IDFS and DRFS began to translate into a numerically favorable OS HR. As previously described, within Cohort 1, a Ki-67 index of ≥20% was associated with a worse prognosis, but similar abemaciclib treatment effects were observed regardless of Ki-67 index. No new safety signals were observed. Conclusion The clinically meaningful benefit of adjuvant abemaciclib added to ET in HR+, HER2-, node-positive, high-risk EBC persists beyond completion of abemaciclib therapy, yielding an increase in absolute IDFS and DRFS benefit at 4 yrs. While OS remains immature at this time, the lower number of deaths in the abemaciclib arm compared to the ET arm suggest that a survival signal favoring abemaciclib is emerging. Citation Format: Stephen Johnston, Masakazu Toi, Joyce O’Shaughnessy, Priya Rastogi, Mario Campone, Patrick Neven, Chiun Sheng Huang, Jens Huober, Georgina Garnica Jaliffe, Irfan Cicin, Sara Tolaney, Matthew P. Goetz, Hope Rugo, Elżbieta Senkus, Laura Testa, Lucia Del Mastro, Chikako Shimizu, Ran Wei, Ashwin Shahir, Maria Munoz, Belen San Antonio, Valerie Andre, Nadia Harbeck, Miguel Martín. Abemaciclib plus endocrine therapy for HR+, HER2-, node-positive, high-risk early breast cancer: results from a pre-planned monarchE overall survival interim analysis, including 4-year efficacy outcomes [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 GS1-09.

The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. These NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of ductal carcinoma in situ and the workup and locoregional management of early stage invasive breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org .

Abstract Background: We compared the predictive and prognostic value of ctDNA dynamics in high-risk hormone receptor-positive/HER2-negative (HR+/HER2-) and triple negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAC) enrolled in the I-SPY 2 trial (NCT01042379). To our knowledge, this is the largest ctDNA study in breast cancer in the neoadjuvant setting. Methods: Blood samples were collected at pre-treatment (T0), during treatment (T1 at 3 weeks, and T2 at 12 weeks) and after NAC (T3 at 24 weeks) from 106 HR+/HER2- and 97 TNBC patients. Plasma samples (n=734) were analyzed using a personalized and tumor-informed mPCR NGS-based ctDNA test (SignateraTM). Patients, all high risk for recurrence by MammaPrint, received paclitaxel-based treatment +/- experimental therapy followed by anthracycline. The median follow-up was 3.0 years (0.5 to 6.5). The predictive and prognostic value of ctDNA dynamics and status at different timepoints were examined. Our analysis is exploratory and does not adjust for other biomarkers. Results: Pretreatment ctDNA positivity (Fisher p<0.0001) and levels (mean tumor molecules/mL, MTM/mL, t test p=0.0062) were significantly higher in TNBC (90.7%, 14.7 MTM/mL) than in high risk HR+/HER2- (66.0%, 5.5 MTM/mL). Early and late ctDNA clearance during treatment (3 and 12 weeks of NAC) was predictive of pathologic complete response (pCR) and residual cancer burden (RCB), class 0-III, in TNBC but not HR+/HER2- (Table). In both subtypes: (1) ctDNA was a significant negative prognostic factor for distant recurrence-free survival (DRFS) at all timepoints (p<0.05) except at pretreatment; (2) all patients who achieved pCR were ctDNA-negative after NAC; (3) among non-responding patients, ctDNA-negativity after NAC was associated with improved DRFS (Table). Conclusions: The predictive value of ctDNA for prediction of pCR and RCB differed between subtypes (HR+/HER2- vs. TNBC), while similar prognostic value was observed. In TNBC, early clearance of ctDNA at 3 weeks was a significant predictor of favorable response to NAC. Compared to patients who were ctDNA-positive after NAC, ctDNA-negative status in both subtypes was associated with improved DRFS even in patients with residual cancer (no pCR or RCB-II/III). These findings could inform on the design of future studies that seek to demonstrate the utility of ctDNA in the curative setting. Predictive and prognostic significance of ctDNA in early breast cancer in the neoadjuvant setting HR+HER2- (n=106) TNBC (n=97) Predictive value for prediction of pCR and RCB Fisher p-value Fisher p-value Early ctDNA clearance (between T0 and T1) and pCR 0.4521 <0.0001 Late ctDNA clearance (between T0 and T2) and pCR 0.8071 0.0004 Early ctDNA clearance (between T0 and T1) and RCB (0-III) 0.1360 <0.0001 Late ctDNA clearance (between T0 and T2) and RCB (0-III) 0.4869 0.0004 Early ctDNA clearance at T1 and pCR rates pCR rate pCR rate ctDNA clearance (ctDNA+ at T0/ctDNA- at T1) 21% 67% Late ctDNA clearance (betweeNo early clearance (ctDNA+ at T0/ctDNA+ at T1) 13% 14% Prognostic value for prediction of DRFS Log rank p-value Log rank p-value ctDNA at T3 and pCR vs no PCR 0.0002 <0.0001 ctDNA at T3 and RCB (0-I vs II-III) 0.0110 <0.0001 Timepoints: T0 - pretreatment; T1 - three weeks after treatment initiation; T2 - at 12 weeks, between paclitaxel-based and anthracycline regimens; T3- after neoadjuvant chemotherapy prior to surgery Citation Format: Mark Jesus Mendoza Magbanua, Lamorna Brown Swigart, Derrick Renner, Svetlana Shchegrova, Gillian L. Hirst, Christina Yau, Denise M. Wolf, Hsin-Ta Wu, Ekaterina Kalashnikova, Amy L. Delson, A. Jo Chien, Debu Tripathy, Smita Asare, Raheleh Salari, Angel Rodriguez, Bernhard Zimmermann, Himanshu Sethi, Alexey Aleshin, Paul Billings, Rita Nanda, Hope S. Rugo, Laura J. Esserman, Minetta C. Liu, Angela DeMichele, Laura van 't Veer. Comparison of the predictive and prognostic significance of circulating tumor DNA in patients with high risk HER2-negative breast cancer receiving neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB111.

The NCCN Guidelines for Hematopoietic Growth Factors provide recommendations for the appropriate use of growth factors in the clinical management of febrile neutropenia (FN), chemotherapy-induced thrombocytopenia (CIT), and chemotherapy-induced anemia (CIA). Management and prevention of these sequelae are an integral part of supportive care for many patients undergoing cancer treatment. The purpose of these guidelines is to operationalize the evaluation, prevention, and treatment of FN, CIT, and CIA in adult patients with nonmyeloid malignancies and to enable the patient and clinician to assess management options for FN, CIT, and CIA in the context of an individual patient’s condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for Hematopoietic Growth Factors, with particular emphasis on the incorporation of a newly developed section on CIT.