Santa‐Maria, Cesar A.

The NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget’s disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The panel convenes annually to update recommendations based on a review of recently published clinical trials. This selection from the NCCN Guidelines for Breast Cancer focuses on the recommendations for the management of recurrent or stage IV (M1) metastatic breast cancer. It summarizes the treatment strategies stratified by tumor biology, including hormone receptor status and HER2 expression, as well as clinical factors such as prior therapy and disease-free interval. Throughout all treatment lines, supportive care, quality of life preservation, toxicity minimization, and clinical trial participation are emphasized as integral components of patient care.

The treatment landscape of invasive early-stage and metastatic breast cancer is evolving constantly. These NCCN Guidelines Insights focus on recent updates included in the most recent version (version 5.2025) of the NCCN Guidelines for Breast Cancer specific to workup, locoregional therapy, surveillance, and systemic neoadjuvant/adjuvant therapy recommendations for invasive, nonmetastatic breast cancer.

Breast cancer is treated with a multidisciplinary approach involving surgical oncology, radiation oncology, and medical oncology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget’s 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 systemic therapy (preoperative and adjuvant) options for nonmetastatic breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org .

Abstract Background: Survival advantages with neoadjuvant chemotherapy (NACT) have been observed in patients (pts) with locally advanced breast cancer (BC) who achieve pathological complete response (pCR). Predicting risk of early recurrence in pts without pCR remains difficult. Circulating tumor DNA (ctDNA) may be a biomarker of neoadjuvant therapy response and recurrence. This study applied tumor genotyping of peripheral blood in pts with HER2− tumor BRCA-mutated (tBRCAm) BC treated with neoadjuvant niraparib. The relationship between ctDNA and tumor response was also characterized, with a focus on circulating TP53 mutant allelic frequency (MAF). Methods: Blood was collected from 21 pts enrolled in the study (NCT03329937) evaluating neoadjuvant niraparib in pts with localized HER2− tBRCAm BC. Pts received niraparib 200 mg once daily for two 28-day cycles. After 2 cycles, pts underwent surgery or received up to 6 cycles of niraparib and/or NACT prior to surgery. Blood samples were collected at screening, Cycle 1 Day 28 (C1D28), Cycle 2 Day 28 (C2D28), and pre-surgery. Ultrasound (USG) was done after each cycle and MRI after Cycle 2. Next-generation sequencing of cell-free plasma DNA was carried out using a proprietary target capture and analysis (Paweletz, Clin Cancer Res 2016). Results: ctDNA and TP53 mutations (TP53m) were detected at screening in 10/21 pts (47.6%). Across all 21 pts there was a correlation between TP53 MAF and baseline tumor stage (T) (mean [standard deviation], T1 0 [0], T2 0.05 [0.09], and T3 0.21 [0.12]; P=0.005). Linear regression modelling showed a positive correlation between tumor volume and baseline TP53 MAF (R2=0.206, P=0.0386). Baseline TP53 MAF also appeared to be associated with advanced disease stage (Table 1). Depletion of detectable TP53m from baseline was evident by C1D28 and persisted to pre-surgery (Table 2). This corresponded with decreases in tumor volume at C1D28 and further decreases at C2D28. Of 11 pts analyzed, 6 pts with >90% tumor volume decreases by MRI or USG at C2D28 had sustained TP53m depletion. Three pts had pCR; of these, 2 had sustained TP53m depletion (data unavailable for third pCR pt). Two pts with less robust tumor responses had increased pre-surgery TP53 MAF. Conclusions: We report the potential utility of ctDNA as a predictive biomarker for neoadjuvant niraparib response in pts with HER2− tBRCAm BC. Although sample size limited analysis of genes other than TP53, baseline ctDNA strongly correlated with tumor volume, and TP53 MAF was associated with tumor volume and trended towards association with disease stage. Longitudinal analysis of TP53 MAF suggested a correlation with niraparib response. Further study of ctDNA dynamics during NACT and correlation with pCR and long-term clinical outcomes is warranted. Funding: GlaxoSmithKline (GSK) study 213355; NCT03329937. Medical writing support was provided by Fishawack Indicia, part of Fishawack Health, funded by GSK. Table 1.Baseline TP53 MAF association with disease stage and subtypeTP53 MAFDisease Stage (I–III)Disease SubtypeStage IStage IIStage IIIHR+TNBC(n=8)(n=10)(n=3)(n=6)(n=15)Mean (SD)0.01 (0.02)0.07 (0.12)0.10 (0.05)0.02 (0.02)0.06 (0.10)HR, hormone receptor; MAF, mutant allelic frequency; SD, standard deviation; TNBC, triple-negative breast cancer. Table 2.TP53 MAF correlation with tumor volume decrease by ultrasound and MRIOutcomeScreeningCycle 1 Day 28 Cycle 2 Day 28 Pre-Surgeryn11997TP53 MAF, mean, (SD)0.09 (0.11)000.01 (0.02)n11112Percent change in tumor volume from baseline by MRI, mean (SD)-N/A*−72.6 (22.5)N/A*Percent change in tumor volume from baseline by ultrasound, mean (SD)-−60.8 (24.0)−80.6 (21.8)−95.9 (4.3)*MRI was only performed at Cycle 2 Day 28. MAF, mutant allelic frequency; MRI, magnetic resonance imaging; N/A, not applicable; SD, standard deviation. Citation Format: Ming Shan, Laura Spring, Minetta C Liu, Erika Hamilton, Hanna Irie, Cesar A Santa-Maria, Steven J Isakoff, James Reeves, Leif W Ellisen, Lee P Lim, Kavita Garg, Caterina Bertucci, Bin Feng, Hailei Zhang, Kaiming Sun, Julie R Graham, Erin Hofstatter, Hyo Han. Relationship between circulating tumor DNA and response to neoadjuvant niraparib in HER2-negative, BRCA-mutated 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 P5-13-21.

Abstract This study evaluated neoadjuvant niraparib antitumor activity and safety in patients with localized HER2-negative, BRCA-mutated breast cancer. Twenty-one patients received niraparib 200 mg once daily in 28-day cycles. After 2 cycles, tumor response (≥30% reduction from baseline) by MRI was 90.5% and 40.0% (6/15) of patients who only received niraparib (2–6 cycles) had pathological complete response. No new safety signals were identified and high niraparib intratumoral concentration was observed.

Abstract Background Inhibition of PD-L1 with atezolizumab combined with chemotherapy has shown acceptable safety and improved survival in patients with metastatic PD-L1 positive triple negative breast cancer (TNBC). Patients with TNBC who do not achieve a pathological complete response (pCR) to neoadjuvant chemotherapy have a high risk of disease recurrence and death. This randomized, open-label, phase 2 trial evaluates neoadjuvant carboplatin and paclitaxel with or without atezolizumab in patients with previously untreated clinical stages II and III TNBC. Methods Women aged ≥18 years with clinical stage T2-T4c, any N, M0 primary tumor by AJCC 7th edition staging TNBC; ECOG PS 0-2; and no prior systemic therapy for the indexed breast cancer were eligible. Patients were randomized in a 1:2 ratio to carboplatin AUC5 q 3 weeks x 4 + paclitaxel 80 mg/m2 q week x 12 (Arm A), or carboplatin AUC5 q 3 weeks x 4 + paclitaxel 80 mg/m2 q week x 12 + atezolizumab 1200 mg q3 weeks x 4 (Arm B). Surgery was 3-6 weeks following neoadjuvant chemotherapy. Adjuvant dose-dense doxorubicin and cyclophosphamide was administered q2 weeks with growth factor support to all patients as per routine care. pCR and tumor infiltrating lymphocyte (TIL) percentages are the co-primary endpoints. pCR-evaluable population includes all eligible women who have been randomized and received at least one dose of combination therapy, while the TIL-evaluable population includes all eligible women who have evaluable TIL percentage after one cycle of therapy. A sample size of 67 (22 in Arm A, and 45 in Arm B) provided 80% power at 1-sided alpha = 0.10 to detect a minimum of 15% difference in TIL and 29% improvement (40% vs. 69%) in pCR, respectively. Herein, we report pCR results in the per protocol modified intent-to-treat population (mITT), which includes all eligible patients who were randomized and received at least one dose of combination therapy. Results Sixty-seven patients were randomized between 8/2017 and 9/2019. Six patients randomized to Arm A withdrew consent; 2 of these received protocol therapy but are excluded from the mITT analyses as they are not evaluable because definitive pathology reports are not available. Median follow up is 6 months (range 0.3 - 12.6 months). Median age is 52 years (range 25 - 78). Forty-three (64.2%) were Caucasian and thirteen (19.4%) were African American. Twenty-five (37.3%) were pre-menopausal. 67.2% and 32.8% had stages II and III disease respectively. Nine (13.4%) had a germline mutation in either BRCA1 or BRCA2. In the mITT population, 3 of 16 patients achieved pCR in Arm A - 18.8% (95% CI 4.0%- 45.6%), versus 25 of 45 patients in Arm B - 55.6% (95% CI 40.0%-70.4%); p value 0.018. pCR in those with BRCA mutations was 50% and 80% in Arm A and Arm B, respectively. Treatment delays were observed in 9 patients (40.9%) in Arm A, and 20 (44.4%) in Arm B; dose reductions occurred in 4 patients (18.1%) in Arm A, and in 6 (13.3%) in Arm B. There were 4 SAEs in Arm A and 10 in Arm B. One patient in Arm B had grade 3 adrenal insufficiency. One patient in Arm B died from recurrent disease during the follow-up period. Conclusions: The addition of atezolizumab to neoadjuvant carboplatin and paclitaxel resulted in an increased pCR rate in patients with clinical stages II and III TNBC. However, the pCR in the control Arm A was lower than expected, possibly due to the absence of neoadjuvant anthracyclines. The high pCR rate observed in the experimental arm of this study is similar to that observed in other neoadjuvant trials utilizing anthracyclines, taxanes, and carboplatin in TNBC. Clinical trial information: NCT02883062. Citation Format: Foluso O Ademuyiwa, Feng Gao, Ina Chen, Donald W Northfelt, Robert Wesolowski, Mili Arora, Adam Brufsky, Claire Dees, Cesar A Santa-Maria, Roisin M Connolly, Jeremy Force, Alvaro Moreno-Aspitia, Sarah Larson, Elad Sharon, William Gillanders. Nci 10013 - A randomized phase 2 study of neoadjuvant carboplatin and paclitaxel, with or without atezolizumab in triple negative breast cancer (TNBC) [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 PD14-09.

Abstract Background: Niraparib is a selective poly(ADP-ribose) polymerase 1/2 inhibitor that has demonstrated antitumor activity in advanced triple-negative breast cancer (TNBC) in combination with a programmed cell death 1 inhibitor, with the greatest clinical activity seen in tumors with breast cancer susceptibility gene (BRCA) mutations. Pharmacologically, niraparib has demonstrated a wide volume of distribution and high cell membrane permeability. In breast and ovarian cancer xenograft mouse models, niraparib achieved tumor exposures that were 3.3 times greater than plasma exposure. The objective of this study is to evaluate the antitumor activity of single-agent niraparib in the neoadjuvant treatment of patients with localized, human epidermal growth factor receptor 2 (HER2)-negative, BRCA-mutated breast cancer. The relative concentration of niraparib in tumor versus plasma was also assessed. Methods: Eligible patients were ≥18 years old, with HER2-negative, BRCA-mutated (germline or somatic) resectable breast cancer with a tumor size of ≥1 cm who had not received prior treatment for the current malignancy. Patients received niraparib 200 mg once daily for 2 months. At the end of 2 months, at their treating physician’s discretion, patients proceeded directly to surgery, received additional cycles of niraparib (maximum of 6 months), or received neoadjuvant chemotherapy. The primary endpoint was tumor response rate measured by magnetic resonance imaging (MRI) after 2 months of treatment. Response was defined as a ≥30% reduction in tumor volume from baseline. Secondary endpoints included tumor response rate measured by ultrasound, quantified percent change in tumor volume measured by MRI or ultrasound, pathological complete response, and safety and tolerability. Additionally, niraparib concentrations were measured in tumor and plasma samples using qualified liquid chromatography-tandem mass spectrometry. Results: Twenty-one patients were enrolled. As of June 2019, 18 patients had both an MRI and ultrasound scan at the end of month 2 and were evaluable for response. Ten patients are currently on treatment. The median age of patients was 43 years (range, 21-73). Fourteen patients had a BRCA1 mutation, 6 patients had a BRCA2 mutation, and 1 patient had both. Fifteen patients had TNBC, and 6 patients had hormone receptor-positive disease. All 18 response-evaluable patients had a clinical response after 2 months of treatment by at least one imaging modality; no patient experienced disease progression. Tumor response rate measured by MRI after 2 months of treatment was 89% (n/N = 16/18). Results measured by ultrasound were similar, with a 94% response rate at cycle 2 (n/N = 17/18). The median percent decrease in tumor volume after 2 months of treatment was 88% (range, 26-100%) and 89% (range, 23-100%) as measured by MRI and ultrasound, respectively. In the 5 samples measured thus far, niraparib concentrations in tumor biopsies after 2 months of treatment ranged from approximately 4-131-fold higher than those in corresponding plasma samples. Efficacy and tumor concentration data for all patients will be presented at the meeting. The most common (≥10%) drug-related treatment-emergent adverse events (TEAEs) of any grade were nausea, fatigue, anemia, insomnia, and decreased appetite. The only drug-related grade ≥3 toxicity in ≥10% of patients was anemia (3 patients). Three patients had a dose reduction due to a TEAE; no patient discontinued treatment due to a TEAE. Conclusion: Niraparib was well tolerated and showed promising antitumor activity in the neoadjuvant treatment of patients with localized HER2-negative, BRCA-mutated breast cancer. Niraparib achieved 4-131-fold higher concentrations in tumor than in plasma. Clinical trial information: NCT03329937. Funding: TESARO: A GSK Company (Waltham, MA, USA) sponsored the study. Citation Format: Hyo Han, Minetta C Liu, Erika Hamilton, Hanna Irie, Cesar A Santa-Maria, James Reeves, Andre Liem, Adrianna Milillo Naraine, Julie Nangia, David Page, Meghan Duncan, Ming Shan, Yongqiang Tang, Julie R Graham, Leif W Ellisen, Steven Isakoff, Laura Spring. Pilot neoadjuvant study of niraparib in HER2-negative, BRCA-mutated resectable breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-03.

Abstract Background: Neoadjuvant chemotherapy is administered to patients with operable breast cancer to downstage the tumor to allow for less extensive surgery and to provide prognostic information about drug efficacy and risk of disease recurrence. Patients who achieve a pathological complete response (pCR) following neoadjuvant treatment have a more favorable outcome than patients with residual invasive disease. Single-agent poly(ADP-ribose) polymerase (PARP) inhibitors have clinical efficacy in BRCA-mutated breast cancer. Niraparib, a potent and selective PARP1/2 inhibitor, is approved for maintenance treatment of patients with recurrent ovarian cancer and has demonstrated strong antitumor activity in in vivo studies with BRCA1-mutant breast cancer. The objective of this study is to evaluate the antitumor activity of single-agent niraparib in the neoadjuvant treatment of patients with localized, human epidermal growth factor receptor 2 (HER2)-negative, BRCAmut breast cancer. Trial Design: This is an open-label, single-arm pilot study with a target enrollment of 20 evaluable patients. Eligible patients are those ≥18 years old with histologically-confirmed HER2-negative localized breast cancer and either a BRCA1 or BRCA2 mutation (germline or somatic) and no prior anti-cancer therapies for the current malignancy. Patients will receive 200 mg of oral niraparib once daily for 2 months, after which they may either proceed directly to surgery or receive chemotherapy at the discretion of the physician. The primary endpoint is tumor response rate based on the change in tumor volume as measured by breast MRI after 2 months of treatment with niraparib; a response is defined as ≥30% reduction of tumor volume from baseline. Secondary endpoints include pCR rate, tumor response rate based on the change in tumor volume as measured by breast ultrasound, and safety and tolerability. Data will be summarized in a descriptive nature by frequency distributions (number and percentage of patients) for categorical variables and by the mean, median, and standard deviation for continuous variables. Tumor response rate will be tabulated together with its 95% binomial exact confidence interval. Funding: TESARO, Inc., Waltham, MA, USA sponsored the study. Citation Format: Han H, Hamilton E, Irie H, Isakoff S, Jelovac D, Liem A, Liu MC, Milillo A, Nangia J, Page D, Reeves J, Santa-Maria C, Duncan M, Graham JR, Chen J, Dezube BJ, Spring L. Open-label, single-arm study evaluating the antitumor activity and safety of niraparib as neoadjuvant treatment in patients with localized, HER2-negative, BRCA-mutant breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-03-01.