Citations

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: 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.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor–positive, HER2-negative breast cancer.

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.

PURPOSE The ATEMPT trial was designed to determine if treatment with trastuzumab emtansine (T-DM1) caused less toxicity than paclitaxel plus trastuzumab (TH) and yielded clinically acceptable invasive disease-free survival (iDFS) among patients with stage I human epidermal growth factor receptor 2–positive (HER2+) breast cancer (BC). METHODS Patients with stage I centrally confirmed HER2+ BC were randomly assigned 3:1 to T-DM1 or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or T 80 mg/m 2 IV with H once every week × 12 weeks (4 mg/kg load →2 mg/kg), followed by H × 39 weeks (6 mg/kg once every 3 weeks). The co-primary objectives were to compare the incidence of clinically relevant toxicities (CRTs) in patients treated with T-DM1 versus TH and to evaluate iDFS in patients receiving T-DM1. RESULTS The analysis population includes all 497 patients who initiated protocol therapy (383 T-DM1 and 114 TH). CRTs were experienced by 46% of patients on T-DM1 and 47% of patients on TH ( P = .83). The 3-year iDFS for T-DM1 was 97.8% (95% CI, 96.3 to 99.3), which rejected the null hypothesis ( P < .0001). Serially collected patient-reported outcomes indicated that patients treated with T-DM1 had less neuropathy and alopecia and better work productivity compared with patients on TH. CONCLUSION Among patients with stage I HER2+ BC, one year of adjuvant T-DM1 was associated with excellent 3-year iDFS, but was not associated with fewer CRT compared with TH.

Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.

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: CRA is a surrogate for ovarian toxicity and associated risk of infertility and long-term menopausal symptoms. Therefore, it is important to assess and report the rate of CRA when we study a new neoadjuvant treatment regimen. In the Adjuvant Paclitaxel and Tratuzumab (APT) trial, we found that CRA rate associated with adjuvant TH (12 weeks of paclitaxel and a year of trastuzumab) for human epidermal growth factor receptor-2 (HER2)-positive breast cancer was lower than historically seen with cyclophosphamide-based regimens. The ATEMPT trial allowed a direct comparison of the CRA rate associated with TDM1 and TH. Methods: The ATEMPT trial randomized patients (pts) with Stage I HER2+ breast cancer 3:1 to T-DM1 3.6 mg/kg IV every 3 weeks (w) x17 vs. T 80 mg/m2 IV with H qw x 12 (4 mg/kg load →2 mg/kg), followed by H (6 mg/kg q3w x 13). Participants who reported that they were premenopausal at enrollment were asked to complete menstrual surveys at baseline and every 6-12 months throughout a 36 month follow-up period. For this analysis, CRA was defined as report of no menstruation within the prior six months on a survey completed 18 months after enrollment. Results: Of 512 ATEMPT enrollees, 497 began protocol therapy, 130 (26%) were premenopausal at enrollment and answered baseline menstrual questions, 42 of these 130 were excluded from the current analyses because they did not complete the 18-month survey, and 7 of the remaining 88 had received gonadotropin-releasing hormone agonist before 18 months, leaving 81 for analysis. None had undergone hysterectomy or oophorectomy. Median age was 44 (range 23-53) among the TH patients (n=20), and 46 (range 34-54) among the T-DM1 patients (n=61). On the 18-month survey, 45% of women treated with TH reported at least one one episode of menses during the prior 6 months compared to 75% of women in the T-DM1 arm (p=0.011). Among those ≤ 40 years old, 50% of TH patients and 100% of T-DM1 patients reported menstruation at that timepoint. Please see Table for additional data in subgroups. Conclusions: In this relatively small sample, CRA at 18 months was less common after adjuvant T-DM1 than after TH (though even with TH, nearly half of women did menstruate after chemotherapy, even in the subset aged 41+). This will be reassuring to young patients with HER2-positive breast cancer who seek to maintain ovarian function. Larger studies are needed to confirm this finding and to assess a possible differential impact of these drugs on subgroups based on age, endocrine therapy, and body mass index. Additional research should also focus on menopausal symptoms and actual fertility after receipt of T-DM1. Menstruation in 61 T-DM1 arm patients with informative surveys at 18 monthsMenstruation in 20 TH arm patients with informative surveys at 18 monthsAge at study entry95% CI95% CI≤4012/12 (100%)74-100%4/8 (50%)16-84%41+34/49 (69%)55-82%5/12 (42%)15-72%BMI&lt;3040/52 (77%)63-87%6/16 (38%)15-65%30+6/9 (67%)30-93%3/4 (75%)19-99%Endocrine therapy currentlyYes27/39 (69%)52-83%2/12 (17%)2-48%No19/22 (86%)65-97%7/9 (78%)40-97% Citation Format: Kathryn J. Ruddy, Lorenzo Trippa, Jiani Hu, William T. Barry, Chau T. Dang, Denise A. Yardley, Steven J. Isakoff, Vincente V. Valero, Meredith G. Faggen, Therese M. Mulvey, Ron Bose, Douglas J. Weckstein, Antonio C. Wolff, Katherine E. Reeder-Hayes, Hope S. Rugo, Bhuvaneswari Ramaswamy, Dan S. Zuckerman, Lowell L. Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit L. Cheng, Frederick M. Briccetti, Bryan P. Schneider, A. Merrill Garrett, P. Kelly Marcom, Kathy S. Albain, Patricia A. DeFusco, Nadine M. Tung, Blair M. Ardman, Rita Nanda, Rachel C. Jankowitz, Michelle K. DeMeo, Harold J. Burstein, Eric P. Winer, Ian E. Krop, Ann H. Partridge, Sara M. Tolaney. Chemotherapy-related amenorrhea (CRA) after adjuvant trastuzumab emtansine (T-DM1) compared to paclitaxel in combination with trastuzumab (TH) (TBCRC033: ATEMPT trial) [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 P2-13-02.