Neoadjuvant Treatment Of Breast Cancer Research Articles

Intermediate results of the prospective randomized controlled trial VOG-01: "Evaluation of the efficacy of neoadjuvant combination hormone therapy in premenopausal patients with ER+ HER2- breast cancer"

To date, the standard of care for neoadjuvant treatment of HER2-negative breast cancer remains chemotherapy with the inclusion of anthracyclines and taxanes in both luminal and triple-negative tumor subtypes. The purpose of this article was to scientifically substantiate the use of combined hormone therapy at the preoperative treatment of premenopausal patients with ER+ HER2- breast cancer. After analyzing the scientific data presented in scientific databases (PubMed, MEDLINE, BMS), as well as studying active clinical trials on the ClinicalTrials.gov, we concluded that most of the studies where hormone therapy was used in the preoperative regimen were conducted in the postmenopausal patient. In this regard, a randomized controlled clinical trial was initiated to study the efficacy and safety of a new method of preoperative treatment in premenopausal women with ER+ HER2- breast cancer, the preliminary results of which will be reported in this article. Currently, the study included 28 patients, of which 13 patients were analyzed who received the neoadjuvant and surgical stages of complex treatment. The research is ongoing.

Anthracycline-Free Neoadjuvant Treatment in Patients with HER2-Positive Breast Cancer: Real-Life Use of Pertuzumab, Trastuzumab and Taxanes Association with an Exploratory Analysis of PIK3CA Mutational Status.

Simple SummaryThis retrospective observational study aims at highlighting the response to pertuzumab, trastuzumab and docetaxel treatment (THP), without using anthracycline, in patients with HER2-positive early breast cancer. We add evidence to the suitability of THP in real life to reach higher pathological complete response rates, with a good safety profile for patients. An exploratory analysis of the mutational status of PIK3CA was performed as well, and 21% mutated samples were identified, with overall higher pCR rates in PIK3CA mutant patients and, particularly, in those who were THP-treated. Our original results open the door to further studies focused on more in-depth analysis of the molecular and clinical features related to the response to anthracycline-free neoadjuvant treatment in HER2-positive early breast cancer patients.HER2 is considered one of the most traditional prognostic and predictive biomarkers in breast cancer. Literature data confirmed that the addition of pertuzumab to a standard neoadjuvant chemotherapy backbone (either with or without anthracyclines), in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC), leads to a higher pathological complete response (pCR) rate, which is known to correlate with a better prognosis. In this retrospective analysis, 47 consecutive patients with HER2-positive EBC received sequential anthracyclines and taxanes plus trastuzumab (ATH) or pertuzumab, trastuzumab and docetaxel (THP). Despite the limited sample size, this monocentric experience highlights the efficacy (in terms of pCR) and safety of THP in the neoadjuvant setting of HER2-positive EBC as an anthracycline-free approach. Given the role of PIK3CA as a prognostic and therapeutic target in breast cancer, tumors were also analyzed to assess the PIK3CA mutational status. Thirty-eight out of forty-seven patients were evaluated, and PIK3CA variants were identified in 21% of tumor samples: overall, one mutation was detected in exon 4 (2.6%), two in exon 9 (5.3%) and four in exon 20 (10.5%). Of note, one sample showed concurrent mutations in exons 9 (codon 545) and 20 (codon 1047). Among patients reaching pCR (n = 13), 38.5% were PIK3CA mutants; on the other hand, among those lacking pCR (n = 25), just 12% showed PIK3CA variants. Regarding THP-treated mutant patients (n = 5), 80% reached pCR (three hormone-receptor-negative, one hormone-receptor-positive). Interestingly, the only patient not achieving pCR had a tumor with two co-occurring PIK3CA mutations. In conclusion, this study provides new evidence about the efficacy and good safety profile of THP, compared to the ATH regimen, as an anthracycline-free neoadjuvant treatment of HER2-positive EBC. Further studies on larger/multicentric cohorts are planned for more in-depth analysis to confirm our molecular and clinical results.

Abstract 2045: Spatial organization of the immune microenvironment after neoadjuvant treatment of breast cancer

Abstract Using the immune system to fight cancer has garnered tangible success, but some treatments, like neoadjuvant chemotherapy (NAC), modulate the immune microenvironment. Recent studies show that the spatial organization of tumor infiltrating lymphocytes (TIL) have greater predictive value than TIL density. The effect of NAC on immune composition and spatial distribution is not fully understood but new insight could help to guide its use in combination with immune therapy and identify patients with potential to derive benefit. We spatially profiled 84 RNA targets (GeoMx®) in a cohort of 12 NAC-treated breast cancer patients (4 Luminal, 4 HER2+ and 4 triple negative), none of whom achieved a pathological complete response. Matched pre- and post-treatment tissue samples were analyzed together with regions of interest (tumor center, invasive margin and TIL aggregates) identified using CD3, CD20, Syto83 and pan-cytokeratin for stromal/tumor segmentation. NAC decreases overall gene expression in breast tumors with the biggest declines seen in tumor promoting (CCND1, AKT1, CTNNB1, EPCAM, VEGFA, KRT and MKI67) and some inflammatory (CXCL10, STAT1 and STAT2) genes (p-value <0.05; other immune related transcripts showed little variation). Expression was compared between patients with a good response (<20% tumor cellularity) and those with a poor response (>50% cellularity). Poor responders expressed higher levels of tumor promoting genes pre-NAC, which remained high after treatment (KRT p=0.023, CTNNB1 p=0.031). No differences were detected in immune genes in the stroma based on patient responsiveness; however, higher antigen presentation and inflammatory gene transcripts were found at the tumor margins of good responders. Post-NAC differences between the margin and center decrease in good responders paralleled by a shift towards higher or equal expression of some inflammatory markers at the tumor center. Poor responders maintain high expression of all immune markers at the margin. A higher number of aggregates (mean n=5 vs n=1.3) were detected in good compared to poor responders together with more tertiary lymphoid structures (mean n=2.4 vs n=0.3) and distinguished by higher immune gene expression (CD8 p=0.046, CCL5 p=0.054, NKG7 p=0.022). NAC induces changes in other cells in the tumor microenvironment while targeting tumor cells. Our data show that spatial analysis of gene expression comparing good and poor responders (without a pathological complete response) reveal that tumor cells in the latter retain expression of tumor promoting genes while the immune compartment remains excluded. Good responders are characterized by a decrease in tumor promoting genes in parallel with lymphoid aggregates, including TLS, of active immune cells in the stroma and at the tumor center. These findings suggest that tailoring adjuvant treatment between good and poor responding patients might be warranted. Citation Format: Noémie Thomas, Soizic Garaud, Mireille Langouo, Ioannis Zerdes, Doïna Sofronii, Anaïs Boisson, Theodoros Foukakis, Alexandre De Wind, Roberto Salgado, Ahmad Awada, Karen Willard-Gallo. Spatial organization of the immune microenvironment after neoadjuvant treatment of breast cancer [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 2045.

Neutrophil-lymphocyte ratio and prediction of pathological complete response to neoadjuvant treatment in breast cancer.

e12627 Background: Pathological complete response (pCR) after neoadjuvant therapy in breast cancer is an important prognostic indicator for improved disease free survival. High tumour grade, low ER-status, HER2-positivity predict higher likelihood of a pCR however better predictive biomarkers are needed. The role of the immune system and specifically the presence of tumour infiltrating lymphocytes in increasing response to chemotherapy has been extensively studied across cancer subtypes2. We sought to determine if neutrophil-to-lymphocyte ratio (NLR) as a marker of immune inflammatory response could be informative in predicting likelihood of pCR. Methods: We identified a cohort of patients who had received neoadjuvant chemotherapy between 2012 to 2018. We extracted clinical, pathological and laboratory data for each case. A pretreatment peripheral blood test was used to calculate a neutrophil-to-lymphocyte ratio. We used R-studio to analyse our data. The primary objective was to determine if there was an association between NLR and pCR. Statistical analysis was performed to assess whether NLR ratio correlated with pCR. Results: We identified 107 patients who had received NAC for early stage breast cancer during our study period. The mean NLR in the cohort was 2.95 (range 0.76-11.9). 35 (32.7%) patients achieved a pCR. There was no statistically significant different in NLR in those who achieved pCR (n=35) and those who did not (n=72) (p value= 0.75). Patients with triple negative breast cancer (TNBC) had a higher rate of pCR (45.1%), compared to HER2-positive (42.1%) and ER-positive HER2-negative (25.4%). The NLR was not significant in predicting pCR within the separate histological cohorts. Conclusions: NLR did not predict for pathological complete response in our cohort. Further studies into the predictive value of NLR in this setting with larger cohorts are needed. Investigation into the dynamic changes of NLR both pre, post during treatment may provide further insights as may larger cohorts for analysis in each histological subtype.

Anlotinib plus tislelizumab combined with chemotherapy as neoadjuvant treatment in triple-negative breast cancer: A prospective, single-arm, open-label phase II study.

TPS618 Background: Neoadjuvant anti-PD-(L)1 therapy confers an improvement in pathological complete response (pCR) rate in unselected triple-negative breast cancer (TNBC). Combination of antiangiogenic agent plus immune checkpoint inhibitor and chemotherapy therapy for advanced TNBC is reported as a promising anti-tumor strategy presented in the FUTURE-C-PLUS study. Tislelizumab is a humanized immunoglobulin G4 anti-PD-1 monoclonal antibody engineered to minimize binding to FcγR on macrophages. Anlotinib is a novel multi-target tyrosine kinase inhibitor that effectively inhibit VEGFR, FGFR, c-KIT, c-MET and RET. Previous studies have proven the efficacy of both anlotinib monotherapy and combination with immune checkpoint inhibitor in advanced breast cancer. This phase II study aims to evaluate the efficacy and safety of anlotinib plus tislelizumab combined with chemotherapy as neoadjuvant treatment in TNBC. Methods: This is a prospective, single-arm, open-label, phase II trial. Eligible patients (pts) were women, aged 18-75 years, ECOG status 0-1, previously untreated invasive TNBC with histologically confirmed (cT1N1-2M0 or cT2-4N0-2M0). 32 pts will be enrolled and received 5 cycles of anlotinib (8 mg qd, d1-14; 21 days per cycle) with 6 cycles of tislelizumab (200 mg, once every 3 weeks) plus nab-paclitaxel (260 mg/m2, once every 3 weeks) and anthracycline (epirubicin 75 mg/m2 or doxorubicin 60 mg/m2), followed by surgery. The primary endpoint is pathological complete response rate (pCR, ypT0/Tis ypN0) and the secondary endpoints include invasive disease-free survival (iDFS), event-free survival (EFS), overall survival (OS), and safety. A sample size of 32 patients was estimated to provide a 80% power to detect a difference of 25% in pCR at a significance level of α = 0.05. The study was initiated in August 2021. Clinical trial information: NCT04914390.

Utility of interval imaging during neoadjuvant treatment of locoregional breast cancer.

e12611 Background: National guidelines for breast cancer management do not recommend routine imaging during preoperative chemotherapy. Despite this, some clinicians use radiographic results as a surrogate marker of treatment response during the preoperative phase. In this retrospective investigation, we studied the correlation between neoadjuvant clinical decision making, midway imaging results and final pathologic responses. Methods: 394 patients with locoregional breast cancer who received neoadjuvant chemotherapy and definitive surgery within the Henry Ford Health System between 2015-2021 were included. Final pathologic response of patients who completed midway imaging were compared with patients who did not. The primary outcome was overall pathologic response rate. Results: Tumor histology and final pathologic response (PR) was compared in patients who received midway imaging (MI) to those who did not (Table). In the MI group, no statistically significant association between midway radiographic response and final PR was found (p = 0.078). Systemic treatment was changed in 14.7% of patients after MI, there was no association with treatment change and complete PR (p = 0.488), however none of patients who received a treatment change after MI had progressive disease on final PR, compared to 9.7% of patients who did not have a treatment change and had progressive disease on final PR (p = 0.035). Multivariate analyses showed no association between MI and complete PR, irrespective of the histological subtypes. 78.4% of patients had imaging at the end of systemic treatment, prior to surgery. Radiographic response on post-treatment imaging correlated with final PR (p < 0.001). Conclusions: This study did not detect an association between midway imaging during neoadjuvant therapy and a complete pathologic response in locoregional breast cancer, however a correlation was detected between post-treatment imaging response and final pathologic response. Changes to systemic treatment based on midway radiographic findings were not shown to improve the likelihood of complete pathologic response but may reduce risk of progressive disease. Based on this study, midway imaging should not be broadly ordered during preoperative treatment, unless there is concern for progressive disease, in which midway imaging may provide diagnostic benefit.[Table: see text]

Nivolumab with chemotherapy as neoadjuvant treatment for inflammatory breast cancer.

e12633 Background: Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer with poor prognosis and is often resistant to neoadjuvant systemic therapy with early recurrence and metastases. PD-L1 expression in IBC is moderate to high, and blockade of the PD-1/PD-L1 axis with checkpoint inhibitors has emerged as a promising treatment to enhance clinical response. We examined the efficacy of neoadjuvant nivolumab (anti-PD-1 antibody) with chemotherapy in IBC. Methods: This is an open-label multicohort multicenter study of nivolumab with neoadjuvant chemotherapy in patients with newly diagnosed non-metastatic IBC (n=52). All breast cancer subtypes (ER/PR/HER2) were allowed. Patients received nivolumab 360 mg on day 1 (21-day cycle) x 4 cycles with standard chemotherapy. Cohort 1 (HER2-negative) received nivolumab with paclitaxel (80 mg/m2)x12 weeks followed by doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) (AC) x 4 cycles. Cohort 2 (HER2-positive) received nivolumab with taxane (paclitaxel 80 mg/m2, docetaxel 75 mg/m2, or nab-paclitaxel 100 mg/m2), trastuzumab (8 mg/kg then 6 mg/kg), and pertuzumab (840 mg then 420 mg) x 4 cycles followed by AC x 4 cycles. All patients underwent modified radical mastectomy (MRM) followed by radiation and adjuvant therapy per institutional standard of care. Primary objective was pathologic complete response (pCR) (ypT0/Tis ypN0). Residual Cancer Burden (RCB) was assessed. Secondary objectives were safety/tolerability and invasive recurrence-free interval at 2 years. Breast biopsies, residual tumor tissue, and peripheral blood samples were collected for correlative biomarker testing. PD-L1 expression in tumor tissue will be assessed as a predictive marker. Study was closed after 8 patients were enrolled due to slow accrual. Results: 8 patients were enrolled from June 2019-December 2020. All completed neoadjuvant systemic therapy with nivolumab and none had disease progression. They underwent MRM between January 2020-June 2021. Mean age was 57 years (range 43-74). 4 were HER2-positive, 3 were TNBC, and 1 was HR-positive/HER2-negative. 3 were Caucasian, 2 were Latino, 2 were Black, and 1 was Asian. There was no grade 4 toxicity. Most common grade 3 toxicity was neutropenia (n=3). Immune-related events were diarrhea/colitis (n=2) and elevated liver transaminases (n=1). At time of MRM, 4 patients had pCR, 1 had RCB-I, 2 had RCB-II, and 1 had RCB-III. They remain with no evidence of disease and are in follow-up. Tumor biological correlatives are being performed. Conclusions: Addition of nivolumab to neoadjuvant therapy was tolerable and safe and demonstrated anti-tumor activity in IBC with high pCR rate in this pilot study. This supports further investigation of the role of checkpoint inhibitors in treatment of IBC. Clinical trial information: NCT03742986. [Table: see text]

Phase 2 study of anlotinib combined with taxanes and lobaplatin in the neoadjuvant treatment of triple-negative breast cancer: Efficacy, safety and biomarker analysis.

e12605 Background: Pathological complete response (pCR) is associated with improved prognosis in triple-negative breast cancer (TNBC). Anlotinib, a novel multi-target tyrosine kinase inhibitor that effectively inhibits VEGFR, FGFR, c-KIT, c-MET, and RET, monotherapy has been proven effective in HER-2 negative metastatic breast cancer, but its efficacy in early-stage TNBC is unknown. This phase 2 study aims to evaluate the efficacy and safety of adding anlotinib to neoadjuvant chemotherapy in patients (pts) with primary TNBC. Methods: Pts with clinical stage II/III TNBC were to be treated with 5 cycles of anlotinib (12mg, d1-14, q3w) plus 6 cycles of taxanes (docetaxel 75 mg/m2 or nab-paclitaxel 260 mg/m2, d1, q3w) and lobaplatin (30 mg/m2, d1, q3w), followed by surgery. The primary endpoint was the total pCR (tpCR; ypT0/is ypN0). A Simon’s two-stage optimum design was used, and ＞5 of 11 pts were required to achieve tpCR in the first stage, with a pre-specified tpCR rate of 54.5% before proceeding to the second stage. A total of 31 participants was required for the study. Results: Six out of 11 pts achieved tpCR in the first stage, reaching the threshold for the second stage. From Jan 2021 to Jan 2022, a total of 22 pts were enrolled and 12 received surgery after the completion of neoadjuvant therapy, but a total of 2 pts withdrew from the study due to the COVID-19 pandemic or serious adverse events. Of the 22 eligible pts, the median age was 49 years (range, 29-64), 64% were postmenopausal, and 73% were nodal involved. At the time of surgery, 58.3% (7/12) achieved tpCR. Of the 9 pts with the node-positive disease at diagnosis, 88.9% (8/9) became ypN0. The results of FUSCC TNBC classification (IHC-based) revealed the tpCR rates were 57.1% (4/7), 100% (3/3), and 0% (0/2) for BLIS subtype, IM subtype and LAR/unknown subtypes, respectively. Biomarker analysis showed the tpCR rates were 100% (3/3) and 100% (4/4) in patients with gBRCA1 mutation and MYC amplification, respectively. The most common grade 3 or 4 treatment-related adverse events were leucopenia (6/22, 27%), neutropenia (6/22, 27%), anemia (5/22, 23%), decreased appetite (5/22, 23%), hypertension (2/22, 9%), ALT increased (1/22, 5%) and oral mucositis (1/22, 5%). No treatment-related deaths occurred. The trial is ongoing. Conclusions: The addition of anlotinib to neoadjuvant chemotherapy showed manageable toxicity and promising antitumor activity for patients with early-stage TNBC. Clinical trial information: ChiCTR2100043027.

Neoadjuvant pegylated liposomal doxorubicin (PLD) plus cyclophosphamide followed by nab-paclitaxel (Nab-P) as primary chemotherapy continuously combined with dual HER2 blockage for HER2-positive breast cancer: A single-arm phase 2 trial (Brecan Trial).

e12622 Background: Despite that AC-THP regimen is one of the commonly used regimens for neoadjuvant treatment of HER2-positive breast cancer, previous studies showed that pCR rate rarely exceeds 70%. We hypothesized that prolonged dual anti-HER2 therapy can increase pCR rate in neoadjuvant therapy. In this study, we designed a single-arm trial of ACHP-THP regimen (continuous dual anti-HER2 therapy of trastuzumab and pertuzumab) in neoadjuvant therapy of HER2 positive breast cancer. To minimize adverse cardiovascular events, we used pegylated liposomal doxorubicin (PLD) and Nab-Paclitaxel (Nab-P) instead of doxorubicin and paclitaxel. We aimed to examine whether continuous dual anti-HER2 therapy can boost pCR rate in the neoadjuvant therapy. The cardiotoxicity was closely monitored when the anti-HER2 therapy was combined with PLD and Nab-P respectively. Methods: Upon approval by the Medical Ethics Committee of Xijing Hospital, patients with HER2-positive breast cancer (cT2-3/N0-1/M0) receiving neoadjuvant therapy, were enrolled. The patients were treated with PldCHP (pegylated liposomal doxorubicin 35mg/m2, cyclophosphamide 600mg/m2, trastuzumab 8 mg/kg loading, then 6 mg/kg, pertuzumab 840 mg loading, then 420 mg, iv, q3w) for 4 cycles followed by Nab-PHP (Nab-Paclitaxel 260mg/m2, trastuzumab 6 mg/kg, pertuzumab 420 mg, iv, q3w) for 4 cycles, with strict monitoring of cardiotoxicity. The primary endpoint was pCR rate, and secondary endpoint was cardiotoxicity during neoadjuvant therapy. Results: From January 2020 to October 2021, a total of 96 patients were recruited. Among the 96 patients with a median age of 49 (21-71), 58 patients were HR positive and 42 patients had positive lymph node status. Overall, the pCR rate was 80.2% (77/96). The ER-positive tumor achieved a higher pCR rate than ER-negative tumor (82.8% vs 76.3%, p=0.439), but the difference was statistically insignificant. Multivariate regression analysis showed that for participants older than 30, HER2 3+ (IHC) showed a statistically significant positive influence on pCR rate. The common adverse reactions of grade ≥3 were neutropenia (30.2%), asthenia (8.3%), and peripheral sensory neuropathy (7.3%). Left ventricular insufficiency was detected in 4 patients, and no cardiotoxic events higher than grade 2 occurred during the neoadjuvant therapy. There was no treatment-related death. Conclusions: The PldCHP---Nab-PHP regimen is a feasible and effective neoadjuvant therapy for early stage HER2-positive breast cancer, showing high pCR rate and acceptable cardiotoxicity. These results support a further random controlled trial testing for continuous dual anti-HER2 therapy combined with PLD in neoadjuvant or adjuvant therapy of HER2 positive breast cancer.

Evaluation of pathological complete response after neoadjuvant systemic treatment of invasive breast cancer using diffusion-weighted imaging compared with dynamic contrast-enhanced based kinetic analysis

PurposeThis study compared the performance of diffusion-weighted imaging (DWI) to dynamic contrast-enhanced (DCE)-MRI for diagnosing pathological complete response (pCR) before surgery. MethodOverall, 133 lesions from 133 patients who underwent pre-surgical MRI evaluation after neoadjuvant systemic treatment were included. Two readers blinded to the pathological diagnosis evaluated the images. MR images were obtained using a routine protocol sequence that included DWI and DCE-MRI. DWI of the target lesion was scored using a three-point scale. Kinetic patterns of lesions on DCE-MRI were scored using a four-point scale. The capacities of DWI and kinetic parameters for discriminating pCR and non-pCR were assessed via receiver operating characteristic (ROC) analysis. ResultsFor DWI scores, ROC analysis showed areas under the ROC curve (AUCs) of 0.84 (95% confidence interval: 0.77–0.90) and 0.85 (0.77–0.90) for readers 1 and 2, respectively; corresponding AUCs of kinetic scores were 0.89 (0.82–0.94) and 0.88 (0.81–0.93). Among the triple-negative subtype, the AUCs of DWI scores were 0.84 (0.70–0.93) and 0.88 (0.75–0.96) for readers 1 and 2, respectively; corresponding AUCs of kinetic scores were 0.94 (0.83–0.99) and 0.93 (0.82–0.99). Among the luminal subtype, the AUCs of DWI scores were 0.85 (0.71–0.94) and 0.82 (0.68–0.92) for readers 1 and 2, respectively; corresponding AUCs of kinetic scores were 0.82 (0.68–0.92) and 0.72 (0.56–0.85). ConclusionsOur DWI-based visual score and kinetic score showed similar diagnostic performances. Both DWI and kinetic scores tended to perform better in predicting pCR for the triple-negative subtype.

Reconstructing virtual large slides can improve the accuracy and consistency of tumor bed evaluation for breast cancer after neoadjuvant therapy

BackgroundTo explore whether the “WSI Stitcher”, a program we developed for reconstructing virtual large slide through whole slide imaging fragments stitching, can improve the efficiency and consistency of pathologists in evaluating the tumor bed after neoadjuvant treatment of breast cancer compared with the conventional methods through stack splicing of physical slides.MethodsThis study analyzed the advantages of using software-assisted methods to evaluate the tumor bed after neoadjuvant treatment of breast cancer. This new method is to use “WSI Stitcher” to stitch all the WSI fragments together to reconstruct a virtual large slide and evaluate the tumor bed with the help of the built-in ruler and tumor proportion calculation functions.ResultsCompared with the conventional method, the evaluation time of the software-assisted method was shortened by 35%(P < 0.001). In the process of tumor bed assessment after neoadjuvant treatment of breast cancer, the software-assisted method has higher intraclass correlation coefficient when measuring the length (0.994 versus 0.934), width (0.992 versus 0.927), percentage of residual tumor cells (0.947 versus 0.878), percentage of carcinoma in situ (0.983 versus 0.881) and RCB index(0.997 versus 0.772). The software-assisted method has higher kappa values when evaluating tumor staging(0.901 versus 0.687) and RCB grading (0.963 versus 0.857).ConclusionThe “WSI Stitcher” is an effective tool to help pathologists with the assessment of breast cancer after neoadjuvant treatment.

Contrast-enhanced ultrasound of breast tumors: an initial experience.

BackgroundThe increase of neoadjuvant treatment for breast cancer creates a capacity challenge as response evaluation by magnetic resonance imaging (MRI) is a limited resource. Contrast-enhanced ultrasound (CEUS) has been proposed as an alternative imaging strategy.PurposeTo get experience with examination of malignant breast tumors with CEUS and evaluate the potential for future use in response evaluation of neoadjuvant treatment.Material and methodsIn this pilot study, the dynamic contrast-enhancement of ultrasound and MRI examinations were analyzed in 14 women with histologically verified breast cancer.ResultsAnalysis of the time intensity curve of CEUS demonstrated the difference between tumor and normal tissue. The peak intensity was five times higher in tumor tissue (mean increase 397%, 95% CI 250–545). The curve was steeper for tumor tissue (mean 1.76, 95% CI 1.26–2.26) than for normal tissue (mean 0.43, 95% CI 0.24–0.62).ConclusionCEUS is a feasible method of examining blood flow in malignant breast tumors.

Nanoparticle albumin-bound paclitaxel is superior to liposomal paclitaxel in the neoadjuvant treatment of breast cancer.

Aim: The present study aimed to retrospectively compare the efficacy and safety between liposomal paclitaxel (Lps-P) and nanoparticle albumin-bound paclitaxel (Nab-P) in neoadjuvant systemic treatment (NST) of breast cancer. Materials & methods: Two hundred thirty-five patients who were diagnosed with invasive breast cancer and then received dose-dense NST with epirubicin and cyclophosphamide followed by paclitaxel were enrolled. Results: Nab-P has an advantage in improving the total and axillary-only pathologic complete response rate over Lps-P. Although Nab-P can cause a higher incidence and severity of peripheral sensory neuropathy (PSN), most symptoms are temporary and reversible. In the Lps-P group, the proportion of patients with residual irreversible PSN is larger. Conclusion: Nab-P might be superior to Lps-P in NST of breast cancer.

The association between body mass index and pathological complete response in neoadjuvant-treated breast cancer patients

Background Obesity seems to be associated with a poorer response to adjuvant chemotherapy in breast cancer (BC); however, associations in the neoadjuvant chemotherapy (NACT) setting and according to menopausal status are less studied. This study aims to investigate the association between pretreatment body mass index (BMI) and pathological complete response (pCR) following NACT in BC according to menopausal and estrogen receptor (ER) status. Material and Methods The study cohort consisted of 491 patients receiving NACT in 2005–2019. Based on pre-NACT patient and tumor characteristics, the association between BMI and achieving pCR was analyzed using logistic regression models (crude and adjusted models (age, tumor size, and node status)) with stratification by menopausal and ER status. Results In the overall cohort, being overweight (BMI ≥25) compared by being normal-weight (BMI <25), increased the odds of accomplishing pCR by 15%. However, based on the 95% confidence interval (CI) the data were compatible with associations within the range of a decrease of 30% to an increase of 89%. Stratification according to menopausal status also showed no strong association: the odds ratio (OR) of accomplishing pCR in overweight premenopausal patients compared with normal-weight premenopausal patients was 1.76 (95% CI 0.88–3.55), whereas for postmenopausal patients the corresponding OR was 0.71 (95% CI 0.35–1.46). Discussion In a NACT BC cohort of 491 patients, we found no evidence of high BMI as a predictive factor of accomplishing pCR, neither in the whole cohort nor stratified by menopausal status. Given the limited precision in our results, larger studies are needed before considering BMI in clinical decision-making regarding NACT or not.

Surrogacy Beyond Prognosis: The Importance of "Trial-Level" Surrogacy.

Many candidate surrogate endpoints are currently assessed using a 2-level statistical approach, which consists in checking whether (1) the potential surrogate is associated with the final endpoint in individual patients and (2) the effect of treatment on the surrogate can be used to reliably predict the effect of treatment on the final endpoint. In some situations, condition (1) is fulfilled but condition (2) is not. We use concepts of causal inference to explain this apparently paradoxical situation, illustrating this review with 2 contrasting examples in operable breast cancer: the example of pathological complete response (pCR) and that of disease-free survival (DFS). In a previous meta-analysis, pCR has been shown to be a strong and independent prognostic factor for event-free survival (EFS) and overall survival (OS) after neoadjuvant treatment of operable breast cancer. Yet, in randomized trials, the effects of experimental treatments on pCR have not translated into predictable effects on EFS or OS, making pCR an “individual-level” surrogate, but not a “trial-level” surrogate. In contrast, DFS has been shown to be an acceptable surrogate for OS at both the individual and trial levels in early, HER2-positive breast cancer. The distinction between the prognostic and predictive roles of a tentative surrogate, not always made in the literature, avoids unnecessary confusion and allows better understanding of what it takes to validate a surrogate endpoint that is truly able to replace a final endpoint.

Platinum is essential in neoadjuvant treatment of triple-negative breast cancer: a network meta-analysis.

Objective:This study aimed to assess the efficacy and safety of various neoadjuvant regimens for patients diagnosed with early-stage or locally advanced triple-negative breast cancer (TNBC).Methods:Medline, EMBASE, Cochrane Library, and Web of Science were searched in May 2020 to identify randomized controlled trials (RCTs). Bayesian network meta-analysis (NMA) was performed (Registration: PROSPERO CRD42020223012).Results:A total of 35 RCTs involving 8,424 participants were reviewed, of which 22 RCTs with 5,203 patients were included in this NMA focusing on pathologic complete response (pCR). An anthracycline-taxane-based (AT) regimen combined with a platinum (ATPt) [odds ratio (OR) = 2.04, 95% credible interval (CrI): 1.69, 2.48] regimen, and a docetaxel regimen combined with a carboplatin (TCb; OR = 2.16, 95% CrI: 1.20, 3.91) regimen improved pCR beyond that with AT only. AT and ATPt combined with targeted therapy [including bevacizumab (Bev), veliparib, atezolizumab, or pembrolizumab] also improved pCR. Five RCTs included in this NMA reported serious adverse events (SAEs) or grade ≥ 3 AEs. TCb was associated with fewer grade ≥ 3 AEs than was AT (OR = 0.66, 95% CrI: 0.23, 1.72) alone. In contrast, ATPt, AT + Bev, ATPt + Bev, ATPt + veliparib, and ATPt + pembrolizumab were associated with more SAEs than was AT alone.Conclusions:In patients with TNBC, platinum-based neoadjuvant regimens ATPt and TCb increase pCR beyond that with AT alone, but TCb appears to be better tolerated than either AT or ATPt. Platinum-based regimens combined with targeted therapies (Bev, PARPi, and PD-1/PD-L1 inhibitor) also improve the pCR rate beyond that with AT alone, but this benefit is accompanied by greater toxicity.

Abstract ES6-4: Parp inhibitors for brca1/2mutation associated breast cancer

Abstract More than 15 years ago we and others showed the use of potent PARP1 inhibitors (PARPi), that both inhibit the catalytic activity of the PARP1 enzyme and trap PARP1 onto DNA, generate a “synthetic lethal” interaction with the malignant cell specific loss of function of genes crucial for homologous recombination (HR) gene function. This phenomenon has now been exploited with therapeutic intent in several contexts leading to approved single agent PARPi treatments for advanced forms of ovarian, prostate, pancreatic and breast cancers. These approvals have in large part been associated a biomarker requirement for evidence of loss of function of HR. Recently a number of trials have investigated PARPi in a (neo)adjuvant breast cancer treatment (NACT) setting in patients with (or enriched for) HR deficiency. These have included phase II neoadjuvant PARPi studies such as the NeoTALA study using single agent talazoparib in germline BRCA1 and BRCA2 mutation carriers and the combination chemotherapy and olaparib therapy studies GeparOLA and PARTNER, enriched for HR deficient breast cancer, that have reported important signals with regard efficacy and tolerability. Two recent phase III trials have influenced recent early breast cancer treatment guidelines. These are the BrighTNess trial in the neoadjuvant setting and OlympiA in the post-(neo)adjuvant setting. BrighTNess recruited patients with biologically heterogeneous triple negative breast cancer (TNBC) and used the weak PARP1 trapping PARPi veliparib and OlympiA restricted eligibility to patients with the germline “pathogenic” or “likely pathogenic” mutation in BRCA1 or BRCA2 but included patients with hormone receptor positive breast cancer. BrighTNess did not show convincing evidence of benefit to the addition of veliparib to standard of care in TNBC NACT but has shown the benefit to the addition of carboplatin to sequential paclitaxel-AC NACT with significant improvements in event free survival (HR 0.57 ) compared to sequential paclitaxel-AC alone. OlympiA has reported following an interim analysis showing 12 months of olaparib in the post-(neo)adjuvant chemotherapy setting improves both invasive disease free and distant disease free survival by approximately 40% with highly statistically significant hazard ratios of 0.58 and 0.57 respectively that met pre-specified early stopping boundaries. The publication of results for OlympiA has led to rapid updates of both genetic testing and treatment international guidelines for BRCA1 and BRCA2 mutation associated breast cancer to include use of olaparib in patients meeting the eligibility criteria for the trial. The lecture will both explore the data and the implications for practice of the adoption of these guidelines and some of the ongoing questions to be addressed by ongoing clinical trial and translational research initiatives. Citation Format: ANJ Tutt. Parp inhibitors for brca1/2mutation associated 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 ES6-4.

Abstract P1-08-19: Utilising artificial intelligence (AI) for analysing multiplex genomic and magnetic resonance imaging (MRI) data to develop multimodality predictive system for personalised neoadjuvant treatment of breast cancer (BC)

Abstract Background: No effective tool is available to predict response to neoadjuvant chemotherapy (NACT). Aim: to enable an accurate prediction of the treatment response for BC patients, with the aid of machine learning based analysis of tumour histopathological, molecular &amp; imaging features before NACT. Methods: The baseline biopsies were immunohistochemistry (IHC) stained for ER, PR, HER2, Ki67 &amp; SPAG5 and genomically analysed. To build up a genomic profiler &amp; multiplex analysis, a tailored mRNA code set of 450 genes was designed using NanoString nCounter Flex Analysis System. In addition, samples have been analysed for currently used prognostic &amp; predictive genomic panels including: Oncotype DX [Genomic Health], MammaPrint [Agendia], Prosigna [Nanostring Technologies] &amp; MD Anderson Genomic Chemo Sensitivity Predictor. The imaging features were extracted from MRI using radiomics measurements and deep learning methods. Our predictive models were trained in a local cohort of 400 BC (300 HER2 negative (HER2-) received 8 cycles of anthracycline &amp; Taxane &amp; 100 HER2 positive (HER2+) received Trastuzumab, anthracycline &amp;Taxane) &amp; was validated in 150 patients from local clinical trial patients. I-SPY-1 clinal trial genomic &amp; imaging data were used as an external validation. The pathological complete response (pCR) defined as absence of tumor cells in both breast &amp; lymph node was used as endpoint. Results: Compared to HER- BC, HER2+ BC had higher expression of GRB7, ERBB2, SPAG5, FGRF4 &amp; CDC6. While HER2 negative BC showed higher level of CCND1, CDK6, FOXM1, FOXC1, MAI, MYC, ANP32E, SFRP1, ACTR3B, RAD51AP1, MCM3, LIN9, CDCA7 &amp; PMAIP1 (Table 1). In both HER2 positive and negative BC; the reduction of &amp;gt;70% in tumour volume (OR (95% CI)=1.72 (1.35-2.7, p&amp;lt;0.0001) &amp; 1.87 (1.44-2.42, p&amp;lt;0.0001);respectively), high mitotic count (OR (95% CI)=2.6 (1.73-3.91), p&amp;lt;0.0001) &amp; 1.98 (1.49-2.65), p&amp;lt;0.000);respectively), ER- (OR (95% CI)=0.51 (0.41-0.64); p&amp;lt;0.0001 &amp; 0.53 (0.42-0.68; p&amp;lt;0.0001; respectively, IHC), PR- (OR (95% CI)=0.67 (0.57-0.80: p&amp;lt;0.0001 &amp; 0.62 (0.51-0.77; p&amp;lt;0.0001; respectively, IHC), SPAG5+ (OR (95% CI)=2.36 ( 1.77-3.15; p&amp;lt;0.0001) &amp; 2.15 (1.51-3.06); p=&amp;lt;0.0001); respectively, IHC) and over-expressions of ERBB2 (OR (95% CI)=3.51 (2.26-5.45) &amp; 3.32 (2.15-5.10) ; ps&amp;lt;0.0001, respectively), EGFR (OR (95% CI)=1.43. (1.01-2.03; p=0.004) &amp; 1.48 (1.16-1.89); p=0.002; respectively), GRB7 (OR (95% CI)= 3.78 (2.52-5.64) &amp; 3.56 (2.39-5.29); respectively, ps&amp;lt;0.0001), and CDC6 (OR (95% CI)=2.19 1.65-2.90; p=0.0002 &amp; 2.1 (1.60-2.77); p=0.0005; respectively) were associated with higher pCR after receiving NACT. In HER2+ BC, the differential expression of DLC1, EBB4, RUNDC1, ARHGEF9 &amp; PIK3CD were associated with higher response to Trastuzumab (ps&amp;lt;0.01).In HER2- BC: the intensity of histogram skewness in MRI (p=0.03) and low expression of CXXC5, AR, TGFB3, TACC3, TUBA4A, AGR2, ESR1, TP73 and BAG1 were associated with high response to chemotherapy (ps&amp;lt;0.01). Integrated models were developed for predicting response to NACT of HER2- BC (AUC (95% CI)= 0.83 (0.76-0.91; p&amp;lt;0.0001) &amp; to chemotherapy plus Trastuzumab in HER2+ BC (AUC (95% CI) = 0.79 (0.67-0.91; p&amp;lt;0.0001). Conclusions: A predictive model was developed for HER2+ and another for HER2- BC with &amp;gt;= 80% accuracy prediction of pCR. AI &amp; multiplex technology could enable robust biomarker discovery. ORLower 95% CIUpper 95% CIAdjusted pGRB7-mRNA9.986.7714.706.76E-24ERBB2-mRNA7.765.3011.401.12E-20FOXC1-mRNA0.100.060.166.44E-19MIA-mRNA0.180.110.282.63E-12ANP32E-mRNA0.500.410.622.30E-09MYC-mRNA0.520.410.678.82E-07SFRP1-mRNA0.310.190.491.65E-06CD99-mRNA1.481.261.732.73E-06SPAG5-mRNA1.891.452.474.68E-06PMAIP1-mRNA0.510.390.685.03E-06CDK6-mRNA0.520.390.699.09E-06FGFR4-mRNA2.621.733.979.21E-06CDCA7-mRNA0.400.270.591.13E-05LIN9-mRNA0.610.490.761.25E-05CDC6-mRNA1.941.452.591.44E-05MCM3-mRNA0.660.550.801.55E-05RAD51AP1-mRNA0.570.450.731.58E-05CCND1-mRNA0.450.310.641.93E-05FOXM1-mRNA0.510.380.681.97E-05 Citation Format: Tarek Ma Abdel-Fatah, Graham Ball, Xin Chen, Dalia Mehaisi, Elisabetta Giannotti, Dorothee Auer, Jayakumar Vadakekolathu, Ruizhe Li, Graham Pockley, Stephen Chan. Utilising artificial intelligence (AI) for analysing multiplex genomic and magnetic resonance imaging (MRI) data to develop multimodality predictive system for personalised neoadjuvant treatment of breast cancer (BC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-19.

Abstract P2-12-19: Platinum is essential in neoadjuvant treatment of triple negative breast cancer: A network meta-analysis

Abstract Background: Due to the heterogeneity of triple negative breast cancer (TNBC) and variety of neoadjuvant regimen, the best way to provide optimal neoadjuvant regimen in early-stage TNBC is still a challenge. However, the preferred regimen, especially when combining target therapy such as bevacizumab, Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors (PARPi), and PD-1/PD-L1 inhibitor, is still not clear. Methods: Medline, EMBASE, Cochrane Library, and Web of Science were searched in May 2020 to identify randomized controlled trials (RCTs). We conducted a fixed-effect network meta-analysis (NMA) with a Bayesian framework to assess the efficacy and safety of different neoadjuvant regimens for patients with early or locally advanced TNBC. (Registration: PROSPERO CRD42020223012). Results: A total of 35 RCTs involving 8424 participants were included, of which, 22 RCTs with 5203 patients were included in this NMA focusing on pathologic complete response (pCR). Compared to anthracycline-taxane based regimen (AT), an improvement in pCR was observed for anthracycline-taxane based combined platinum (ATP) (odds ratio [OR]=2.04, 95% credible interval [CrI]: 1.69, 2.48), TCb (T= docetaxel; Cb= carboplatin; OR=2.16, 95%CrI: 1.20, 3.91). Combining target therapy (including bevacizumab [Bev], veliparib, atezolizumab, or pembrolizumab) with AT or ATP also improved pCRs. Eleven RCTs reported serious adverse events (SAEs), and five RCTs were included in NMA. TCb was associated with less serious adverse events than AT. However, ATP, AT+Bev, ATP+Bev, ATP+Veliparib and ATP+Pembro were associated with more serious AEs than AT. Conclusions: Platinum-based neoadjuvant regimens increased pCRs in TNBC patients, among which TCb was preferred with less SAEs. Platinum-based regimens should also be considered a preferred option when combining target therapy such as Bev, PARPi, and PD-1/PD-L1 inhibitor. Citation Format: Junjie Li, Li Chen, Wei Tan, Fang Qi, Yang Zhang, Zhonghua Wang, Zhimin Shao. Platinum is essential in neoadjuvant treatment of triple negative breast cancer: A network meta-analysis [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 P2-12-19.

Ultrafast dynamic contrast-enhanced breast MRI: association with pathologic complete response in neoadjuvant treatment of breast cancer.

The purpose of this study was to investigate whether pretreatment kinetic features from ultrafast DCE-MRI are associated with pathological complete response (pCR) in patients with invasive breast cancer and according to immunohistochemistry (IHC) subtype. Between August 2018 and June 2019, 256 consecutive breast cancer patients (mean age, 50.2years; range, 25-86years) who underwent both ultrafast and conventional DCE-MRI and surgery following neoadjuvant chemotherapy were included. DCE-MRI kinetic features were obtained from pretreatment MRI data. Time-to-enhancement, maximal slope (MS), and volumes at U1 and U2 (U1, time point at which the lesion starts to enhance; U2, subsequent time point after U1) were derived from ultrafast MRI. Logistic regression analysis was performed to identify factors associated with pCR. Overall, 41.4% of all patients achieved pCR. None of the kinetic features was associated with pCR when including all cancers. Among ultrafast DCE-MRI kinetic features, a lower MS (OR, 0.982; p = 0.040) was associated with pCR at univariable analysis in hormone receptor (HR)-positive cancers. In triple-negative cancers, a higher volume ratio U1/U2 was associated with pCR at univariable (OR, 11.787; p = 0.006) and multivariable analysis (OR, 14.811; p = 0.005). Among conventional DCE-MRI kinetic features, a lower peak enhancement (OR, 0.993; p = 0.031) and a lower percentage of washout (OR, 0.904; p = 0.039) was associated with pCR only in HR-positive cancers at univariable analysis. A higher volume ratio of U1/U2 derived from ultrafast DCE-MRI was independently associated with pCR in triple-negative invasive breast cancer. • The ratio of tumor volumes obtained at the first (U1) and second time points (U2) of enhancement was independently associated with pCR in triple-negative invasive breast cancers. • Ultrafast MRI has the potential to improve accuracy in predicting treatment response and personalizing therapy.