Axillary Node-positive Breast Cancer Research Articles

Long-Term Outcomes of Adjuvant Trastuzumab for 9 Weeks or 1 Year for ERBB2-Positive Breast Cancer

The standard adjuvant treatment for patients with ERRB2-positive breast cancer is chemotherapy plus 1 year of trastuzumab. Shorter durations of trastuzumab administration improve cardiac safety, but more information is needed about their effect on survival. To compare survival outcomes after 9-week vs 1-year administration of trastuzumab with the same adjuvant chemotherapy. This post hoc secondary analysis of an open-label, multicenter, noninferiority-design randomized clinical trial included women aged 18 years or older with early ERBB2-positive, axillary node-negative or axillary node-positive breast cancer who were enrolled from January 3, 2008, to December 16, 2014, at 65 centers in 7 European countries. The current exploratory analysis was conducted after achieving the maximum attainable follow-up data when the last patient enrolled had completed the last scheduled visit in December 2022. Chemotherapy consisted of 3 cycles of docetaxel administered at 3-week intervals followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide at 3-week intervals. Trastuzumab was administered in both groups for 9 weeks concomitantly with docetaxel. In the 9-week group, no further trastuzumab was administered after chemotherapy, whereas in the 1-year group, trastuzumab was continued after chemotherapy to complete 1 year of administration. The primary objective was disease-free survival (DFS). Distant DFS and OS were secondary objectives. Survival between groups was compared using the Kaplan-Meier method and log-rank test or univariable Cox proportional hazards regression. Among the 2174 women analyzed, median age was 56 years (IQR, 48-64 years). The median follow-up time was 8.1 years (IQR, 8.0-8.9 years); 357 DFS events and 176 deaths occurred. Trastuzumab for 9 weeks was associated with shorter DFS compared with trastuzumab for 1 year (hazard ratio [HR], 1.36; 90% CI, 1.14-1.62); 10-year DFS was 80.3% in the 1-year group vs 78.6% in the 9-week group. The 5-year and 10-year OS rates were comparable between the 9-week and 1-year groups (95.0% vs 95.9% and 89.1% vs 88.2%, respectively; HR for all time points, 1.20; 90% CI, 0.94-1.54). In multivariable analyses, 9-week treatment was associated with shorter DFS compared with 1-year treatment (HR for recurrence or death, 1.36; 95% CI, 1.10-1.68; P = .005), but there was no between-group difference in OS (HR, 1.22; 95% CI, 0.90-1.64; P = .20). Only 4 patients (0.2%) died of a cardiac cause. In this secondary analysis of a randomized clinical trial, 1-year vs 9-week adjuvant trastuzumab was associated with improved DFS among patients with ERRB2-positive breast cancer receiving chemotherapy, but there was no significant difference in OS between the groups. ClinicalTrials.gov Identifier: NCT00593697.

Abstract PO2-23-06: Clinical study of stained region lymph node biopsy (SrLNB) in axillary surgery after neoadjuvant systemic therapy in patients with axillary lymph node positive breast cancer

Abstract Background The probability of axillary lymph node converting from positive to negative after neoadjuvant systemic therapy (NST) for breast cancer patients is approximately 40%. A variety of axillary lymph node biopsy surgeries based on sentinel lymph node biopsy (SLNB) can help to omit axillary lymph node dissection (ALND). The common disadvantages, however, are mainly the restrictions, such as the need for strict regulation of the use of radiotracers, the high number of retrieved lymph nodes required, and the need to purchase ancillary equipment. The more restrictions there are, the more they limit the spread and availability of the technique and, more importantly, reduce the number of patients who will benefit. In fact, for patients with metastatic lymph nodes, the sentinel lymph nodes must be included in the lymph nodes that have metastasized. If these metastatic lymph nodes can be accurately marked and precisely retrieved after NST, it is possible to assess whether the axillary lymph nodes are converted from positive to negative without the need for SLNB. Materials and methods Breast cancer patients with pathologically confirmed axillary lymph node metastases who were receiving NST were recruited for this study. Before NST, carbon nanoparticles suspension injections were injected into the cortex of the pathologically confirmed metastatic lymph node to stain the region where the metastatic lymph node was located. The lymph nodes in the stained region were retrieved by stained region lymph node biopsy (SrLNB) during the axillary surgery, followed by ALND, without the use of SLNB. Finally, the identification rate and false-negative rate (FNR) of SrLNB were statistically analyzed according to pathology data. Results A total of 159 patients were successfully enrolled in this study between September 24, 2020 and December 2, 2022, with an axillary pCR rate of 40.9% (65/159). The identification rate of SrLNB was 100% (159/159), with an overall FNR of 5.3% (5/94). Subgroup analysis revealed that in the subgroups of 1, 2, 3 and ≥4 SrLN, the FNR was 0%, 0%, 0% and 8.9% (5/56), respectively, whereas in the cN1, cN2 and cN3 subgroups the FNR was 7.7% (3/39), 2.6% (1/38) and 5.9% (1/17), respectively. The FNR indexes were within the safety threshold of 10% in all subgroups. Conclusion SrLNB has a high identification rate and a low FNR and is useful for screening patients with positive to negative axillary lymph nodes for omitting ALND. srLNB requires only the use of an affordable and radiation-free carbon nanoparticles suspension injection for marking, making the whole technique simpler and easier to disseminate. The data from this study also suggest that SLNB may not be mandatory for axillary biopsy in patients with positive axillary lymph nodes undergoing NST. Table 1. General characteristics of enrolled patients. Table 2. Analysis of factors affecting axillary pCR rates. Table 3. Analysis for the FNR of SrLNB. Citation Format: Jue Wang, Rui Chen, Cuiying Li, Hailing Zha, Qiannan Zhu, Lifeng Huang, Xiaoming Zha. Clinical study of stained region lymph node biopsy (SrLNB) in axillary surgery after neoadjuvant systemic therapy in patients with axillary lymph node positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-23-06.

Abstract 4773: Interferon regulatory factor 8 (IRF8) as a biomarker for early detection and prevention of axillary lymph node-positive breast cancer

Abstract Breast cancer (BC) remains a leading health concern worldwide and is often undetected until the cancer metastasizes. Early detection can limit the need for aggressive treatments and improve prognosis. We analyzed early immune and molecular markers in benign breast disease (BBD) biopsies prior to BC development to identify women at elevated risk of developing node-positive invasive BC, which might direct surveillance and prevention efforts aimed at reducing incidence of this disease. Utilizing the Mayo Clinic BBD cohort, we compared women who developed node-positive BC following their BBD biopsy (cases; n=42) with those who remained cancer-free (controls; n=37), matched on patient age and biopsy date. We used NanoString nCounter system to identify differentially expressed genes (DEGs) between cases and controls. We also developed a multiplex immunofluorescence (mIF) approach using Opal system by Akoya Biosciences for comprehensive marker detection in FFPE tissue, enabling correlation of cells expressing DEGs with innate and adaptive immune cells. Digitized images were segmented, and cell phenotyping, and spatial relationships were compared between cases and controls. Our findings revealed significantly increased expression levels of IRF8 (interferon regulatory factor 8, a factor involved in immune cell differentiation) in controls as compared to cases and found that increased IRF8 expression in cases is correlated with delayed cancer onset. Additionally, controls exhibited higher frequencies of CD4+, CD8+, CD68+, CD20+ and CD11c+ immune cells, and lower frequency of Ki67+ staining, with a notable increase of CD11c+/CD68+ cells, a marker for M1 type macrophages, indicating a pro-inflammatory, antitumorigenic immune microenvironment polarization. Furthermore, our mIF analyses offer new insights into spatial biomarker localization, enhancing prognostic accuracy. Our findings suggest that decreased numbers of immune cells in BBD biopsies may be associated with increased risk of developing axillary node-positive BC. This research underscores the importance of dissecting molecular and immune interactions in BBD for assessing the risk of this disease. Our results have the potential to improve individualized risk assessment, leading to more targeted surveillance and informed screening, potentially reducing BC incidence and mortality through early intervention. This study not only contributes to our understanding of BC pathogenesis but also opens avenues for developing novel preventive strategies. Citation Format: Matilde Rossi, Nicole Cruz-Reyes, Melody L. Stallings Mann, Bryan M. McCauley, Tanya L. Hoskin, Robert A. Vierkant, Stacey J. Winham, Amy C. Degnim, Mark E. Sherman, Derek C. Radisky. Interferon regulatory factor 8 (IRF8) as a biomarker for early detection and prevention of axillary lymph node-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4773.

Development of a prognostic nomogram for lymph node positive HR+/HER2- breast cancer patients: a study of SEER database and a Chinese cohort.

The hormone receptor+/human epidermal growth factor receptor 2- (HR+/HER2-) breast cancer (BC) patients account for the largest proportion in all patients and are still at high risk of long-range recurrence. This current study aimed to construct a prognostic nomogram to predict 3-year and 5-year BC-specific survival (BCSS) in HR+/HER2- BC patients with axillary lymph node metastasis. A total of 25,338 HR+/HER2- patients with axillary lymph node-positive BC were enrolled from the Surveillance, Epidemiology and End Results (SEER) database and randomly divided into the training (n=17,738) and validation (n=7,600) cohorts using a ratio of 7:3. Univariate and multivariable Cox regression hazards were used to build a prognostic nomogram based on the training cohort. The nomogram was validated with two independent cohorts. Receiver operating characteristic (ROC) curves and calibration plots were used to evaluate the performance of the model, and Kaplan-Meier survival analyses were applied to test the clinical utility of the risk stratification system. Twelve factors including age, race, marital status, grade, T stage, N stage, radiotherapy, chemotherapy, and metastasis to the bone, brain, lung and liver were identified and incorporated to construct the nomogram (P<0.001). The area under the ROC curve (AUC) values at 3- and 5-year in the training and internal validation sets were 0.800, 0.800, 0.831 and 0.819, respectively, while those of the external set were 0.765 and 0.735, indicating a satisfactory discrimination with our nomogram. The calibration curves showed highly consistent results for the actual and predicted survival probabilities. Furthermore, patients were divided into three risk groups according to the total scores of the nomogram. The risk stratification system accurately differentiated between patients with different BCSS rates. We constructed the first nomogram and corresponding risk stratification system to predict the 3-year and 5-year BCSS for HR+/HER2- patients with lymph node-positive BC, indicating a satisfactory accuracy and clinical application.

Adjuvant Capecitabine after Neoadjuvant Chemotherapy in Triple Negative Breast Cancer with Lymph Node Metastasis.

To evaluate the effect of complete pathological response (pCR) on prognosis in patients with axillary lymph node-positive triple-negative breast cancer (TNBC) and the efficiency of adjuvant capecitabine. Analytical study. Place and Duration of the Study: University of Health Sciences, Dr Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, between March 2015 and December 2021. The study included 92 patients with TNBC with enlarged axillary lymph nodes and treated with neoadjuvant chemotherapy. The patients were classified as those with and without postoperative pCR and compared in terms of survival. Subsequently, the patients who did not achieve pCR were classified as receiving and not receiving adjuvant capecitabine and were compared for DFS (disease-free survival) and OS (overall survival). Parameters that showed statistical significance were re-evaluated with Cox regression analysis. The 5-year DFS rate was 84.3% in those who achieved pCR, while it was 55.1% in those who did not (p=0.026). The 5-year OS rate was 82.8% in the pCR arm, while it was 51.0% in the non-pCR arm (p=0.070). The 5-year DFS rate was 66.3% in adjuvant capecitabine-receiving patients, while it was 40.8% in the non-capecitabine arm (HR=0.40, p=0.031). The 5-year OS rate was 68.9% in adjuvant capecitabine-receiving patients, while it was 29.6% in the non-capecitabine arm (HR= 0.40, p=0.062). Conclusion: Obtaining pCR following NAC in a locally advanced TNBC is an independent prognostic marker for DFS and OS. In the presence of residual disease, improvement in DFS and OS with adjuvant capecitabine was demonstrated by the real-life data. Triple-negative breast cancer, Neoadjuvant chemotherapy, Capecitabine, Survival.

Noninvasive prediction of node-positive breast cancer response to presurgical neoadjuvant chemotherapy therapy based on machine learning of axillary lymph node ultrasound

ObjectivesTo explore an optimal model to predict the response of patients with axillary lymph node (ALN) positive breast cancer to neoadjuvant chemotherapy (NAC) with machine learning using clinical and ultrasound-based radiomic features.MethodsIn this study, 1014 patients with ALN-positive breast cancer confirmed by histological examination and received preoperative NAC in the Affiliated Hospital of Qingdao University (QUH) and Qingdao Municipal Hospital (QMH) were included. Finally, 444 participants from QUH were divided into the training cohort (n = 310) and validation cohort (n = 134) based on the date of ultrasound examination. 81 participants from QMH were used to evaluate the external generalizability of our prediction models. A total of 1032 radiomic features of each ALN ultrasound image were extracted and used to establish the prediction models. The clinical model, radiomics model, and radiomics nomogram with clinical factors (RNWCF) were built. The performance of the models was assessed with respect to discrimination and clinical usefulness.ResultsAlthough the radiomics model did not show better predictive efficacy than the clinical model, the RNWCF showed favorable predictive efficacy in the training cohort (AUC, 0.855; 95% CI 0.817–0.893), the validation cohort (AUC, 0.882; 95% CI 0.834–0.928), and the external test cohort (AUC, 0.858; 95% CI 0.782–0.921) compared with the clinical factor model and radiomics model.ConclusionsThe RNWCF, a noninvasive, preoperative prediction tool that incorporates a combination of clinical and radiomics features, showed favorable predictive efficacy for the response of node-positive breast cancer to NAC. Therefore, the RNWCF could serve as a potential noninvasive approach to assist personalized treatment strategies, guide ALN management, avoiding unnecessary ALND.

Abstract OT3-15-01: TBCRC-053: P-RAD: A Randomized Study of Preoperative Chemotherapy, Pembrolizumab and No, Low or High Dose RADiation in Node-Positive, HER2-Negative Breast Cancer

Abstract Background: The introduction of immune checkpoint inhibitors (ICI) to standard neoadjuvant chemotherapy regimens has been shown to significantly improve outcomes in patients with triple negative breast cancer and is being investigated for high-risk hormone receptor-positive (HR+)/human epidermal growth factor-2 negative (HER2-) breast cancer. Preclinical evidence suggests radiation therapy (RT) can stimulate intra-tumoral T cell infiltration and enhance the expression and immune detection of tumor-specific neoantigens. This phase II pilot randomized study (NCT04443348) aims to evaluate the safety and efficacy of two different doses of preoperative primary tumor RT boost when combined with neoadjuvant pembrolizumab, then followed by standard neoadjuvant chemotherapy. Dual co-primary endpoints include determining the pathologic complete response (pCR) rate in the non-irradiated and pathologically confirmed metastatic axillary lymph node(s) in each treatment arm and quantifying tumor-infiltrating T lymphocytes in on-treatment (C1D14) tumor biopsies. We hypothesize that high-dose RT will increase the proportion of tumors with high T cell infiltration (i.e., top quartile) from 25% to 55%. Secondary endpoints include measuring residual cancer burden, evaluating tolerability of the regimen, and assessing quality of life. Exploratory endpoints include evaluation of treatment-associated changes in the tumor immune microenvironment, circulating immune cell analyses, and circulating tumor DNA kinetics. Methods: The study plans to enroll 128 participants with either triple negative (n=80) or high-risk HR=/HER2- (n=48) breast cancer who will be randomized to receive no, low (9 Gy), or high (24 Gy) dose of preoperative RT boost, after which 24 participants of either breast cancer subtype will be enrolled to an exploratory high dose proton therapy boost cohort. The eligibility criteria include patients who have biopsy-proven, axillary lymph node-positive breast cancer that is either triple negative (defined as ER&amp;lt; 10%, PR&amp;lt; 10%, and HER2-negative) or high-risk HR+/HER2- (grade III or having a high-risk genomic assay score). Study treatment is given in 6-week cycles, with 400 mg Pembrolizumab given on day 1 of each cycle. For those participants randomized to receive a preoperative RT boost, treatment is delivered in 3 fractions (3 × 3 Gy or 3 × 8 Gy) over consecutive business days, where one of the fractions is given on the same day as C1D1 Pembrolizumab. Standard neoadjuvant chemotherapy begins on C1D15 with paclitaxel (plus carboplatin for triple negative) administered weekly for 12 weeks, and then starting on C3D15, dose-dense doxorubicin/cyclophosphamide is administered every 2 weeks for 8 weeks. Following neoadjuvant treatment, participants will receive standard breast surgery (including removal of the pathologically confirmed metastatic lymph node) followed by adjuvant pembrolizumab, radiation therapy, and standard-of-care systemic therapy as clinically indicated. Tissue samples from the primary tumor and biopsy-proven lymph node are taken at baseline, C1D14, and at the time of surgery. There are eleven blood collection timepoints throughout the neoadjuvant and adjuvant settings. Participants will be followed for 2 years after surgery to assess safety and durability of responses. Results: This study has accrued 12 participants to date, including 10 with triple negative breast cancer and 2 with high-risk HR+/HER2- breast cancer. Formal results for this study are forthcoming, as the trial is actively accruing at 6 institutions, with plans to open at 3 more within the year. For persons with a specific interest in this trial, please contact Joseph Connolly, Multi-Center Coordinator, at jconnolly28@mgh.harvard.edu. Citation Format: Joseph J. Connolly, Laura M. Spring, Alphonse G. Taghian, Michele Gadd, Laura Warren, Ana C. Garrido-Castro, Tari King, Elizabeth A. Mittendorf, Jose P. Leone, Dana L. Casey, Lisa Carey, Tiffany A. Traina, Yara Abdou, Atif Khan, George Plitas, Jean Wright, Cesar Augusto Santa-Maria, Lisa Jacobs, Rachel Blitzblau, E Shelley Hwang, Carey Anders, Ian Krop, Antonio C. Wolff, Alastair M. Thompson, Elyssa Denault, Gaorav Gupta, Alice Ho. TBCRC-053: P-RAD: A Randomized Study of Preoperative Chemotherapy, Pembrolizumab and No, Low or High Dose RADiation in Node-Positive, HER2-Negative Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-15-01.

Axillary ultrasound after neoadjuvant therapy reduces the false-negative rate of sentinel lymph node biopsy in patients with cytologically node-positive breast cancer.

This study aimed to determine whether post-neoadjuvant therapy (NAT) axillary ultrasound (AUS) could reduce the false-negative rate (FNR) of sentinel lymph node biopsy (SLNB). We also performed subgroup analyses to identify the appropriate patient for SLNB. A total of 220 patients with cytologically proven axillary node-positive breast cancer who underwent both SLNB and axillary lymph node dissection (ALND) after NAT were included. We calculated the FNR of SLNB. In the case of post-NAT AUS results available, AUS was classified as negative or positive. Then the FNR of post-NAT AUS combined with SLNB was evaluated. Subgroup analyses based on the number of sentinel lymph nodes removed, molecular subtypes, and the clinical N stage were also performed. The overall axillary lymph node pathological complete response rate was 45.5% (100/220). The FNR of SLNB alone was 15.8% (95%CI: 9.2 to 22.5%). Post-NAT AUS results were available for 181 patients. When combined negative post-NAT AUS results and SLNB, the FNR was reduced to 7.5% (95%CI: 2.4 to 12.7%). Subgroup analyses of the FNR for SLNB alone and negative post-NAT AUS combined with SLNB were shown as follows: in cases patients with less than three sentinel lymph nodes (SLNs) and at least three SLNs removed, the FNR was decreased from 24.5 to 13.2%, and 9.0 to 5.0%, respectively. The FNR was decreased from 20.8 to 10.5% in HR+/HER2+subgroup, 21.4 to 16.7% in HR-/HER2+subgroup, 15.9 to 7.0% in HR+/HER2- subgroup, and 0% in HR-/HER2- subgroup, respectively. For cN1 patients, the FNR was decreased from 18.1 to 12.1% while 17.1 to 3.6% for cN2 patients and 0% for cN3 patients. Using negative post-NAT AUS may help to decrease the FNR and improve patient selection for SLNB.

Abemaciclib: The First FDA-Approved CDK4/6 Inhibitor for the Adjuvant Treatment of HR+ HER2- Early Breast Cancer.

To review the new indication of cyclin-dependent kinase (CDK4/6) inhibitor abemaciclib for the adjuvant treatment of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), axillary lymph node (LN) positive early breast cancer (EBC) at high risk of recurrence and a Ki-67 ≥20%. A literature search was performed through PubMed, ClinicalTrials.gov, and Food and Drug Administration (FDA) website (February 1, 2018, to December 23, 2021) to identify relevant information. Human and animal studies related to pharmacology, pharmacokinetics, efficacy, and safety of abemaciclib were identified. Addition of abemaciclib to standard of care endocrine therapy (ET) for patients with high-risk clinicopathologic features and Ki-67 ≥20% demonstrated 30% reduction in the risk of developing invasive disease and distant recurrence. At 15.5 months, abemaciclib + ET demonstrated a significant improvement in invasive disease-free survival (IDFS) vs ET alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.60-0.93, P = 0.01). At 27 months, IDFS benefit was maintained (HR, 0.70; 95% CI, 0.59-0.82, P < 0.0001). Diarrhea occurred in more than 80% of patients in the abemaciclib arm. This review describes the clinical applicability of adjuvant abemaciclib for patients with HR+, HER2- EBC at high risk for recurrence. Adjuvant abemaciclib significantly reduces the risk for early development of invasive disease and distant recurrence in patients with HR+, HER2- node positive EBC. Longer follow-up is needed to determine the impact of adjuvant abemaciclib on late disease recurrence and survival outcomes.

Adjuvant Capecitabine for Early Breast Cancer: 15-Year Overall Survival Results From a Randomized Trial.

Few data are available regarding the influence of adjuvant capecitabine on long-term survival of patients with early breast cancer. The Finland Capecitabine Trial (FinXX) is a randomized, open-label, multicenter trial that evaluates integration of capecitabine to an adjuvant chemotherapy regimen containing a taxane and an anthracycline for the treatment of early breast cancer. Between January 27, 2004, and May 29, 2007, 1,500 patients with axillary node-positive or high-risk node-negative early breast cancer were accrued. The patients were randomly allocated to either TX-CEX, consisting of three cycles of docetaxel (T) plus capecitabine (X) followed by three cycles of cyclophosphamide, epirubicin, and capecitabine (CEX, 753 patients), or to T-CEF, consisting of three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil (CEF, 747 patients). We performed a protocol-scheduled analysis of overall survival on the basis of approximately 15-year follow-up of the patients. The data collection was locked on December 31, 2020. By this date, the median follow-up time of the patients alive was 15.3 years (interquartile range, 14.5-16.1 years) in the TX-CEX group and 15.4 years (interquartile range, 14.8-16.0 years) in the T-CEF group. Patients assigned to TX-CEX survived longer than those assigned to T-CEF (hazard ratio 0.81; 95% CI, 0.66 to 0.99; P = .037). The 15-year survival rate was 77.6% in the TX-CEX group and 73.3% in the T-CEF group. In exploratory subgroup analyses, patients with estrogen receptor-negative cancer and those with triple-negative cancer treated with TX-CEX tended to live longer than those treated with T-CEF. Addition of capecitabine to a chemotherapy regimen that contained docetaxel, epirubicin, and cyclophosphamide prolonged the survival of patients with early breast cancer.

POstmastectomy radioThErapy in Node-posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL): a study protocol for a multicenter prospective phase III randomized controlled trial

BackgroundVarious randomized trials have demonstrated that postmastectomy radiotherapy (RT) to the chest wall and comprehensive regional nodal areas improves survival in patients with axillary node-positive breast cancer. Controversy exists as to whether the internal mammary node (IMN) region is an essential component of regional nodal irradiation. Available data on the survival benefit of IMN irradiation (IMNI) are conflicting. The patient populations enrolled in previous studies were heterogeneous and most studies were conducted before modern systemic treatment and three-dimensional (3D) radiotherapy (RT) techniques were introduced. This study aims to assess the efficacy and safety of IMNI in the context of modern systemic treatment and computed tomography (CT)-based RT planning techniques.MethodsPOTENTIAL is a prospective, multicenter, open-label, parallel, phase III, randomized controlled trial investigating whether IMNI improves disease-free survival (DFS) in high-risk breast cancer with positive axillary nodes (pN+) after mastectomy. A total of 1800 patients will be randomly assigned in a 1:1 ratio to receive IMNI or not. All patients are required to receive ≥ six cycles of anthracycline and/or taxane-based chemotherapy. Randomization will be stratified by institution, tumor location (medial/central vs. other quadrants), the number of positive axillary nodes (1–3 vs. 4–9 vs. ≥10), and neoadjuvant chemotherapy (yes vs. no). Treatment will be delivered with CT-based 3D RT techniques, including 3D conformal RT, intensity-modulated RT, or volumetric modulated arc therapy. The prescribed dose is 50 Gy in 25 fractions or 43.5 Gy in 15 fractions. Tiered RT quality assurance is required. After RT, patients will be followed up at regular intervals. Oncological and toxilogical outcomes, especially cardiac toxicities, will be assessed.DiscussionThis trial design is intended to overcome the limitations of previous prospective studies by recruiting patients with pN+ breast cancer, using DFS as the primary endpoint, and prospectively assessing cardiac toxicities and requiring RT quality assurance. The results of this study will provide high-level evidence for elective IMNI in patients with breast cancer after mastectomy.Trial registrationClinicalTrails.gov, NCT04320979. Registered 25 Match 2020, https://clinicaltrials.gov/ct2/show/NCT04320979

Dose-Dense Docetaxel versus Weekly Paclitaxel following Dose-Dense Epirubicin and Cyclophosphamide as Adjuvant Chemotherapy in Node-Positive Breast Cancer Patients: A Retrospective Cohort Analysis.

Methods This study included patients from two prospective studies conducted in our institute from April 2007 to March 2009. Ninety-one women with axillary lymph node-positive breast cancer who had received four cycles of dose-dense epirubicin and cyclophosphamide were treated with either weekly paclitaxel (80 mg/m2) for 12 doses or biweekly docetaxel (75 mg/m2) for four cycles. Results After a median follow-up of 88 and 109 months, 11 (23.4%) and 10 (22.7%) patients had experienced disease recurrence (p = 0.16), while 10 (21.3%) and 5 (11.4%) patients had died in the paclitaxel and docetaxel arm, respectively (p = 0.56). No significant difference could be seen in 5-year DFS or OS among groups (HR: 0.58; 95% CI: 0.19–1.81, p = 0.35; HR: 0.58; 95% CI: 0.19–1.81, p = 0.35, respectively). Conclusion In conclusion, both evaluated adjuvant chemotherapy regimens have comparable effectiveness regarding DFS and OS.

El papel pronóstico del SUVmáx basal y cambio del SUVmáx en la PET/TC con18F-FDG en pacientes con cáncer de mama con ganglios positivos que reciben quimioterapia neoadyuvante

ObjectiveThis study aimed to determine the prognostic role of baseline maximum standardized uptake value (SUVmax) obtained by pretreatment PET/CT and the change in SUVmax (ΔSUVmax [%]) in patients with axillary lymph node–positive breast cancer receiving neoadjuvant chemotherapy (NAC). MethodsOne hundred and eighty patients with baseline SUVmax and 121 patients with SUVmax measurement after treatment were evaluated in the study. The baseline SUVmax value of the breast (SUVmaxBI) and axilla (SUVmaxAI) and the change in the SUVmax of the breast (ΔSUVmaxB) and axilla (ΔSUVmaxA) were measured. The optimal cut-off value of SUVmax and ΔSUVmax were determined by ROC curve analysis. Disease-free survival (DFS) and overall survival (OS) were calculated using Kaplan–Meier curves. ResultsΔSUVmaxB, pCRB, pCRA, and pCR parameters were found to be associated with relapse (p < 0.001, p = 0.033, p = 0.016, and p = 0.013, respectively). ΔSUVmaxB and SUVmaxAI were associated with mortality (p = 0.001 and p = 0.006, respectively). Multiple Cox regression analyses revealed that ΔSUVmaxB value was an independent prognostic factor for relapse and mortality (p = 0.013 and p = 0.010, respectively). ConclusionThe results showed that ΔSUVmaxB was an independent prognostic factor for relapse and mortality in patients with axillary lymph node–positive breast cancer who received NAC.

Early reflector localization improves the accuracy of localization and excision of a previously positive axillary lymph node following neoadjuvant chemotherapy in patients with breast cancer.

Clipped axillary lymph node (CALN) localization after neoadjuvant chemotherapy (NAC) for axillary node positive breast cancer can be difficult due to significant shrinkage or disappearance of the CALN after NAC. This study compares wire localization to a radar-based localization system utilizing a reflector that can be placed before or during NAC, in the months before definitive surgery, to facilitate accurate localization and excision of the CALN. Between 2016 and 2019, women with T0-4 N1-3 M0 breast cancer who underwent NAC followed by axillary surgery with planned excision of a biopsy positive or clinically suspicious axillary node via wire or reflector localization were identified. A retrospective chart review was performed comparing successful localization and CALN retrieval by each localization technique. Ninety-nine patients met inclusion criteria. Forty-two patients underwent wire localization while 57 patients underwent reflector localization of the CALN. Successful identification of the CALN by wire or reflector was equivalent (83.3% vs 84.2%, respectively). Twenty-two reflectors placed before or during early/mid NAC (early placement) had 100% successful CALN localization and retrieval in the OR. Placement of wire or reflector localization devices within 8weeks of surgery (late placement) only resulted in 79.2% localization success (p = .02). This study suggests a benefit of axillary lymph node reflector placement in the early NAC setting. Early reflector placement allows for more accurate excision of the CALN during axillary surgery after NAC as compared to placement of localization wires or reflectors in the few weeks prior to surgery.

The prognostic role of baseline 18F-FDG PET/CT SUVmax and SUVmax change in patients with node-positive breast cancer receiving neoadjuvant chemotherapy

ObjectiveThis study aimed to determine the prognostic role of baseline maximum standardized uptake value (SUVmax) obtained by pretreatment PET/CT and the change in SUVmax (ΔSUVmax [%]) in patients with axillary lymph node–positive breast cancer receiving neoadjuvant chemotherapy (NAC). MethodsOne hundred and eighty patients with baseline SUVmax and 121 patients with SUVmax measurement after treatment were evaluated in the study. The baseline SUVmax value of the breast (SUVmaxBI) and axilla (SUVmaxAI) and the change in the SUVmax of the breast (ΔSUVmaxB) and axilla (ΔSUVmaxA) were measured. The optimal cut-off value of SUVmax and ΔSUVmax were determined by ROC curve analysis. Disease-free survival (DFS) and overall survival (OS) were calculated using Kaplan–Meier curves. ResultsΔSUVmaxB, pCRB, pCRA, and pCR parameters were found to be associated with relapse (P < .001, P = .033, P = .016, and P = .013, respectively). ΔSUVmaxB and SUVmaxAI were associated with mortality (P = .001 and P = .006, respectively). Multiple Cox regression analyses revealed that ΔSUVmaxB value was an independent prognostic factor for relapse and mortality (P = .013 and P = .010, respectively). ConclusionThe results showed that ΔSUVmaxB was an independent prognostic factor for relapse and mortality in patients with axillary lymph node–positive breast cancer who received NAC.

Survival in Cytologically Proven Node-Positive Breast Cancer Patients with Nodal Pathological Complete Response after Neoadjuvant Chemotherapy.

Simple SummaryIt is unknown whether patients with cytologically proven axillary node-positive breast cancer, who achieve axillary pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) have a comparable prognosis to patients with axillary pathological node-negative disease (pN-) without NAC. The aim of this retrospective study was to clarify the clinical impact of axillary pCR after NAC on survival and to compare survival outcomes between breast cancer patients with axillary pCR, and those with axillary pN- without NAC, using propensity score matching to adjust for baseline characteristics other than nodal status. Axillary pCR after NAC was associated with improved prognosis in patients with axillary node-positive disease, and patients with axillary pCR and matched pairs with axillary pN- without NAC had comparable outcomes.Background: It is unknown whether patients with cytologically proven axillary node-positive breast cancer who achieve axillary pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) have comparable prognosis to patients with axillary pathological node-negative disease (pN-) without NAC. Methods: We retrospectively reviewed the data of patients with cytologically proven axillary node-positive disease who received NAC and those with axillary pN- without NAC for control between January 2007 and December 2012. We compared outcomes according to response in the axilla to NAC and between patients with axillary pCR and matched pairs with axillary pN- without NAC using propensity scores. Results: We included 596 patients with node-positive breast cancer who received NAC. The median follow-up period was 64 months. Patients with axillary pCR showed significantly better distant disease-free survival (DDFS) and overall survival (OS) than patients with residual axillary disease (both p < 0.01). There was no significant difference in DDFS and OS between patients with axillary pCR and matched pairs with axillary pN- without NAC. Conclusion: Axillary pCR was associated with improved prognosis. Patients with axillary pCR and matched pairs with axillary pN- without NAC had comparable outcomes. This information will be useful when considering the intensity of follow-up and adjuvant therapy.

The efficacy of frozen gel packs on postoperative pain, and NSAID or narcotic use in patients undergoing surgery for axillary node-positive breast cancer.

The efficacy of frozen gel packs on postoperative pain, and NSAID or narcotic use in patients undergoing surgery for axillary node-positive breast cancer.

Association between FGFR1 copy numbers, MAP3K1 mutations, and survival in axillary node-positive, hormone receptor-positive, and HER2-negative early breast cancer in the PACS04 and METABRIC studies.

Hormone receptor-positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) early breast cancer (BC) is the most prevalent BC subtype with substantial biological heterogeneity. Although clinicopathological (CP) characteristics have a clear prognostic value, additional biomarkers could refine survival prediction and guide treatment decision. Copy number aberrations and somatic driver mutations were obtained with OncoScan CGH array and sequencing of 36 genes on HR+/HER2- node-positive early BC patients treated with chemotherapy from the PACS04 trial. We built a two-gene genomic score (GS) associated with distant disease-free survival (DDFS), whose prognostic value was assessed on the external METABRIC data (n = 1413) using overall survival (OS) and breast cancer-specific survival (BCSS). In the PACS04 trial (n = 327), the median follow-up for DDFS (65 events) was 9.6years. FGFR1 amplifications ([Formula: see text] = 2.44, 95% CI [1.25; 4.76], p = 0.009) and MAP3K1 mutations ([Formula: see text] = 0.10, [0.01; 0.78], p = 0.03) were associated with DDFS beyond CP characteristics. A prognostic GS combining FGFR1 amplifications and MAP3K1 mutations added more information to CP model ([Formula: see text] = 12.97, [Formula: see text] < 0.001 and [Formula: see text] = 11.52, [Formula: see text] < 0.001). In the METABRIC study (n = 1413), FGFR1 amplifications ([Formula: see text] = 2.00 [1.40; 2.87], p < 0.001) and MAP3K1 mutations ([Formula: see text] = 0.58 [0.41; 0.83], p = 0.003) were significantly associated with BCSS beyond CP characteristics. The prognostic GS added significant prognostic information to CP model ([Formula: see text] = 15.39, [Formula: see text] < 0.001 and [Formula: see text] = 5.62, [Formula: see text] = 0.02). In axillary node-positive, HR+, and HER2- early BC, amplifications of FGFR1 gene were strongly associated with increased risk for distant disease, while mutations of MAP3K1 gene were significantly associated with decreased risk.

Lymph Node Ratio (LNR): Predicting Prognosis after Neoadjuvant Chemotherapy (NAC) in Breast Cancer Patients.

Axillary lymph node status is an important prognostic factor in breast cancer (BC). Residual nodal disease burden after neoadjuvant chemotherapy (NAC) is one of the important prognostic factors to determine the prognosis and in the treatment of BC. Lymph node ratio (LNR) defined as the ratio of the number of positive lymph nodes to total excised axillary lymph nodes, may be a stronger determinant of prognosis than pN in axillary nodal staging, although there is very limited data evaluating its prognostic value in the setting of NAC. In this cohort of patients, we studied the utility of LNR in predicting recurrence and overall survival (OS) after NAC. An Institutional cancer registry was queried from 2009 to 2014 for women with axillary node-positive BC with no evidence of distant metastasis, and who received NAC followed by surgery for loco-regional treatment (axillary dissection with breast conserving surgery or total mastectomy). Patients with axillary complete response were excluded. Locoregional recurrence (LRR), distant recurrence (DR) and overall survival (OS) rates were reviewed regarding pN and LNR. A total of 179 patients were analyzed. Median follow up time was 24 [25%, 75%: 13-42] months. Patients with pN1 in comparison to pN2 and pN3 had lower rate of LRR (9% vs. 15% and 14%, respectively; p=0.41), lower rate of DR (14% vs. 25% and 27%, respectively, p=0.16) and increased rate of OS (89% vs. 79% and 78%, respectively, p=0.04). In comparison to patients with LNR >20%, patients with LNR ≤20% had lower LRR (9% vs. 14%, p=0.25), lower DR (13% vs. 27%, p=0.01) and improved OS (89% vs. 79%, p=0.02) rates. In the pN1 group, patients who had a LNR >20% had higher DR (22% vs. 14%, p=0.48) rates in comparison to patients with LNR ≤20%. In ER/PR (+) patients who had LNR ≤20% DR was 6% compared with 23% in patient who had LNR >20% (p=0.02), and in triple negative patients' OS rate was significantly better compared the LNR less/equal or more than 20% (71% vs 33%, p=0.001). Our study demonstrated that LNR adds valuable information for the prognosis after NAC and this additional information should be considered when deciding further treatment and follow-up for patients who had residual tumor burden on the axilla. This observation should be tested in a larger study.

Intensity-Modulated Radiation Therapy versus 3D Conformal Radiation Therapy in Patients Undergoing Regional Nodal Irradiation/Postmastectomy Radiation Therapy for Breast Cancer: Looking Beyond Dosimetric Outcomes

Prospective data and meta-analyses support the use of adjuvant regional nodal irradiation (RNI)/postmastectomy radiation therapy (PMRT) for the majority of women with axillary lymph node positive breast cancer. However, RNI increases dose to the heart and lung compared resulting in increased toxicity. Inverse-planned intensity modulated radiation therapy (IMRT) has the ability to reduce high dose to the heart/lung compared to traditional 3D conformal radiation therapy (3DCRT). Early concerns with IMRT were that it may be too conformal resulting in increased risk of local-regional failures (LRF). To date, clinical outcomes with IMRT have not been well studied in patients receiving RNI/PMRT. We have used planning target volume (PTV)-based, dose-volume analysis driven RNI/PMRT planning since 2013 using primarily 3DCRT but IMRT as needed to meet heart/lung planning objectives. We hypothesize that toxicity and LRF rates are similar between patients treated with IMRT and 3DCRT. We identified patients that received RNI/PMRT from 2013-2016. Patients received conventional fractionation (200 cGy/day) to the breast/chestwall, axillary, supraclavicular (SCV), and internal mammary chain (IMC) PTVs. We divided the cohort into 2 groups (IMRT vs. 3DCRT). We collected patient and disease characteristics, acute toxicity, LRF, and distant metastases (DM) events. Differences in characteristics were evaluated with the t-test or Chi-square test. The primary endpoint was the cumulative incidence of LRF as a first failure. We also evaluated the cumulative incidence of DM. We included 241 patients (69 IMRT, 172 3DCRT): 60% had stage III disease; 60% (ER+ or PR+)/HER2-; 20% triple-negative; 20% HER2+. IMRT group had higher rates of left-sided (65% vs. 47%, p=0.009) and grade 3 (58% vs. 43%, p=0.04) disease. The IMCs were irradiated in 97%. Treatment was well tolerated: grade 3 dermatitis 6% in each group with no other grade 3 toxicities. Grade 2 pneumonitis occurred in 2 (0.83%), both 3DCRT. Median follow-up is 3.5 years. There were 5 LRF events (2 IMRT, 3 3DCRT): 2 patients with isolated LRF (iLRF) and 3 patients with simultaneous LRF+DM resulting in 4-year LRF=2.1% (4.1% IMRT vs. 1.4% 3DCRT, p=0.55) and 4-yr iLRF=1.1% (1.5% vs. 0.8%, p=0.43). The iLRF (1 IMRT, 1 3DCRT) both occurred in the SCV region. The other LRF+DM event in the IMRT group was a chestwall/axillary/IMC recurrence post-mastectomy. The additional 2 LRF+DM events in the 3DCRT group included: ipsilateral SCV and level V nodes post-lumpectomy; and a lumpectomy bed recurrence. Most failures were DM: 4-year rate=15% (21.0% IMRT vs. 13.2% 3DCRT, p=0.58). In this modern cohort of patients receiving RNI/PMRT with a PTV-based approach, we saw rare high-grade toxicity, and we found no difference in LRF and DM rates between IMRT and 3DCRT patients. These data should provide reassurance that IMRT does not compromise disease outcomes and that IMRT can safely be used when needed to meet normal tissue constraints.