Recurrence In Early-stage Breast Cancer Research Articles

Abstract PO1-01-11: Development and Validation of a Breast Cancer Recurrence Model Demonstrates Accurate Identification of Patients with Favorable Long-Term Outcomes

Abstract Background: The Oncotype DX (ODX) test is a 21-gene expression assay widely used for the prediction of risk recurrence in early-stage breast cancer, but it may be possible to identify patients who can forgo testing using only clinicopathologic variables. In 2018, the National Cancer Database (NCDB) began reporting quantitative histologic parameters for estrogen receptor (ER), progesterone receptor (PR), and Ki-67 expression in breast cancer patients. Inclusion of these variables may improve the development of nationally applicable models to predict ODX results using clinicopathologic variables alone. Methods: Using a cohort of patients from the NCDB diagnosed from 2018–2020 with hormone receptor (HR)-positive, HER2-negative, Stage I-III breast cancer, we trained machine learning models to predict high-risk (26-100) ODX score. A subset comprising 80% of patients was used for model training, while the remaining data were set aside for internal validation. An external validation cohort was selected from the University of Chicago Medical Center (UCMC), including patients diagnosed from 2009–2021. Feature selection, model architecture selection, and hyperparameter tuning were performed using 10-fold cross-validation within the NCDB training set. We compared a model with quantitative ER, PR, and Ki-67; a model with only quantitative ER and PR, and a model without quantitative immunohistochemistry – to best reflect the likely data available in a variety of practice patterns. The primary endpoint was the area under the receiver operating characteristic curve (AUROC) for prediction of high-risk ODX results in the UCMC validation cohort. Models were also evaluated as rule-out tests to identify low-risk patients who did not require further ODX testing, using a high (90%) sensitivity threshold, fit in the NCDB training dataset. Results: We identified 53,346 patients from the NCDB cohort meeting the inclusion criteria; 7% had a high risk ODX score, with a median follow-up time of 28 months. The UCMC validation cohort included 896 patients, and was more diverse, with 30% non-Hispanic Black patients (versus 8% in NCDB), more high-risk patients (18% with high ODX), and a longer median follow-up time of 55 months. In the NCDB validation cohort, models incorporating quantitative ER/PR (AUROC 0.78, 95% CI 0.77–0.80) and quantitative ER/PR/Ki-67 (AUROC 0.81, 95% CI 0.80–0.83) both performed better than the non-quantitative model (AUROC 0.70, 95% CI 0.68–0.72). These results were preserved in the external UCMC cohort, where the ER/PR model (AUROC 0.86, 95% CI 0.80–0.92, p = 0.032) and the ER/PR/Ki-67 model (AUROC 0.87, 95% CI 0.81–0.93) outperformed the non-quantitative model (AUROC 0.80, 95% CI 0.73–0.87, p = 0.009). The high sensitivity rule-out threshold of the ER/PR model predicted that 30% of patients in the UCMC cohort would be low ODX, and the ER/PR/Ki-67 model predicted 44% as low risk – negative predictive value was over 96% for prediction of high ODX. Of the patients predicted to be low risk by the quantitative models, none had a documented high ODX score, and recurrence was < 3% at 5 years. The hazard ratio for recurrence free interval, adjusted for age and comorbidity score, of patients predicted to be high risk by this threshold was 2.96 (95% CI 1.02–8.58) for the ER/PR model and 3.84 (95% CI 1.48–9.97) for the ER/PR/Ki-67 model. Conclusions: We present externally validated and nationally applicable models that identify approximately half of HR-positive/HER2-negative breast cancer patients who are unlikely to have high ODX results using widely available quantitative clinicopathologic variables. Patients identified as low risk by these models have excellent long-term outcomes and may be able to forgo adjuvant chemotherapy without further genomic testing. Citation Format: Asim Dhungana, Augustin Vannier, Fangyuan Zhao, Jincong Freeman, Poornima Saha, Megan Sullivan, Katharine Yao, Elbio Flores, Olufunmilayo Olopade, Dezheng Huo, Alexander Pearson, Frederick Howard. Development and Validation of a Breast Cancer Recurrence Model Demonstrates Accurate Identification of Patients with Favorable Long-Term Outcomes [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 PO1-01-11.

Increased PI3K pathway activity is associated with recurrent breast cancer in patients with low and intermediate 21-gene recurrence score

AimsWe investigated key signalling pathways’ activity and mutational status of early-stage breast carcinomas with low and intermediate 21-gene recurrence score (RS) to identify molecular features that may predict recurrence.MethodsThis is...

Matrix Metalloproteinase as Predictors of Local Recurrence in Early-Stage Breast Cancer After Mastectomy and Chemotherapy A Cross-Sectional Study in Single Centre

Introduction: The prognosis for early-stage breast cancer is generally favourable. However, in cases when a recurrence manifests after therapy, the prognosis becomes significantly poor. To determine early breast cancer recurrence risk, a marker is needed. Currently, previous tumour markers are used to predict general breast cancer, lacking specificity in the context of early breast cancer. Matrix Metalloproteinase1 (MMP1) is already acquainted with the local recurrence process of invasive ductal carcinoma (IDC). MMP1 expression may better predict early recurrence in early-stage IDC than other approaches. This research examined the potential predictive value of MMP1 expression in early-stage IDC for early local recurrence and its correlation with clinicopathological factors. Methods: This study was a cross-sectional analysis of a single center's medical records. The sample size was 25 subjects for the group without recurrence and 25 subjects with recurrence. Mastectomy and chemotherapy were performed from January 2014 through December 2019. Using immunohistochemistry, paraffin blocks of surgical specimens were examined for MMP1. The data processing was done utilising the trial version of IBM SPSS 25. and Openepi 3.0 programs and analysed using Bivariate, which is performed using the Chi-square test or Fisher's exact test. Result: The statistic test showed a significant difference (p < 0.000) in the average expression of MMP1 for non-recurrence cases (3,95±5,36) compared to recurrence cases (14,95±5,36). We also found a statistically significant correlation between recurrence and high expression of MMP1 (odd ratio [OR]= 60.38, 95% confidence interval [CI]=10.01-364.3, p<0.001). Clinicopathological variables and MMP1 expression did not have a significant correlation. Conclusions: In early-stage IDC, MMP1 expression had the potential to predict and could be an independent prognostic factor for early recurrence.

Uveitis, a rare but important complication of adjuvant zoledronic acid for early-stage breast cancer.

Bisphosphonates such as zoledronic acid are an important part of adjuvant therapy to reduce the risk of recurrence in early-stage breast cancer. Uveitis remains one of the lesser-known side effects of zoledronic acid; prompt recognition is essential to ensure patients receive appropriate and timely care to help prevent permanent vision loss. We report a case of anterior uveitis in a postmenopausal woman who presented with visual symptoms after receiving the first dose of zoledronic acid. This case report serves to educate and increase awareness of the risk of uveitis in patients who are given zoledronic acid. This is the first and only reported case of zoledronic acid when used in the adjuvant setting for the treatment of breast cancer.

Abstract P5-15-07: Let's talk about it: Communicating about risk of recurrence in early-stage breast cancer

Abstract Introduction: Risk of recurrence underlies virtually all decision-making in early-stage breast cancer (EBC). Yet, patients and physicians (HCPs) express challenges, limitations, and unmet needs related to HCP-patient communication about recurrence risk. Methods: This qualitative study included: (A) 16 individual interviews with patients diagnosed with EBC in the last 2 years, for their ability to draw on their experience and (B) 2 focus groups with consumers who have never had a cancer diagnosis, for their ability to provide the “cancer-naïve” perspective that may more closely match newly diagnosed patients. Prior to and after the qualitative research, several breast cancer HCP thought leaders were consulted regarding questions and takeaways. Patients were identified via Wellness House, a cancer support organization, whose staff provided counseling support in case the topic was distressing to interviewees. Consumers were identified via a nationwide market research panel. Research took place online in 02/2021. Within the domain of HCP-patient communication about risk of recurrence, questions differed a bit for patients vs consumers but focused on: Experience, Desires, Objectives, and Reactions to methods of explaining risk. Discussion guides, recruiting/screening materials, informed consent documents, and processes were submitted to Advarra IRB and received exempt status. Results: A total of 32 women (16 patients; 16 consumers) participated, with a mix of ages, educational attainment, and racial and ethnic social identities. Information needs were high with objectives centered on being part of treatment decision-making and being motivated to adhere to treatment, screening, and follow-up. Respondents noted that communication about hard topics is central to building a trusting HCP relationship. Many patients felt they had not heard much about their risk, with some admitting they did not want to hear about it. HCPs face a mix of attitudes, but no patients thought they were told too much. Communication timing was a central theme. Many described the information overload that occurs at/near diagnosis and felt they might need a general understanding of recurrence risk at that time, with intentional revisiting of recurrence risk at each decision or transition point (most often connected to changes in modalities or treatments). Within ER+/HER2- disease, patients discussed the transition to oral (endocrine) therapies and specifically noted that time with physicians was limited at that point. In such cases, recurrence risk was insufficiently linked to the recommendation to take a long course of oral therapy that often has significant side effects. Some interviewees were reticent to continue oral therapy, particularly without knowing why it mattered. Communication methods garnered a wide mix of reactions and revealed misinterpretations, underscoring the need to simplify and individually tailor tools. Some group-level tailoring is also possible with degree of risk over time differing by subtype and stage. From a “misunderstanding” standpoint, it seemed time horizons were even less likely to be recalled or understood by patients with ER+/HER2- disease. Respondents focused on wanting information on how they could reduce risk (e.g., diet, exercise, alcohol) and many felt they received inadequate information from HCPs. This led them to search elsewhere for such information. Conclusions: Improving HCP-patient communication about risk of recurrence appears very likely to contribute to shared decision-making and adherence. In particular, the timing of communication may offer a key opportunity to achieve these objectives. In addition, providing tips and tools to oncologists to enhance two-way communication may be helpful, particularly to simplify and tailor by subtype and patient need. Citation Format: Mary L Smith, Elda M Railey, Carol B White. Let's talk about it: Communicating about risk of recurrence in early-stage breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-15-07.

Abstract P2-01-07: Detection of early-stage breast cancer recurrence using a personalised liquid biopsy-based sequencing approach

Abstract BACKGROUNDDetection of minimal residual disease (MRD) using circulating tumor DNA (ctDNA) represents an attractive alternative to imaging, currently considered the gold standard in routine surveillance of early breast cancer (BrCa) following primary therapy. ctDNA has the potential to identify patients who may eventually develop distant metastatic disease and, as such, its implementation in the routine clinical follow-up setting may offer the means for earlier intervention for patients with oligometastatic disease and improved overall survival. However, due to the highly heterogeneous nature of the genomic alterations in BrCa, ultra-sensitive ctDNA assays are required for follow-up surveillance. Here we evaluate RaDaR™, a personalised liquid biopsy-based sequencing assay for the detection of residual disease and monitoring after standard treatment in early-stage BrCa. METHODS38 early-stage BrCa patients recruited through the BRandO BiO registry study were included (18% TNBC, 74% HR+/HER2-, 8% HER2+). 21 patients experienced clinical recurrence (13 distant and 8 local), with a median time to progression of 18.9 months. The remaining 17 case-control patients had no disease recurrence at the time of 3-year follow-up. Whole exome sequencing (WES) was performed on formalin-fixed, paraffin-embedded (FFPE) tumor tissue from curative-intent surgery and selected variants were used to design personalised RaDaR panels (38-54 variants/panel: median 49). In total, 52 plasma samples were analyzed using RaDaR. This included samples taken at the time of recurrence and at 12-months post-diagnosis where available (33 samples from 21 patients), or in the case of no recurrence, samples taken at 3-year follow up, including one control case that had two additional samples analyzed at 12-months and 4-years of follow up (19 samples from 17 patients). RESULTSIn total, ctDNA was detected in 12/13 (92%) patients with distant recurrence and 3/8 (38%) patients with local recurrence at an estimated median variant allele frequency (VAF) of 0.827% (range: 0.0029% - 38%). The lowest levels were seen in the 3 patients with local recurrence (0.0029%, 0.0146% and 0.0248% VAF). Of the 6 patients negative for ctDNA, 5 had local and one distant recurrence of unusual histology, indicating a possible alternative origin or second primary tumor. Only one of the 17 control cases was positive for ctDNA (0.0085% VAF), from a patient with a Luminal A, stage I tumor, potentially indicating the presence of early molecular recurrence that precedes clinical progression. Two additional time points from this patient also showed positive ctDNA results, which could be indicative of residual disease remaining dormant. Of the 12 patients with disease recurrence for which an earlier plasma sample was available, 4 patients (3 with distant and one with local recurrence) had ctDNA detected at the earlier time point, a median of 92 days (range 42 – 308 days) prior to clinical recurrence. 3 patients had ctDNA detected only at the time of recurrence (one distant and 2 local). None of the 5 patients with ctDNA negative results at the time of recurrence had detectable ctDNA levels at the earlier timepoint. CONCLUSIONIn this real-world pilot study, the RaDaR assay detected the presence of ctDNA in plasma to levels as low as 0.0029% VAF. We found that ctDNA detection was strongly associated with distant recurrence in early-stage BrCa, with a sensitivity of 92% (12 of 13 cases detected). In a limited number of cases where samples were available prior to recurrence, ctDNA could be detected ahead of clinical progression, potentially offering the opportunity for earlier intervention. Citation Format: Wolfgang Janni, Jens Huober, Sophia Huesmann, Christodoulos Pipinikas, Tatjana Braun, Volkmar Müller, Giovanni Marsico, Angelina Fink, Paula Freire-Pritchett, Karin Koretz, Charlene Knape, Amelie deGregorio, Brigitte Rack, Thomas WP Friedl, Lisa Wiesmueller, Peter Möller, Karen Howarth, Klaus Pantel, Nitzan Rosenfeld. Detection of early-stage breast cancer recurrence using a personalised liquid biopsy-based sequencing approach [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 P2-01-07.

Predictors of lymphovascular invasion in estrogen receptor positive/Her-2 negative breast cancer patients treated with neoadjuvant chemotherapy.

Lymphovascular invasion (LVI) is considered a high-risk factor for recurrence in early-stage breast cancer, hence examination of LVI in pathological samples is an absolute recommendation. We aim to investigate predictive factors of LVI in preneoadjuvant chemotherapy (NAC) patients with estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) molecular subtypes of breast cancer. One hundred and thirty-four patients treated with NAC were included in this study who were ER+/HER2-. The clinical characteristics of the patients, the data obtained from the core needle biopsy before NAC and the LVI status in the pathology that examined after breast surgery were collected. Univariate and multivariate analysis were performed using the logistic regression model. An examination of the association between LVI and clinical-pathological patient characteristics showed that advanced age (>40 years old) (p = 0.021), ductal histology (p = 0.039), and presence of axillary lymph node metastasis (p = 0.005) were predictors of LVI. Independent predictors of LVI in a multivariate logistic model included advanced age (p = 0.037), and the presence of axillary lymph node metastasis prior to NAC (p = 0.006). The median RFS (Recurrence-free survival) time was 22.8 months for all patients. RFS was shorter in patients with LVI (log-rank p = 0.037). Independent predictors of LVI are advanced age and lymph node positivity at the time of diagnosis. Our study is the first study that evaluates pre-NAC predictive factors of LVI in ER+/HER2- breast cancer patients treated with NAC.

Can high Ki67 predict distant recurrence in early-stage breast cancer with low Oncotype Dx score?

e12561 Background: Ki-67 is a marker of proliferating cells. The recurrence score based on the 21-gene breast cancer assay also called Oncotype Dx provides prognostic and predictive information for recurrence in early stage breast cancer patients. We previously showed that there is a moderate correlation between Ki67 and oncotype Dx recurrence score. In this retrospective study, we aimed to examine whether high Ki67 could predict the distant recurrence in early stage breast cancer with low oncotype Dx scores ( < 25). Methods: This retrospective study included 278 consecutive cases of hormone receptor-positive, HER2 negative (T1-2 N0 M0) breast cancer who were diagnosed between 2008 and 2015 with low oncotype Dx ( < 25). Patients’ clinical outcome in terms of distant recurrence after breast surgery was determined up to December 2020 (median follow-up of 7 years). Patients were divided in to low risk (Ki67 < 15%) and high risk (Ki67 > = 15%) groups. Results: Of 278 cases with average and median age of 59 and 60 respectively, 148 (53%) were in Ki67 low risk and 130 (47%) were in Ki67 high risk group. Average and median oncotype Dx were 13.86 and 15 respectively in Ki67 low risk versus 15.23 and 16 respectively in Ki67 high risk group. 13 patients (4%) experienced distant metastasis in lung, liver, bone and skin. Of these 13 cases with average and median oncotype Dx 15.84 and 19 respectively, 12 (92%) were in the Ki67 high risk group and only 1 (8%) belonged to the low risk category. High Ki67 patients were overrepresented in group with recurrent distant metastasis compare to group without recurrent disease (Pearson Chi-Square = 51.18 with 1 degree of freedom and P = < 0.001). Conclusions: Ki67 high patients in the low risk oncotype Dx group are relapsing at a significantly higher rate suggesting that Ki67 combined with low oncotype Dx further refines the risk of distant relapse.

Abstract PS6-61: Survivin immunoexpression: An independent prognostic marker of recurrence in early-stage breast cancer

Abstract Survivin is a small protein member of the inhibitor of apoptosis protein family. Its expression occurs in G2/M phase of cell cycle, acting inhibiting apoptosis blocking caspases cascade directly or indirectly, and also controlling cell division. Survivin was found to be overexpressed in breast cancer, and its expression have been associated mostly with poor outcome. The aim of this case-control study was to evaluate the prognostic value of Survivin immunoexpression in early stage (pT1pN0 or pT2pN0) breast cancer. The study was conducted collecting data from 170 women with invasive breast carcinoma. The case group (n=57) and control group (n=113) consisted of patients with and without tumor recurrence, respectively. Immunohistochemical Tissue Microarray analyses were conducted to detect Survivin expression. In addition, molecular classification was done based on immunohistochemistry, and classic clinical and histological breast cancer variables were collected. The findings were submitted to the chi-square test and Fisher’s exact test, followed by multivariate analysis with multinomial logistic regression. The level of statistical significance was set at 5% (p<0.05). Median follow-up time was 6 years, ranging from 4 to 13 years. In the univariate analysis, patients with recurrence presented a higher histologic grade (p=0.005), percentage of tumor cells expressing survivin (p=0.006) and stronger immunostaining for this protein (p=0.021). In the multivariate analysis, stronger immunostaining for survivin (OR 1.850; p=0.023) and greater percentage of survivin expression (OR 2.290; p=0.016) persisted independently associated which higher rates of recurrence. Higher immunoexpression of survivin was independently associated with recurrence in early stage invasive breast tumors. Multinomial logistic regression model. In the first model, variables with p <0.200 were used in order to highlight the first order factors independently associated with disease-free survival. In the second model, variables with a significant association in model 1 were excluded in order to highlight second order factors independently associated with disease-free survival. In the third model, there were no factors independently associated with disease-free survival. Table 1 - Clinical-pathological characterization of the 170 cases of early stage breast cancer patients with and without recurrence.RecurrenceTotalNoYespAge≤ 55 years8658280,78650,6%51,3%49,1%> 55 years84552949,4%48,7%50,9%Histological subtypeDuctal158104540,24492,9%92,0%94,7%Lobular5502,9%4,4%,0%Others7434,1%3,5%5,3%StagespT1a7520,9024,1%4,4%3,5%pT1b2113812,4%11,5%14,0%pT1c65452038,2%39,8%35,1%pT277502745,3%44,2%47,4%Histological gradeI332850,00519,4%24,8%8,8%II75492644,1%43,4%45,6%III41192224,1%16,8%38,6%Ignored2117412,4%15,1%7,0%Breast surgeryMastectomy8557281,00050,0%50,4%49,1%Conservative85562950,0%49,6%50,9%Sentinel lymph node biopsyNo3220120,35318,82%17,7%18,2%Yes137934481,5%82,3%80,0%Ignored1010,6%0,0%1,8%ChemotherapyNo5135160,69730,0%31,0%28,1%Yes119784170,0%69,0%71,9%TrastuzumabNo156105510,76192,3%92,9%91,1%Yes13857,7%7,1%8,9%Hormone therapyNo2918110,58117,1%15,9%19,3%Yes141954682,9%84,1%80,7% Table 2 - Patterns of Survivin expression in tumors of patients with breast cancer with and without recurrence.RecurrenceTotal**NoYespSubcellular localizationAbsent4220,9422,7%2,1%3,8%Cytoplasmic89573260,1%60,0%60,4%Nuclear2315815,5%15,8%15,1%Cytoplasmic and Nuclear32211121,6%22,1%20,8%IntensityAbsent4220,0212,7%2,1%3,8%Weak7353*2049,3%55,8%37,7%Moderate62382441,9%40,0%45,3%Strong927*6,1%2,1%13,2%Percentage of expression≤ 50%10977320,00673,6%81,1%60,4%> 50%39182126,4%18,9%39,6%*p<0,05** 22 patients (12,9%) of sample loss in tissue microarray. Table 3 - Cox survival regression model of patients diagnosed and treated for invasive breast carcinoma.p-ValorAdjusted ORModel 1Histological grade*0,0072,108Survivin - intensity*0,0231,850Survivin - percentage of expression0,1001,876Breast cancer subtype classified by immunohistochemistry0,2631,126Model 2Survivin - percentage of expression*0,0162,290Breast cancer subtype classified by immunohistochemistry0,0931,170Model 3Breast cancer subtype classified by immunohistochemistry0,2411,107 Citation Format: Heloisa OM Belchior, Victor P Andrade, Marcos VA Lima, Maria do PSS Cunha, Monique BC Lemos, Paulo GB Silva, Isabelle JL Silva-Fernandes. Survivin immunoexpression: An independent prognostic marker of recurrence in early-stage breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-61.

Relationship of circulating immune cells with lifestyle factors and cancer recurrence in early-stage breast cancer.

To evaluate the relationship of circulating immune cells with recurrence and metabolic/lifestyle factors in patients with early-stage breast cancer. Patients with early-stage breast cancer were identified from the electronic record and institutional registry. Lymphocyte and monocyte counts were obtained from blood samples at time of diagnosis prior to any chemotherapy. Correlations between lymphocyte and monocyte and recurrence were assessed in the entire cohort and among obese patients, those reporting alcohol consumption and smoking. Competing risk regression was used to analyze time to recurrence. A total of 950 patients with ≥ 5years of follow-up were identified; 433 had complete data and were eligible for analysis. 293 (68%) had hormone receptor-positive breast cancer, 82 (19%) HER2 positive, and 53 (13%) triple negative. Patients in the highest quintile of lymphocytes compared to the lowest quintile had lower risk of recurrence (subhazard ratio (SHR) = 0.17, 95% CI [0.03-0.93], p = 0.041) while patients in the highest quintile of monocytes had lower risk for recurrence (SHR = 0.19, 95% CI [0.04, 0.92], p = 0.039). Higher monocytes were more strongly associated with lower recurrence among those reporting alcohol consumption (HR = 0.10, 95% CI [0.01, 0.91], p = 0.04). In obese patients, higher lymphocytes were associated with lower risk of recurrence (p = 0.046); in non-obese patients, higher monocytes were associated with lower risk of recurrence (p = 0.02). There were no correlations among patients who reported tobacco use. High lymphocyte and monocyte counts are associated with lower recurrence rate in early-stage breast cancer, particularly in obese patients and those reporting alcohol consumption.

Identifying Risk Factors for Regional Recurrence in Early-Stage Breast Cancer with pT1-2 and Negative Sentinel Lymph Node Biopsy.

BackgroundDue to the low rate of regional recurrence (RR) in early-stage breast cancer with pT1-2 and negative sentinel lymph node biopsy (SLNB), no regional therapy is suggested for them. However, whether there is a subset of patients who were with high risk of regional failure and may benefit from regional treatment is still unknown. The current study was designed to identify the patients with high risk of RR, thereby providing clues for enhanced regional therapy.MethodsWe analyzed a total of 1124 breast cancer patients with pT1-2N0 from May 2004 to Dec 2014. All the patients were treated with breast-conservation surgery (BCS) and adjuvant whole-breast radiotherapy. The regional recurrence-free survival (RRFS), local regional recurrence-free survival (LRRFS), disease-free survival (DFS) and overall survival (OS) were assessed by using the Kaplan–Meier method. Cox proportional hazards regression was performed to detect factors in predicting the RRFS.ResultsIn multivariable analysis, both T stage and molecular type were significant predictors of RRFS. Patients with T2 stage had a lower RRFS than those with T1stage. Triple-negative patients were more likely to suffer regional failure than the patients with other molecular types. The two predictors were then employed to divide all the patients into three groups based on the risk level of RR. Patients with both T2 and triple-negative molecular type had the lower RRFS, LRRFS, DFS and OS than the patients with one or no risk factor.ConclusionFor early-stage breast cancer patients with negative SLNB, those who were with both T2 stage and triple-negative molecular type had a high rate of RR and enhance regional therapy may be needed for them.

Location of Recurrence in Women Treated with Conventionally Planned Whole Breast Radiotherapy

Whole breast radiotherapy (RT) following breast-conserving therapy is known to reduce local recurrence in early-stage breast cancer. Conventionally, the external palpable breast has been used as the clinical target volume (CTV). In the era of CT simulation/planning, post-operative tumour bed (cavity) localization is also important as it is a high risk area of local recurrence. This study evaluates the location of the tumour bed cavity and its relationship to the area of recurrence in women previously treated with whole breast RT without explicit delineation of the cavity. A consecutive sample of 50 women with breast tumours (Tis-T3,Nx-1) previously treated with whole breast RT+/-boost was identified. The planning CTV was based on patient's palpable breast wired with radio-opaque markers during CT simulation and treated to a minimum of 92% prescription dose (50Gy-25fx or 40/42.4Gy-16fx) using forward planned intensity modulated RT (IMRT). The tumour bed was retrospectively contoured and expanded by 10mm (excluding skin and lung) for the planning target volume (cPTV). Geographic miss was defined as any part of the target volume receiving <50% of the prescription dose (D50). Five-year follow-up and the location for local and/or distant recurrence were collected. Descriptive statistics and unpaired Student's t-tests were performed, p-values <0.05 were considered as statistically significant. Five (10%) women had geographic miss to the cavity contours (CAVmiss). Women with CAVmiss had cavities located in extreme aspects of the breast: lateral (3); medial (1); or superior (1). The median follow-up was 4.5years and time to failure was 3.5years (1 to 5 years). Within the CAVin cohort (45), 2 (6%) patients recurred locally within the ipsilateral breast (1-year and 3-year follow-up, respectively); 1 (3%) patient developed regional disease to the infraclavicular lymph nodes at 4-year follow-up, and 1 (3%) developed contralateral inflammatory breast disease at 4-year follow-up; 11 patients were lost to follow-up. Of the 5 women with CAVmiss: 1 developed local recurrence at the edge of the original fields near the tumour bed and regional disease to the axilla and supraclavicular nodal basins (4yr follow-up); 1 developed distance disease (3yr follow-up). Local recurrence can occur near the tumour bed following whole breast RT. Without delineation of the post-operative cavity, 10% of women had inadequate coverage to their tumor bed despite the use of standard tangential RT fields. The adoption of cavity delineation would reduce the risk of geographic miss and ensure the accuracy of radiotherapy.

Predictive Value of Molecular Subtyping for Locoregional Recurrence in Early-Stage Breast Cancer with N1 without Postmastectomy Radiotherapy.

PurposeThis study was designed to investigate the relationship between molecular subtype and locoregional recurrence (LRR) in patients with early-stage breast cancer with 1–3 positive axillary lymph nodes (ALNs) and improve the individualized indications for postmastectomy radiotherapy (PMRT).MethodsThe records of 701 patients with pT1-2N1M0 breast cancer who did not undergo PMRT were retrospectively analyzed. Tumors were subclassified as follows: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, and basal-like subtypes. Multivariate Cox analysis was used to determine the risk of LRR associated with the different subtypes and to adjust for clinicopathologic factors.ResultsLuminal A, luminal B, HER2-enriched, and basal-like subtypes accounted for 51.2%, 28.0%, 8.1%, and 12.7% of cases, respectively. The median follow-up duration was 67 months (range, 9–156 months). Univariate analysis revealed that, compared with the luminal A subtype, the HER2-enriched and basal-like subtypes were associated with significantly higher 5-year LRR rates (5.6% vs. 21.6% and vs.15.7% respectively; p=0.002 each), lower 5-year LRR-free survival (LRFS) rates (90.6% vs. 73.8% and 78.5%, respectively; p=0.001 each), and poorer 5-year breast cancer-specific survival (BCSS) rates (93.7% vs. 82.2% [p=0.002] and 84.9% [p=0.001], respectively). Multivariate analysis revealed that the HER2-enriched and basal-like subtypes, age ≤35 years, a medial tumor, and pT2 stage were poor prognostic factors for LRR and LRFS; furthermore, 2 to 3 positive ALNs represented an independent prognostic factor affecting LRR. The 10-year LRR rates of patients with 0, 1, 2, 3, and 4 risk factors were 1.0%, 6.9%, 14.3%, 30.4%, and 54.3%, respectively (p<0.001); the 10-year BCSS rates were 86.6%, 88.5%, 84.4%, 79.7%, and 38.8%, respectively (p<0.001).ConclusionMolecular subtyping allows for individualized evaluation of LRR risk in patients with pT1-2N1M0 breast cancer. PMRT should be recommended for patients with ≥3 LRR risk factors.

Prognostic Factors for Local, Loco-regional and Systemic Recurrence in Early-stage Breast Cancer.

Aim: The risk of recurrence in breast cancer depends on factors such as treatment but also on the intrinsic subtype. We analyzed the risk factors for local, loco-regional and systemic recurrence, evaluated the differences and analyzed the risk of recurrence for different molecular subtypes. Material and Methods: A total of 3054 breast cancer patients who underwent surgery followed by adjuvant treatment at HSK hospital or Essen Mitte Hospital between 1998 and 2011 were analyzed. Based on immunohistochemical parameters, cancers were divided into the following subgroups: luminal A, luminal B (HER2-), luminal B (HER2+), HER2+ and TNBC (triple negative breast cancer). Results: 67 % of tumors were classified as luminal A, 13 % as luminal B (HER2-), 6 % as luminal B (HER2+), 3 % as HER2+ and 11 % as TNBC. After a median follow-up time of 6.6 years there were 100 local (3.3 %), 32 loco-regional (1 %) and 248 distant recurrences (8 %). Five-year recurrence-free survival for the overall patient collective was 92 %. On multivariate analysis, positive nodal status, TNBC subtype and absence of radiation therapy were found to be independent risk factors for all forms of recurrence. Age < 50 years, tumor size, luminal B (HER2-) subtype and breast-conserving therapy were additional risk factors for local recurrence. Compared to the luminal A subtype, the risk of systemic recurrence was higher for all other subtypes; additional risk factors for systemic recurrence were lymphatic invasion, absence of systemic therapy and mastectomy. Conclusion: Overall, the risk of local and loco-regional recurrence was low. In addition to nodal status, subgroup classification was found to be an important factor affecting the risk of recurrence.

Hormonal treatment (HT) and late recurrence in early-stage breast cancer (BC) patients.

563 Background: BC patients who are disease free after 5 years (Y) of diagnosis still remain at risk of developing a late recurrence. We assessed the effect of HT on the risk of late recurrence in ...

Abstract P5-21-01: Effect of adjuvant systemic therapy in reducing rates of loco-regional recurrence in early-stage breast cancer: Results from nine NSABP randomized phase III trials

Abstract Background Adjuvant systemic therapy reduces risk of distant recurrence (DR) and breast cancer death. In addition, adjuvant systemic therapy reduces risk of loco-regional recurrence (LRR). We examined the magnitude of the effect of adjuvant systemic therapy (tamoxifen, chemotherapy, and chemotherapy + trastuzumab) in reducing incidence rates and cumulative incidence rates of LRR as first event in nine recent NSABP randomized trials that were conducted from 1981 to 2005 and included a total of 21,815 patients. Methods Nine NSABP clinical trials of adjuvant (or neoadjuvant) systemic therapy, in which a reduction in LRR or DR was observed, were included in the analysis (NSABP B-13, B-14, B-19, B-20, B-21, B-27, B-28, B-30, and B-31). The cumulative incidence rates of LRR as the first disease-free survival (DFS) event were estimated and compared across treatment arms via log-rank tests. The sub-distribution proportional hazards models were applied to estimate the reduction in incidence rate of LRR from adjuvant systemic therapies. The corresponding magnitude of reduction in the incidence rate of any DFS event was estimated from Cox proportional hazards models. Results Across all nine clinical trials, adjuvant systemic therapy resulted in reductions in LRR that were comparable to or greater than the reductions in DFS events (Table). The observed reductions in LRR with adjuvant chemotherapy were of greater magnitude in trials of node-negative patients (35-58%) than in trials of node-positive patients (13-15%). Reductions in LRR were of similar magnitude with adjuvant chemotherapy as with adjuvant tamoxifen. In B-27, the sequential addition of neoadjuvant or adjuvant docetaxel to neoadjuvant AC reduced LRR rates by 27%. The addition of trastuzumab to adjuvant chemotherapy decreased LRR rates by 34%. Conclusions Rates of LRR have steadily declined over time in NSABP adjuvant clinical trials. This decline can be attributed to improvements in surgical and radiotherapy techniques but is also the result of the use of increasingly effective adjuvant systemic therapy. NSABP TrialPopulationTreatment ComparisonHR(95%CI)DFSHR(95%CI)LRR10-yr Cum Incidence of LRR(%)Log rank p-valueB-13 (n=1,084)N(-) / ER(-)MF v No Adj Rx0.66 (0.55,0.79)0.42 (0.29-0.62)5.9 v 13.5&amp;lt;0.001B-14 (n=4,028)N(-) / ER(+)TAM v Placebo0.70 (0.65, 0.77)0.54 (0.45-0.66)5.2 v 11.2&amp;lt;0.001B-19 (n=1,074)N(-) / ER(-)CMF v MF0.69 (0.57, 0.84)0.48 (0.31-0.73)5.3 v 10.0&amp;lt;0.001B-20 (n=2,299)N(-) / ER(+)CMF/MF+TAM v TAM0.76 (0.66, 0.88)0.57 (0.41-0.78)3.7 v 7.1&amp;lt;0.001B-21 (n=645)N(-) / ≤1cmTAM v Placebo0.93 (0.71, 1.21)0.65 (0.38-1.09)4.7 v 8.80.10B 27 (n=2,346)Operable T1-3 N0-1AC→T v AC (neoadj)0.92 (0.81, 1.05)0.73 (0.56-0.94)9.1 v 12.20.015B-28 (n=3,036)N(+)AC→P v AC0.90 (0.81, 1.00)0.87 (0.69-1.1)8.6 v 10.00.24B-30 (n=5,240)N(+) / HER2(-)AC→T v AT/TAC0.84 (0.76, 0.93)0.85 (0.65-1.1)4.6 v 5.40.23B-31 (n=2,063)N(+) / HER2(+)AC→P+H v AC→P0.59 (0.50, 0.69)0.66 (0.46-0.94)5 v 7.40.02N: Node; M: Methotrexate; F: 5-FU; TAM: Tamoxifen; C: Cyclophosphamide; A: doxorubicin; T: Docetaxel; P: Paclitaxel; H: trastuzumab Citation Format: Eleftherios P Mamounas, Gong Tang, Qing Liu, Jong-Heyon Jeong, Thomas B Julian, Priya Rastogi, Charles E Geyer, Sandra M Swain, Soonmyung Paik, D Lawrence Wickerham, Joseph P Costantino, Norman Wolmark. Effect of adjuvant systemic therapy in reducing rates of loco-regional recurrence in early-stage breast cancer: Results from nine NSABP randomized phase III trials [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-21-01.

Dosimetric evaluation of whole-breast radiation therapy: Clinical experience

Radiation therapy of the intact breast is the standard therapy for preventing local recurrence of early-stage breast cancer following breast conservation surgery. To improve patient standard of care, there is a need to define a consistent and transparent treatment path for all patients that reduces significance variations in the acceptability of treatment plans. There is lack of consistency among institutions or individuals about what is considered an acceptable treatment plan: target coverage vis-à-vis dose to organs at risk (OAR). Clinical trials usually resolve these issues, as the criteria for an acceptable plan within the trial (target coverage and doses to OAR) are well defined. We developed an institutional criterion for accepting breast treatment plans in 2006 after analyzing treatment data of approximately 200 patients. The purpose of this article is to report on the dosimetric review of 623 patients treated in the last 18 months to evaluate the effectiveness of the previously developed plan acceptability criteria and any possible changes necessary to further improve patient care. The mean patient age is 61.6 years (range: 25.2 to 93.0 years). The mean breast separation for all the patients is 21.0cm (range: 12.4 to 34.9cm), and the mean planning target volume (PTV_eval) (breast volume for evaluation) is 884.0cm3 (range: 73.6 to 3684.6cm3). Overall, 314 (50.4%) patients had the disease in the left breast and 309 (49.6%) had it in the right breast. A total of 147 (23.6%) patients were treated using the deep inspiration breath-hold (DIBH) technique. The mean normalized PTV_eval receiving at least 92% (V92% PD) and 95% (V95% PD) of the prescribed dose (PD) are more than 99% and 97%, respectively, for all patients. The mean normalized PTV_eval receiving at least 105% (V105% PD) of the PD is less than 1% for all groups. The mean homogeneity index (HI), uniformity index (UI), and conformity index (CI) for the PTV_eval are 0.09 (range: 0.05 to 0.15), 1.07 (range: 0.46 to 1.11), and 0.98 (range: 0.92 to 1.0), respectively. Our data confirm the significant advantage of using DIBH to reduce heart dose when compared with the free-breathing technique. The p values analyses of the results for the V5Gy, V10Gy, V15Gy, V20Gy, and V30Gy for the heart comparing DIBH and free-breathing techniques are well less than 0.05 (i.e., p < 0.05). However, similar analyses for the lung give values greater than 0.05 (i.e., p > 0.05), indicating that there is no significant difference in lung dose comparing the 2 treatment techniques.

Abstract 4683: Neuropathic pain in breast cancer patients undergoing radiotherapy

Abstract Post-surgery radiotherapy (RT) significantly reduces recurrence of early-stage breast cancer. However, many patients experience side effects from RT, such as neuropathic pain (NP), experienced by one third of patients during RT. Breast cancer survivors report moderate to severe NP symptoms, including hypersensitivity to cold/mechanical stimuli, itching, and numbness, which not only impact patient's functional performance and health-related quality of life, but also may interfere with treatment. Therefore, we evaluated prevalence of pain and neuropathic pain symptom (NPS) in 330 breast cancer patients undergoing RT for changes over time in these pain scales, and to determine the effect of body mass index (BMI) on the RT-induced NP (RINP) at baseline, immediately post-RT, and 1 month after completion of RT. Pain prevalence was assessed using Brief Pain Inventory (0-10) for pain at the worst over the past 4 weeks. NPS index (NPSI, 0-33) was developed using 9 questions from the National Surgical Adjuvant Breast Cancer and Bowel B39 Quality of Life questionnaire specific for breast cancer patients. Changes in these pain scales over time were assessed using a multivariate mixed model. The study consists of 56 Non-Hispanic Whites, 209 Hispanic Whites, and 66 African Americans. There were significant racial/ethnic differences in BMI (p&amp;lt;0.001) and cancer stage at diagnosis (p=0.018). About 85% of cases received the standard RT (50-50.4 Gy in a 200 cGy fraction) and 83% received boost of 10 Gy to the breast scar. Pain prevalence changed over time (p&amp;lt;0.001): 58% at baseline, 78% at the end of RT, and 71% at 1 month after RT. NPSI also changed over time; 4.9 at baseline, 10.0 at the end of RT, and 6.7 at 1 month after RT. There were significant differences in NPSI by race/ethnicity and BMI. Obese patients have worse NPS at RT completion and 1 month after RT compared to women with BMI&amp;lt;30. Obese patients had a higher prevalence and NPSI at both RT completion (21.7% and 6.9) and follow-up (16.0% and 3.6) while normal, over-weight patients showed less increase in prevalence and NPSI at RT completion (11.8% and 5.3) and recovered to the baseline levels after 1 month of RT. In summary, our data suggest that RT-related NP is associated with race/ethnicity and obesity in breast cancer patients. To improve quality of life, including NP, as an important survivorship issue for cancer patients, our ongoing biomarker studies are warranted to elucidate the molecular mechanisms and identify potential targets for intervention. Citation Format: Eunkyung Lee, Cristiane Takita, Jean L. Wright, Wei Zhao, Isildinha Reis, Omar L. Nelson, Jennifer J. Hu. Neuropathic pain in breast cancer patients undergoing radiotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4683. doi:10.1158/1538-7445.AM2014-4683

Cost-effectiveness analysis of Mammostrat&amp;reg; compared with Oncotype DX&amp;reg; to inform the treatment of breast cancer

PurposeTo compare the cost-effectiveness of the tumor subtyping assays Mammostrat® and Oncotype DX® for assessing risk of recurrence in early-stage breast cancer and the potential benefit of adjuvant chemotherapy.MethodsCost-effectiveness analysis from a US third-party payer perspective. A 10 year Markov model was developed to estimate costs and effects of using each method of risk assessment. The percentages of patients assessed as high, moderate, or low risk were obtained from multicenter, prospective, randomized controlled trials. The analysis simulated the experience of women progressing through various model states representing clinical treatments and subsequent disease. Published recurrence data for Mammostrat® were adjusted appropriately to account for differences between definitions and samples of Oncotype DX® and Mammostrat® in the original clinical trials. Cost and utility data were obtained from previously published studies. Sensitivity analyses examined how base-case results might differ when input values and assumptions varied.ResultsBase-case costs for women assessed using Mammostrat® were $15,782, compared with $18,051 for women assessed with Oncotype DX®. Thus, cost savings of $2,268 resulted from using Mammostrat®. Both Mammostrat® and Oncotype DX® resulted in similar life years (9.880 and 9.882) and quality-adjusted life years (7.935 and 7.940), respectively. Sensitivity analyses demonstrated that the assumptions made about recurrence are the key drivers of model results.DiscussionCost savings associated with the use of Mammostrat® instead of Oncotype DX® are largely due to the difference in cost between the two tests. Since survival and quality-adjusted life years were similar using either assay, Mammostrat® has economic advantages for women with early-stage breast cancer.

Prediction of early and late distant recurrence in early-stage breast cancer with Breast Cancer Index.

594 Background: Breast Cancer Index (BCI) is a continuous risk index based on the combination of HOXB13:IL17BR (H:I) and the Molecular Grade Index (MGI) that estimates the individual risk of recurrence in ER+, LN- breast cancer patients. In the current study, a modified BCI model was developed using untreated breast cancer patients in order to evaluate its pure prognostic value, and to better optimize BCI for both early and late risk assessment. Methods: A model was built by linearly combining H:I and MGI weighted by their corresponding Cox regression coefficients using ER+ LN- patients from the untreated arm of the prospective Stockholm trial (N=283). Validation was performed in 2 independent ER+, LN- cohorts: the TAM arm of the Stockholm trial (N=317), and a multisite cohort of TAM-treated patients (N=358). Correlation of BCI with distant metastasis was evaluated by Kaplan-Meier analysis using the log rank test, and multivariate analysis adjusting for standard prognostic factors was performed using Cox proportional hazards. Results: The BCI linear model was significantly associated with risk of cumulative (0-10y), early (&lt;5y) and late (≥5y) distant metastasis. Based on pre-specified cutpoints, BCI classified 64% and 55% patients as low-, 21% and 22% as intermediate-, and 16% and 23% as high-risk, with 10-y rates of distant recurrence (95% CI) of 4.8% (1.7-7.8%) and 6.6% (2.9–10.0%), 11.7% (3.1–19.5%) and 23.3% (12.3-33.0%), 21.1% (18.5–32.0%) and 35.8% (24.5–45.5%), in the Stockholm TAM and multisite cohort, respectively. Conclusions: BCI demonstrated significant prognostic performance beyond clinicopathological factors to predict cumulative, early and late risk of recurrence in early stage breast cancer patients. Use of BCI at diagnosis should enable clinicians to identify patients who are at high risk of late recurrence and may benefit from an additional 5y of hormonal therapy. [Table: see text]