Axillary Node-negative Breast Research Articles

Omission of sentinel lymph node biopsy in patients with clinically axillary lymph node-negative early breast cancer (OMSLNB): protocol for a prospective, non-inferiority, single-arm, phase II clinical trial in China

IntroductionSentinel lymph node biopsy (SLNB) is a standard procedure for patients with clinically assessed negative axillary lymph nodes (cN0) during early-stage breast cancer (EBC). However, the majority of EBC patients...

Abstract PO1-01-10: Comparison of the cost-effectiveness of multigene assays for HR+/HER2- node-negative early-stage breast cancer in the US

Abstract Background Traditional clinico-pathologic features, such as tumor grade and size, age, and menopausal status, may provide incomplete prognostic information, and have limited ability to predict chemotherapy benefit for patients with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2)-, axillary lymph node-negative (N0) early-stage breast cancer, leading to both under- and over-treatment with adjuvant chemotherapy. Multigene expression profile tests have been used in clinical practice to complement clinico-pathologic information to optimize treatment decisions. To date, the Oncotype DX Breast Recurrence ScoreÒ test is the only multigene assay with the ability to predict chemotherapy benefit validated by evidence from randomized clinical trials and supported by NCCN and ASCO guidelines. Other commercially available assays in the US include MammaPrintÒ, EndoPredictÒ and Prosigna RORÒ, which offer prognostic information beyond traditional clinico-pathologic features to improve treatment decisions. The relative cost-effectiveness of the four multigene assays compared to using clinico-pathologic risk alone to guide chemotherapy decisions was assessed from a societal perspective in the US. Methods A cost-effectiveness model built in Microsoft Excel estimated the cost-effectiveness of the Oncotype DXÒ test, MammaPrint, EndoPredict and Prosigna ROR compared to using clinical-pathological risk alone over a lifetime horizon. The model structure consisted of a decision-tree portion informed using published studies for the distribution of distant recurrence risk categories as defined by each test (low, intermediate, and high risk for the Oncotype DX test and Prosigna ROR, low and high risk for MammaPrint and EndoPredict). Decision impact studies and clinical expert opinion informed the proportion of patients allocated to adjuvant chemotherapy conditional on test result category. A Markov discrete health state model then simulated the future risk of distant recurrence, and long-term adverse effects of chemotherapy: acute myeloid leukemia (AML), and congestive heart failure (CHF), and aggregated the costs and outcomes of treatment decisions over a patient’s lifetime. The probability of distant recurrence of breast cancer conditional on test result category was derived from the most up-to-date studies assessing the performance of tests: TAILORx for the Oncotype DX test, MINDACT for MammaPrint, and TransATAC for EndoPredict and Prosigna ROR. Costs were estimated from a US societal perspective in 2020 US dollars (including Medicare healthcare costs, lost productivity and patient out-of-pocket chemotherapy costs from literature), and outcomes were expressed in terms of life-years, quality-adjusted life-years (QALYs), and net monetary benefit (NMB). The cost-effectiveness of each multigene assay compared to using clinico-pathologic risk alone was presented using the incremental cost-effectiveness ratio (ICER). Results Using the Oncotype DX test resulted in the largest lifetime cost savings (-$13,395) and generated the largest QALY gain (0.25) out of the four multigene assays included in the model, when compared to using clinico-pathologic risk alone (Table 1). All four multigene assays represented a cost-effective use of resources from a societal perspective (based on the accepted willingness-to-pay threshold of $100,000 per QALY gained), with a low net lifetime cost or net cost savings with positive QALY gain. Conclusion These results support the use of multigene assays to guide treatment decisions in node-negative HR+/HER2- early-stage breast cancer to improve treatment outcomes, and also result in substantial net cost savings from a societal perspective. The prediction of chemotherapy benefit using the Oncotype DX test resulted in substantially higher cost savings and improved breast cancer outcomes. Citation Format: Vladislav Berdunov, Gebra Cuyun Carter, Christy Russell, Sara Campbell, Jennifer Racz, Yara Abdou. Comparison of the cost-effectiveness of multigene assays for HR+/HER2- node-negative early-stage breast cancer in the US [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 PO1-01-10.

Carbon nanoparticles versus patent blue dye for detection of sentinel lymph node in patients with early breast cancer

Background Sentinel lymph nodes biopsy (SLNB) has replaced axillary lymph node dissection (ALND) in a considerable percentage of patients with early-stage breast cancer which was a great advance in preventing many surgical complications and enhancing their health welfare. Although there are different sentinel lymph nodes (SLNs) tracers with different identification rates, there is no agreement about the idealistic method. Aim The study was designed to compare carbon nanoparticles and patent blue v dye regarding SLNs detection rate, number of SLNs, time of detection, metastatic SLNs, cost, and safety in patients with early breast cancer and clinically node-negative axilla. Patients and methods A total of 40 patients with axillary lymph node-negative early-stage breast cancer patients were divided into two groups and subjected to carbon nanoparticles and patent blue V dye in group A and group B, respectively. Patients who were pregnant or lactating had node-positive axilla (N1-3) or metastatic breast cancer (M1) or had neoadjuvant chemotherapy were excluded. Results The mean age was 48.3±9.5 and 47 ±8.9, while the mean BMI of 33.3±4.8 and 32.834±4.862, the SLN detection rates were 95% and 90% in groups A and B, respectively. A total of 128 sentinel lymph nodes (SLNs) were removed from patients in the two groups (65 with Carbon Nanoparticles and 63 with patent blue dye). The mean number of SLNs was 3.4±0.7 (range, 2–5) and 3.5±1.2 (range, 2–7), mean time of SLNs detection was 13.5±4.5 (range, 7–22) and 12.7± 3.6 (range, 7–18 min) between group A and B, respectively. Conclusion There is no significant difference between carbon nanoparticles and patent blue dye regarding axillary SLNs in early breast cancer regarding identification rate, number of SLNs, time of detection, metastatic SLNs, cost, and safety with slight preference to carbon nanoparticles regarding postoperative skin staining and Egyptian market availability.

Real-world impact of TAILORx on chemotherapy use and SOFT/TEXT on ovarian function suppression uptake in a population based-cohort of women 40 years and under with HR-positive, HER2-negative, axillary lymph node negative breast cancer.

534 Background: Gene expression profiling (GEP) testing is prognostic for distant recurrence risk in women with hormone receptor positive (HR+), human epidermal growth factor receptor-2 negative (HER2-), axillary lymph node negative (LN-) breast cancer (BC). The TAILORx trial generated prospective evidence demonstrating the 21-gene recurrence score (RS) is also predictive of chemotherapy (CT) benefit. The literature suggests that GEP testing reduces adjuvant CT prescription and is cost-effective. In the same era, the SOFT/TEXT trials demonstrated disease-free survival benefit for the addition of ovarian function suppression (OFS) to endocrine therapy in premenopausal women. Real-world uptake and impact of these advances in the management of HR+, HER2-, LN- BC in young women may be limited due to complex reasons. This retrospective study evaluated GEP and CT use post TAILORx and OFS use post SOFT/TEXT in women 40 years old or younger diagnosed with HR+, HER2-, LN BC from 2011 to 2020 in Alberta, Canada. Methods: Clinical variables were retrieved from the Alberta Health Services Cancer Care Breast Data Mart and through review of the electronic medical record. GEP testing and CT use were compared between 3 cohorts of women defined by diagnosis: pre RS funding/pre TAILORx (before April 2014), post RS funding/pre TAILORx (April 2014-May 2018), post TAILORx (June 2018 and beyond). OFS use was compared between 2 cohorts of women defined by diagnosis pre- and post SOFT/TEXT (May 2015). In subgroup analyses, we compared CT use by GEP status and RS category and OFS use by CT status. Results: Among the 291 women identified, GEP testing increased by 37% post GEP funding (pre 2% vs. post 39%; P = < .0001) and by additional 15% post TAILORx (pre 39% vs. post 54%; P < .0001) whereas overall CT use declined by 15% post GEP funding (pre 85% vs. post 70%; P = .01) and by additional 16% post TAILORx (pre 70% vs. post 54%; P = .01). Although not significant, OFS use increased by 8% post SOFT/TEXT (pre 13% vs. post 21%; P = .08). In subgroup analyses, post TAILORx was associated with a significant reduction in CT use of 19.5% in non-GEP tested women (pre 85% vs. post 65% P = .01) and non-significant increase in CT use of 6% in RS tested women (pre 40% vs. post 46%; P = .61) mainly driven by high mid range RS 21-25 and lower high range RS 26-30. There was no significant change in OFS use in non-CT treated women post SOFT/TEXT (Pre 5.3% vs. Post 8%, P = .68) whereas OFS use increased by 15% in women treated with CT post SOFT/TEXT (pre 15% vs. post 30%; P = .01). Conclusions: Public GEP funding and TAILORx led to widespread adoption of GEP and real-world decline in CT use in women 40 years of age or younger diagnosed with HR+, HER2-, LN- BC in Alberta. SOFT/TEXT led to real-world incline in OFS use in those treated with CT but adoption remained suboptimal.

Effect, sensitivity, specificity and accuracy of ultrasonic assessment of axillary lymph node-negative breast cancer.

To investigate the diagnostic value of ultrasound for patients with axillary lymph node-negative breast cancer (ALNNBC). A retrospective analysis was performed on the clinical data of 204 breast cancer patients who were admitted by Quanzhou First Hospital Affiliated to Fujian Medical University between October 2020 and May 2022. According to the results of axillary lymph node (ALN) examination, the patients were assigned to a positive group(n=102) and a negative group(n=102). All patients underwent diagnosis with color Doppler ultrasound, with pathological diagnosis as the "gold standard" to determine the sensitivity and specificity of ultrasonic diagnosis. A receiver operating characteristic(ROC) curve was established to analyze the efficiency of ultrasonic diagnosis and compare the ultrasonographic features and flow grades between the two groups. Differences were statistically significant between the two groups in ultrasonographic features of lesions(negative vs positive, all p<0.05), including morphological irregularity(59.8% vs 85.3%), spiky margins(19.6% vs 63.7%), posterior echo attenuation(19.6% vs 44.1%) and microcalcification(40.2% vs 55.89%). The negative group had a lower proportion of patients with grade 2-3 ultrasound blood flow when compared with the positive group(32.4% vs 56.86%), and the difference was statistically significant(p<0.05). Ultrasonic diagnosis of ALNNBC had a sensitivity of 88.24%(90/102), a specificity of 92.16%(94/102), a coincidence rate of 90.20% (184/204), a 95% CI of 0.845-0.928, and an AUC of 0.879. Ultrasonic diagnosis of ALNNBC is relatively efficient as ultrasonographic features and ultrasound blood flow signals can provide a scientific basis for the diagnosis of ALNNBC.

Recent Advances in the Tracer Technology Used for Sentinel Lymph Node Biopsy in Breast Cancer

The high incidence of breast cancer poses one of the greatest risks to female health worldwide. Sentinel lymph node biopsy (SLNB) is the standard of treatment for patients with axillary lymph node-negative early-stage breast cancer. Herein, the precise use of tracers is the key to ensuring the success of SLNB. However, owing to select-few limitations of traditional tracers, their clinical application is limited. New tracer techniques, such as the near-infrared fluorescent dye method (using indocyanine green), contrast-enhanced ultrasound, and superparamagnetic iron oxide nanoparticles are being applied in clinical practice. In this paper, we review the recent progress in SLNB tracer technology.

Four Cycles of Docetaxel-Cyclophosphamide versus Anthracycline-Taxane as Adjuvant Chemotherapy for HER2-Negative, Axillary Lymph Node Negative Breast Cancer: A Real-World Comparison of Alberta Patients Treated 2008-2012.

Uncertainty exists around the need to include an anthracycline if taxane-based adjuvant chemotherapy is being used for human epidermal growth factor receptor-2 (HER2) negative and axillary lymph node negative (LNN) breast cancer. We identified all patients who were diagnosed with HER2-negative, LNN breast cancer treated with docetaxel-cyclophosphamide for four cycles (DC4) or an anthracycline-taxane (AT) regimen following surgical resection in Alberta from 2008 through 2012. We used propensity score methods to match each patient treated with AT to up to four patients treated with DC4 on potentially confounding clinicopathologic and treatment variables. We compared the 10-year invasive disease free survival (iDFS), breast cancer specific-survival (BCSS) and overall survival (OS) and assessed the effect of the type of adjuvant chemotherapy on these outcomes using Cox regression. Of the 726 eligible patients, 657 (90.5%) were treated with DC4 and 69 (9.5%) were treated with AT. Matching created a group of 202 women treated with DC4 and eliminated differences in clinicopathologic and treatment factors. There was no statistically significant difference for the treatment effects of matched DC4 patients compared to the AT patients on iDFS (75.7% vs. 76.8%, p = 0.75; hazard ratio (HR) = 1.05, 95% CI = 0.65 to 1.8), BCSS (88.1% vs. 87%, p = 0.8; HR = 0.91, 95% CI = 0.42 to 1.9), or OS (87.1% vs. 86.9%, p= 0.96; HR = 0.98, 95% CI = 0.46 to 2.1). Four cycles of DC as compared with an AT regimen yielded similar 10-year iDFS, BCSS and OS amongst patients with HER2-negative, LNN breast cancer.

Abstract PS6-34: Real life impact of TAILORx trial in a multi-center healthcare system: A comparison of management practice one year before and after the release of the trial

Abstract Introduction: Oncotype DX is a 21 gene assay which has been shown to be useful in predicting the risk of breast cancer recurrence. TAILORx trial compared survival with the use of hormonal therapy (HT) vs. chemo-hormonal therapy (CHT) in early-stage, Hormone receptor-positive, HER2-negative, axillary lymphnode-negative breast cancer who had an Oncotype DX recurrence score in the intermediate range (11-25), The study found HT to be non-inferior to CHT in that group, especially in women older than 50. Materials and methods: We studied 1084 patients with hormone receptor-positive, HER-2 negative early stage breast cancer at a multi-center setting in South Dakota and North Dakota who were diagnosed one year before and after the results of the TAILORx trial were presented. We aimed to identify any change in practice after the trial was published as compared to the year prior. Chi-square analysis was used to compare demographics of patients and management practices before and after the TAILORx trial publication. Results: We did not find any statistically significant change in Oncotype DX testing frequency across various age groups, tumor sizes, tumor grades or amongst patients who had lymphnode negative or one axillary lymph node positive disease (Table-1).We also did not find any statistically significant difference in management of early stage breast cancer patients (Table-2) that matched our inclusion criteria and had an intermediate risk Oncotype Dx score of 11-25(n=266). Conclusion: Our results indicate that management of early stage breast cancer at our center was not significantly impacted by the results of TAILORx. Rare use of CHT prior to TAILORx reporting suggests that practice prior to this trial was largely based on earlier trials suggesting minimal benefit for CHT in the intermediate risk group. Larger studies may be able to identify smaller changes in practice resulting from this study and should be pursued. Table-1: Frequency of Oncotype Dx testing one year before and after the TAILORx trial was released overall and in various sub-categories based on age of the patient, tumor size and tumor grade. Last row indicates the frequency comparison in patients who had one axillary lymph node positive status.Before TAILORx (N=512)After TAILORx (N=572)p-valuen (%)n (%)Overall204 (40)234 (41)0.7212Age&amp;lt; 5044 (46)31 (37)0.225450 - 69121 (46)146 (49)0.4519Equal or &amp;gt; 7039 (26)57 (30)0.3986Tumor Size&amp;lt; 1 cm41 (25)50 (28)0.53881 - 1.9 cm97 (51)122 (53)0.60552 - 2.9 cm40 (44)44 (42)0.77283+ cm24 (39)18 (32)0.4161Tumor Grade156 (39)63 (42)0.62002113 (48)135 (47)0.8542334 (26)35 (27)0.9768LN Positive31 (33)36 (32)0.9403 Table-2: Comparison of treatment received by patients in the intermediate risk group (score:11-25) based on Oncotype Dx test before and after the release of TAILORx trial , Chi sq p-value=0.5635, HT (Hormonal Therapy), CT (Chemotherapy).Before TAILORxAfter TAILORxHT + CTn=15n=135.91%5.12%HT Alonen=108n=11842.52%46.46% Citation Format: Mahum Shahid, Moataz Ellithi, Mohamed Abdallah, Arsalan Arshad, Mansi Oberoi, Mckenna L Eisenbeisz, Christopher M VanHove, Ty A Moody, Isaak N Ailts, Andrew J Foley, Morgan Nelson, Jonathan Bleeker. Real life impact of TAILORx trial in a multi-center healthcare system: A comparison of management practice one year before and after the release of the trial [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 PS6-34.

Cost-effectiveness analysis of multigene expression profiling assays to guide adjuvant therapy decisions in women with invasive early-stage breast cancer.

Gene expression profiling (GEP) testing using 12-gene recurrence score (RS) assay (EndoPredict®), 58-gene RS assay (Prosigna®), and 21-gene RS assay (Oncotype DX®) is available to aid in chemotherapy decision-making when traditional clinicopathological predictors are insufficient to accurately determine recurrence risk in women with axillary lymph node-negative, hormone receptor-positive, and human epidermal growth factor-receptor 2-negative early-stage breast cancer. We examined the cost-effectiveness of incorporating these assays into standard practice. A decision model was built to project lifetime clinical and economic consequences of different adjuvant treatment-guiding strategies. The model was parameterized using follow-up data from a secondary analysis of the Anastrozole or Tamoxifen Alone or Combined randomized trial, cost data (2017 Canadian dollars) from the London Regional Cancer Program (Canada) and secondary Canadian sources. The 12-gene, 58-gene, and 21-gene RS assays were associated with cost-effectiveness ratios of $36,274, $48,525, and $74,911/quality-adjusted life year (QALY) gained and resulted in total gains of 379, 284.3, and 189.5 QALYs/year and total budgets of $12.9, $14.2, and $16.6 million/year, respectively. The total expected-value of perfect information about GEP assays' utility was $10.4 million/year. GEP testing using any of these assays is likely clinically and economically attractive. The 12-gene and 58-gene RS assays may improve the cost-effectiveness of GEP testing and offer higher value for money, although prospective evidence is still needed. Comparative field evaluations of GEP assays in real-world practice are associated with a large societal benefit and warranted to determine the optimal and most cost-effective assay for routine use.

MicroRNA-10b expression in node-negative breast cancer-correlation with metastasis and angiogenesis.

Metastasis accounts for the majority of cases of mortality in patients with axillary lymph node-negative (ANN) breast cancer. Angiogenesis is an essential component of the metastatic pathway. Studies regarding microRNA (miR)-10b expression in patients with ANN breast cancer and the function of angiogenesis in breast cancer remain scarce. The present study was performed in order to determine the biological significance of miR-10b, and investigate the association between miR-10b and microvessel density (MVD) measured in ANN breast cancer. miR-10b expression and immunohistochemical analysis for MVD were assessed in 195 patients with ANN of invasive ductal carcinoma, including 65 cases with distant metastasis ‘poor group’, and 130 cases without any recurrence ‘good group’. miR-10b expression was higher in the ‘poor group’ (73.8%) compared with that in the ‘good group’ (51.5%; P=0.003). Multivariate logistic regression demonstrated that miR-10b retained independent prognostic significance for distant metastasis along with MVD and vascular invasion. Among 195 patients, miR-10b expression was significantly associated with tumor grade, tumor size and molecular subtypes (P<0.05). In addition, miR-10b expression was positively associated with the MVD count (r=0.370; P<0.001), tumor grade (r=0.168; P=0.019) and tumor size (r=0.175; P=0.014). The results of the current study suggest that miR-10b is a useful marker for predicting metastasis and angiogenesis in ANN breast cancer.

Apparent diffusion coefficient in estrogen receptor-positive and lymph node-negative invasive breast cancers at 3.0T DW-MRI: A potential predictor for an oncotype Dx test recurrence score.

To measure the apparent diffusion coefficient (ADC) values in estrogen receptor-positive (ER+) and axillary lymph node-negative (LN-) invasive breast cancer and investigate the correlation of ADC with Oncotype Dx test recurrence scores (ODxRS). This was a Health Insurance Portability and Accountability Act (HIPAA)-compliant single-site retrospective study. Patients underwent preoperative 3.0T MRI scans with additional diffusion-weighted imaging sequential scans (b = 0, 600 and b = 0, 1000 s/mm2 ) from January 2011 to 2013. The study population included 31 ER+/LN- invasive breast cancers, which underwent ODxRS genomic testing. ADC600 and ADC1000 parametric maps were generated, and ADC values were calculated from a user-drawn region of interest. ODxRS predicts 10-year recurrence risk in individual patients: low (RS <18), intermediate (RS: 18-30), or high (RS >30). All breast lesions, including subgroups of invasive ductal carcinoma (IDC) lesions and mass-only lesions were dichotomized by RS scores, low-risk versus intermediate/high-risk, and statistical analysis was performed using Mann-Whitney's test (statistical significance at P < 0.05) and receiver operating characteristic (ROC) curves. Multivariate analysis was also performed. Invasive breast cancers, when scored as low-risk by ODxRS, had significantly higher ADC values compared with intermediate/high-risk lesions for both ADC600 (P = 0.007) and ADC1000 (P = 0.008) mean values. This was true both when analyzing only mass-lesions (P = 0.03 and 0.01) or only IDCs (P = 0.001 and 0.009). Preliminary findings suggest that lesion ADC values correlate with recurrence risk likelihood stratified using ODxRS. Hence, ADC is a potential surrogate biomarker for tumor aggressiveness. 3 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;47:401-409.

Abstract P1-12-02: Sequential versus concurrent administration of epirubicin and docetaxel as adjuvant chemotherapy in women with high-risk axillary lymph node negative early breast cancer. An interim analysis of a multicenter randomized study from the Hellenic oncology research group

Abstract Purpose: To compare the sequential versus the concurrent administration of epirubicin and docetaxel as adjuvant therapy in high risk axillary node negative women with early breast cancer. Patients and treatment: Women 18-75 years old with invasive breast adenocarcinoma surgically resected with no infiltrated axillary lymph nodes and absence of metastatic disease were randomized to receive 4 cycles of epirubicin 90mg/m2 followed by 4 cycles of docetaxel 75mg/m2 (sequential regimen) or 6 cycles of epirubicin 75mg/m2 followed by docetaxel 75mg/m2 (concurrent regimen). All chemotherapy cycles were administered every 21 days with prophylactic G-CSF support for days 3-10 only for the concurrent regimen. Stratification was based on menopausal status, tumor size and hormone receptor expression. By protocol amendment in 2008 women with HER2 positive tumors were excluded. The primary endpoint of the study was to compare the disease-free survival (DFS) at 5 years and 329 patients were scheduled to enroll on each arm. Results: Between 2001-2013, 658 women were randomized and received the sequential (n=329) or the concurrent (n=329) regimen. The median age was 53 and 52 years, premenopausal status 43.8% versus 44.1%, tumor size &amp;lt;2cm in 44.1% versus 44.4%, histological grade 3 tumor in 52% versus 53.5% and hormone receptor negative disease in 33.1% versus 37.4% of patients in the sequential and concurrent regimens, respectively. After a median follow up of 70.5 and 70 months, there were 29 (8.8%) versus 42 (12.8%) disease relapses (p=0.102) and 11 (3.3%) versus 19 (5.8%) deaths (p=0.135), in the sequential and concurrent arms, respectively. The median DFS has not yet been reached in either arm (p=0.053) and the 5-year DFS rates were 92.6% versus 88.2% for sequential and concurrent arms, respectively. Dose reduction was required in 1.2% versus 3% (p=0.001) of the treatment cycles in the sequential and concurrent arms, respectively. Toxicity included grade 2-4 neutropenia in 54% versus 41% (p=0.001), febrile neutropenia 2.7% versus 6.1% (p=0.06), anemia 12% versus 17% (p=0.07), nausea/vomiting 18.5% versus 12.4% (p=0.03) of patients in the sequential and concurrent arms, respectively. There were no toxic deaths. Conclusion: In this interim analysis both the efficacy and the toxicity profile seem to favor the sequential over the concurrent regimen. Citation Format: Mavroudis D, Saloustros E, Boukovinas I, Papakotoulas P, Kakolyris S, Ziras N, Christophylakis C, Kentepozidis N, Timotheadou E, Rigas G, Varthalitis I-I, Kalbakis K, Agelaki S, Georgoulias V. Sequential versus concurrent administration of epirubicin and docetaxel as adjuvant chemotherapy in women with high-risk axillary lymph node negative early breast cancer. An interim analysis of a multicenter randomized study from the Hellenic oncology research group. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-12-02.

Partial mastectomy using manual blunt dissection (MBD) in early breast cancer.

BackgroundBreast-preserving surgery (Bp) and sentinel lymph node biopsy (SNB) are established as standard treatment for axillary lymph node-negative early breast cancer.MethodsA surgical technique using manual blunt dissection (MBD), in which use of electrocautery, an ultrasonically activated scalpel, and ligation is minimized, is described. This involves an approach from small incisions in the axilla or areola to avoid injury to skin flaps, and with adequate mobilization of the breast, so that regardless of the tumor site, surgical wounds are not noticeable. The usefulness and tolerability of this surgical technique were examined.ResultsThis surgical technique was evaluated in 233 patients. Surgery could be performed rapidly, with a mean operative time of 67 ± 21 min and a low mean blood loss of only 35 ± 28 ml. There was little need for postoperative analgesia, and surgery was well tolerated without postoperative bleeding or wound infection.ConclusionOur proposed technique for partial mastectomy using MBD provides good curative and cosmetic results.

Abstract S3-03: Ten year update of E1199: Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in patients with axillary node-positive or high-risk node-negative breast cancer

Abstract Background: We had previously reported after a median followup of 5.3 years that disease free survival (DFS) was improved with either adjuvant weekly paclitaxel (hazard ratio [HR] 0.73, p=0.0006) or every 3 week docetaxel (HR 0.77, p=0.02) compared with every 3 week paclitaxel (N Eng J Med 2008; 358; 1663), and that obesity and black race were independently associated with inferior outcomes in estrogen receptor (ER)-positive disease after a longer followup (Cancer 2012: 118: 5937 &amp; JNCI 2012; 104: 406). We now report updated results after a median followup of 12.1 years. Methods: Eligibility included axillary lymph node positive or high-risk (tumor at least 2 cm) node-negative breast cancer. All patients received 4 cycles of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) every 3 weeks, followed by either: (1) paclitaxel 175 mg/m2 every 3 weeks x 4 (P3), (2) paclitaxel 80 mg/m2 weekly x 12 (P1), (3) docetaxel 100 mg/m2 every 3 weeks x 4 (D3), or (4) docetaxel 35 mg/m2 weekly x 12 (D1). Patients with ER-positive breast cancer also received endocrine therapy for at least 5 years, including either tamoxifen and/or an aromatase inhibitor. The primary comparisons included taxane (P vs. D) and schedule (every 3 weeks vs. weekly), and the primary endpoint was DFS, defined as local, regional, and/or distant relapse, second primary breast cancer, or death without recurrence. Results: A total of 4954 eligible patients were accrued between October 1999 and January 2002. At the time of this analysis, 90% of surviving patients were followed for at least 10 years, and there were substantially more DFS events (1639 vs. 1048) and deaths (1283 vs. 686) than the original report. For the primary comparison, there remains no significant difference in DFS by taxane (p=0.33) or schedule (p=0.88), although there was a significant interaction between taxane and schedule (p&amp;lt;0.007). When comparing the standard arm (P3) to the other arms (with a hazard ratio [HR] &amp;lt; 1 favoring the experimental arms using a stratified Cox model), the HRs for DFS were 0.84 (p = 0.011) for arm P1 and 0.79 (p=0.001) for arm D3 arm, and for overall survival (OS) were 0.87 (p=0.09) and 0.86 (p=0.054), respectively. When evaluated by subtypes in exploratory analyses, the P1 arm (but not the D3 arm) was associated with improved DFS (HR 0.69, p=0.01) and OS (HR 0.69, p=0.019) in the 1025 patients with triple negative breast cancer (TNBC), and the D3 arm (but not P1 arm) was associated with improved DFS (HR 0.76, p=0.004) but not OS (HR 0.87, p=0.20) in the 2785 patients with ER-positive, HER2-negative/unknown breast cancer (ERBC). In ERBC but not other subtypes, black race (HR 1.60, p=0.002) and obesity (HR 1.23, p=0.009) were associated with inferior OS, and obesity was associated with a higher recurrence risk between 3-8 years after diagnosis. Conclusions: Improvements in DFS observed at 10 years for the P1 and D3 arms compared with the P3 arm are qualitatively similar but quantitatively less than at 5 years, and the effects on OS are marginal in the overall population. The relative effectiveness of weekly paclitaxel and every 3 week docetaxel may vary by subtype. Citation Format: Joseph A Sparano, Fengmin Zhao, Silvana Martino, Jennifer Ligibel, Thomas Saphner, Antonio C Wolff, George W Sledge Jr, Edith A Perez, William C Wood, Nancy E Davidson. Ten year update of E1199: Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in patients with axillary node-positive or high-risk node-negative breast cancer [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 S3-03.

Abstract P6-08-46: Clinical outcomes of breast cancer patients with intermediate oncotype DX recurrence scores (RS): A review of the Cleveland Clinic Experience

Abstract Background: The 21 gene RT-PCR assay (Oncotype Dx, Genomic Health, Inc, Redwood City, CA) performed on formalin-fixed paraffin-embedded tissue quantifies the likelihood of distant recurrence in patients with estrogen receptor (ER)-positive, axillary lymph node-negative breast cancer. The 21 gene recurrence score (RS) also quantifies the magnitude of clinical benefit of adjuvant cytotoxic chemotherapy to endocrine therapy. Patients with a high risk RS clearly benefit from the addition of adjuvant chemotherapy, while patients with a low RS do not. However, approximately one-third of patients have an intermediate RS (18-31) and the incremental benefit from adjuvant chemotherapy is unclear. The primary objective of this study was to evaluate the clinical outcomes of early stage breast cancer patients with intermediate RS. Methods: We identified 262 patients with intermediate RS (18-31) in a prospectively maintained registry of patients with Oncotype Dx testing at the Cleveland Clinic from 2004-2013. ER status, progesterone receptor (PR) status, HER2 gene amplification, treatment with chemotherapy, follow-up for distant recurrences and other clinical and pathological variables were collected for all patients in the registry. Results: Patient characteristics are listed in Table 1. One hundred patients (38.2 %) were treated with chemotherapy plus endocrine therapy, while 156 (59.5%) were treated with endocrine therapy alone. Treatment data was unavailable for 6 patients (2%). Distant recurrence status is unknown for 2 patients. The overall rate of distant plus local recurrence for all 262 patients was 3.8% (3 local and 7 distant recurrences). There were 6 and 4 recurrences respectively, for patients received chemotherapy plus endocrine therapy (6%), and in patients treated with endocrine therapy alone (2.5%), which was not significantly different (p=.21). Table 1. Patient CharacteristicsMedian age at diagnosis (Range)58 (27-88)Median RS (Range)22 (18-31)ER+ (%)262 (99.6)PR+ (%)234 (89)HER-2 amplified (%)10 (3.8)Grade (%) 184 (32.8)2136 (53.1)336 (14.1)Histology (%) Ductal187 (71.1%)Lobular45 (17.1%)Mixed31 (11.8%)Median Tumor size (range)1.6 cm (0.2-6.5)Lymph Node Status (%) pN0238 (90.8)1-3 positive nodes24 (9.2) Conclusions: With a median follow-up of 45 months, our data indicate that the realized distant recurrence rate for patients with an intermediate range RS was less than 5%. These data do not exclude the possibility that some patients with an intermediate RS may derive a small incremental benefit from the addition of adjuvant chemotherapy. Larger, randomized prospective trials like TAILORx should provide additional guidance for the management of this patient population. Citation Format: Lindsey M Goodman, Alberto J Montero, Lisa Rybicki, Karen Mrazeck, Benjamin Calhoun, Raymond Tubbs, Halle Moore. Clinical outcomes of breast cancer patients with intermediate oncotype DX recurrence scores (RS): A review of the Cleveland Clinic Experience [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 P6-08-46.

Immunohistochemical detection of axillary lymph node micrometastases in node negative breast cancer patients using cytokeratin and epithelial membrane antigen.

Background and Objective:The study was conducted to detect occult metastases in lymph node negative breast cancer patients using cytokeratin (CK) and epithelial membrane antigen (EMA) immunohistochemistry (IHC) and correlate this with primary tumor size and grade.Materials and Methods:A total of 32 cases including 12 prospective and 20 retrospective cases of axillary lymph node negative breast cancer were studied. CK and EMA IHC were performed to detect micrometastases.Results:Axillary lymph node metastases were detected in 18.75% of previously node negative cases using CK and EMA IHC. CK was found to be more sensitive for detection of metastases compared to EMA. A highly significant correlation was observed between tumor grade and axillary lymph node metastases detected by CK and EMA. However, no significant correlation was found between tumor size and axillary lymph node metastases detected by IHC.Conclusion:In the present study, there was an increase of 18.75% in the occult metastases detection rate using CK and EMA. To conclude, IHC detection of occult metastases should be done using CK in all axillary node negative cases, especially in T1 and T2 stage tumors.

Age at diagnosis in relation to survival following breast cancer: a cohort study

BackgroundAge is an important risk factor for breast cancer, but previous data has been contradictory on whether patient age at diagnosis is also related to breast cancer survival. The present study evaluates age at diagnosis as a prognostic factor for breast cancer on a large cohort of patients at a single institution.MethodsAll 4,453 women diagnosed with breast cancer in Malmö University Hospital, Sweden between 1961 and 1991 were followed up on for 10 years with regards to breast cancer-specific mortality (BCSM) in different age groups. Corresponding relative risks (RR), with 95% confidence intervals, were obtained using Cox’s proportional hazards analysis. All analyses were adjusted for potential confounders and stratified for axillary lymph node involvement (ALNI) and diagnostic period.ResultsAs compared to women aged 40 to 49 years, those who were aged under 40 (RR: 1.40; 95% CI: 1.04 to 1.88) and 80 or more years (RR: 1.80; 95% CI: 1.45 to 2.25) had a statistically significant higher 10-year mortality rate. When adjusted for potential confounders, including stage at diagnosis, the associations only remained statistically significant for women aged 80 years or more. In the analyses stratified on ALNI, ALNI-negative women under 40 years had a statistically significant higher five-year mortality rate (RR: 2.65; 95% CI: 1.23 to 5.70). In the analyses stratified on diagnostic period, the positive association between women aged under 40 or aged 80 or more years and high BCSM rate remained, with statistically significant results for women aged 80 years or more in all periods.ConclusionsWomen under 40 years of age had a poor prognosis, and this association was strongest among young women with axillary lymph node negative breast cancer. An age of 80 years or more was a prognostic factor for poor survival, independent of stage at diagnosis and diagnostic period.

Prediction of early breast cancer metastasis from DNA microarray data using high-dimensional cox regression models.

BACKGROUNDDNA microarray studies identified gene expression signatures predictive of metastatic relapse in early breast cancer. Standard feature selection procedures applied to reduce the set of predictive genes did not take into account the correlation between genes. In this paper, we studied the performances of three high-dimensional regression methods – CoxBoost, LASSO (Least Absolute Shrinkage and Selection Operator), and Elastic net – to identify prognostic signatures in patients with early breast cancer.METHODSWe analyzed three public retrospective datasets, including a total of 384 patients with axillary lymph node-negative breast cancer. The Amsterdam van’t Veer’s training set of 78 patients was used to determine the optimal gene sets and classifiers using sensitivity thresholds resulting in mis-classification of no more than 10% of the poor-prognosis group. To ensure the comparability between different methods, an automatic selection procedure was used to determine the number of genes included in each model. The van de Vijver’s and Desmedt’s datasets were used as validation sets to evaluate separately the prognostic performances of our classifiers. The results were compared to the original Amsterdam 70-gene classifier.RESULTSThe automatic selection procedure reduced the number of predictive genes up to a minimum of six genes. In the two validation sets, the three models (Elastic net, LASSO, and CoxBoost) led to the definition of genomic classifiers predicting the 5-year metastatic status with similar performances, with respective 59, 56, and 54% accuracy, 83, 75, and 83% sensitivity, and 53, 52, and 48% specificity in the Desmedt’s dataset. In comparison, the Amsterdam 70-gene signature showed 45% accuracy, 97% sensitivity, and 34% specificity. The gene overlap and the classification concordance between the three classifiers were high. All the classifiers added significant prognostic information to that provided by the traditional prognostic factors and showed a very high overlap with respect to gene ontologies (GOs) associated with genes overexpressed in the predicted poor-prognosis vs. good-prognosis classes and centred on cell proliferation. Interestingly, all classifiers reported high sensitivity to predict the 4-year status of metastatic disease.CONCLUSIONSHigh-dimensional regression methods are attractive in prognostic studies because finding a small subset of genes may facilitate the transfer to the clinic, and also because they strengthen the robustness of the model by limiting the selection of false-positive predictive genes. With only six genes, the CoxBoost classifier predicted the 4-year status of metastatic disease with 93% sensitivity. Selecting a few genes related to ontologies other than cell proliferation might further improve the overall sensitivity performance.

The prognostic relevance of the mitotic activity index in axillary lymph node-negative breast cancer.

The aim of the present study is to look at the mitotic activity index (MAI) as a prognostic factor in a prospective population-based cohort of lymph node-negative invasive breast cancer patients. Analyses were based on 2,048 breast-conserving therapies in 1,971 patients, node-negative, and without any form of adjuvant systemic therapy with long-term follow-up. The 15-year distant metastases-free survival (DMFS) for women ≤55 years was 88.3 % for low MAI values (≤12) versus 73.4 % for high MAI values (>12); (HR 2.8; 95 % CI 1.8-4.4; p < 0.001). Multivariate analyses for DMFS showed significance for MAI. For MAI and Bloom-Richardson grading, by performing a likelihood ratio test, we showed the statistical significance for both. For women >55-years, the MAI was not an independent significant factor. We also confirmed the above findings for disease-specific survival. When multi-gene assays are not available, the MAI remains a robust prognostic marker in women younger than 55 years of age with early node-negative breast cancer.

Can mammographic and sonographic imaging features predict the Oncotype DX™ recurrence score in T1 and T2, hormone receptor positive, HER2 negative and axillary lymph node negative breast cancers?

To determine whether mammographic or sonographic features can predict the Oncotype DX™ recurrence scores (RS) in patients with TI-II, hormone receptor (HR) positive, HER2/neu negative and node negative breast cancers. Institutional board review was obtained and informed consent was waived for this retrospective study. Seventy-eight patients with stage I-II invasive breast cancer that was HR positive, HER2 negative, and lymph node negative for whom mammographic and or sonographic imaging and Oncotype DX™ assay scores were available were included in the study Four breast dedicated radiologists blinded to the RS retrospectively described the lesions according to BI-RADS lexicon descriptors. Multivariable logistic regression was used to test for significant independent predictors of low (<18) versus intermediate to high range (≥18). Two imaging features reached statistical significance in predicting low from intermediate or high risk RS: pleomorphic microcalcifications within a mass (P=0.017); OR 8.37, 95% CI (1.47-47.79) on mammography and posterior acoustic enhancement in a mass on ultrasound (P=0.048); OR 4.35, 95% CI (1.01-18.73) on multivariable logistic regression. A mass with pleomorphic microcalcifications on mammography or the presence of posterior acoustic enhancement on ultrasound may predict an intermediate to high RS as determined by the Oncotype DX(TM) assay in patients with stage I-II HR positive, HER2 negative, and lymph node negative invasive breast cancer.