Node-negative Tumors Research Articles

Clinical Outcomes in Breast Cancer Patients with HER2-Positive, Node-Negative Tumors (≤3 cm)

Purpose The present study aimed to evaluate clinical outcomes in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) with node-negative tumors ≤ 3 cm who received adjuvant chemotherapy and HER2-targeted therapy. Methods The present study enrolled patients with HER2-positive BC who underwent breast and axillary surgery between January 2007 and August 2020. Patients receiving neoadjuvant chemotherapy were excluded. The endpoint was time to distant disease-free survival (D-DFS) as estimated using Kaplan-Meier curves. The secondary endpoints were disease-free survival (DFS) and overall-survival (OS). These outcomes were compared between patients with pT1a or pT1b tumors (the pT1a/b group), those with pT1c tumors (the pT1c group), and those with pT2 tumors (the pT2 group). Results In total, 135 patients were included. Among these, 28 (20.7%) had pT1a or pT1b tumors (the pT1a/b group), 67 (49.6%) had pT1c tumors (the pT1c group), and 40 (29.6%) had pT2 tumors (the pT2 group). After a median follow-up period of 5.4 years, the 5-year-D-DFS was 100%, 94.2%, and 97.1% in the T1a/b-, T1c-, and T2 group, respectively. The 5-year-DFS rate was 100%, 92.1%, and 93.3%, and the 5-year-OS rate was 100%, 94.9%, and 97.0%, in the respective groups. Conclusions Patients with HER2-positive, node-negative tumors ≤ 3 cm who received trastuzumab and chemotherapy had a favorable 5-year-D-DFS (96.3%). Among them, those with a tumor 1 cm or less in size had better outcomes.

Latest evidence on the management of early‐stage and locally advanced rectal cancer: a narrative review

Rectal cancer is a challenging disease process to manage, with a rising incidence in young adults. Several clinical advances have been made in the past decade with regards to optimal treatment strategies in early-stage (T1-2, node negative tumours) and locally advanced cancers (T3-4 and/or nodal positivity) utilizing a multimodal approach of surgery, neoadjuvant chemoradiotherapy, and adjuvant chemotherapy, all aiming to optimize oncological outcomes, while minimizing associated morbidity. This narrative review aimed to summarize trial level evidence apropos the management of early and locally advanced rectal cancer. All relevant prospective clinical trials were identified through a computer-assisted search of PubMed, EMBASE, Medline databases between 1990 and 30 June 2021. With regards to early rectal cancer, there is limited trial-level evidence in the literature. Total mesorectal excision (TME) is the current standard of care, but local excision could be considered in select patients with pT1 tumours, or patients with near or complete clinical response to neoadjuvant CRT. As for locally advanced rectal cancer, the current standard of care consists of long-course chemotheradiotherapy or short-course radiotherapy, followed by TME. However, the role of total neoadjuvant therapy is promising, with respect to both oncological outcomes, as well as in reducing toxicity. Both induction and consolidation chemotherapy treatment approaches have been described in literature, with encouraging early results. The optimal management of rectal cancer is constantly evolving. More research is needed to investigate the long-term oncological and functional outcomes following new multimodal therapies in the management of early-stage and locally advanced rectal cancer.

Perioperative HER2 targeted treatment in early stage HER2-positive breast cancer.

Although human epidermal growth factor receptor 2 (HER2)-positive breast cancer was associated with poor prognosis, it has been changed after the development of trastuzumab. There has been great progress in perioperative HER2-targeting treatment, and investigations of several novel drugs and their combinations are ongoing. Adjuvant trastuzumab with or without pertuzumab for 1 year in combination with concomitant chemotherapy has become a standard treatment in high-risk node-negative tumors or node-positive HER2-positive early breast cancer patients without residual disease or who have not received neoadjuvant treatment. For low-risk HER2-positive early breast cancer patients, adjuvant paclitaxel and 1-year trastuzumab are possible alternatives. For residual disease after neoadjuvant treatment, adjuvant trastuzumab emtansine (T-DM1) for 14 cycles is a standard treatment. Non-anthracycline chemotherapy with dual anti-HER2 targeting of trastuzumab and pertuzumab represents one of the preferred neoadjuvant regimens to achieve higher pathologic complete response (pCR) rates and better clinical outcomes. Further research is needed to develop and validate potential biomarkers to predict pCR, which could help escalate or de-escalate anti-HER2 therapy. Trials incorporating novel agents such as T-DM1, trastuzumab deruxtecan (T-DXd), and immune checkpoint inhibitors and trying to de-escalate treatments in neoadjuvant setting are ongoing. In the future, tailored treatments such as no adjuvant therapy, various HER2-directed therapies alone with chemotherapy, combinations of various HER2-directed therapies and chemotherapy, addition of immune checkpoint inhibitors, and omission of surgery will be individualized in HER2-positive early breast cancer patients.

Outcome without any adjuvant systemic treatment in stage I ER+/HER2− breast cancer patients included in the MINDACT trial

Adjuvant systemic treatments (AST) reduce mortality, but have associated short- and long-term toxicities. Careful selection of patients likely to benefit from AST is needed. We evaluated outcome of low-risk breast cancer patients of the EORTC 10041/BIG 3-04 MINDACT trial who received no AST.Patients with estrogen receptor-positive, HER2-negative, lymph node-negative tumors ≤2 cm who received no AST were matched 1 : 1 to patients with similar tumor characteristics treated with adjuvant endocrine therapy (ET), using propensity score matching and exact matching on age, genomic risk (70-gene signature) and grade. In a post hoc analysis, distant metastasis-free interval (DMFI) and overall survival (OS) were assessed by Kaplan-Meier analysis and hazard ratios (HR) by Cox regression. Cumulative incidences of locoregional recurrence (LRR) and contralateral breast cancer (CBC) were assessed with competing risk analyses.At 8 years, DMFI rates were 94.8% [95% confidence interval (CI) 92.7% to 96.9%] in 509 patients receiving no AST, and 97.3% (95% CI 95.8% to 98.8%) in 509 matched patients who received only ET [absolute difference: 2.5%, HR 0.56 (95% CI 0.30-1.03)]. No statistically significant difference was seen in 8-year OS rates, 95.4% (95% CI 93.5% to 97.4%) in patients receiving no AST and 95.6% (95% CI 93.8% to 97.5%) in patients receiving only ET [absolute difference: 0.2%, HR 0.86 (95% CI 0.53-1.41)]. Cumulative incidence rates of LRR and CBC were 4.7% (95% CI 3.0% to 7.0%) and 4.6% (95% CI 2.9% to 6.9%) in patients receiving no AST versus 1.4% (95% CI 0.6% to 2.9%) and 1.5% (95% CI 0.6% to 3.1%) in patients receiving only ET.In patients with stage I low-risk breast cancer, the effect of ET on DMFI was limited, but overall significantly fewer breast cancer events were observed in patients who received ET, after the relatively short follow-up of 8 years. These benefits and side-effects of ET should be discussed with all patients, even those at a very low risk of distant metastasis.

External validation of the American Joint Committee on Cancer melanoma staging system eighth edition using the surveillance, epidemiology, and end results program.

The American Joint Committee on Cancer (AJCC) melanoma staging system eighth edition (AJCC-8) was recently released to provide accurate staging reflecting advances in the treatment of melanoma. Using population registry data, this study independently validates and compares the prognostic performance of AJCC-8 to the seventh edition (AJCC-7). We extracted patient-, tumor-related, and survival data from the SEER-18 registry between 2010 and 2015. To assess overall survival (OS) and cancer-specific survival (CSS) for AJCC-7 and AJCC-8, we performed Kaplan-Meier analysis and computed cumulative hazard functions using Nelson-Aalen function. Of 126,408 individuals, 59,989 (47%) and 60,411 (48%) had available data for pathological and clinical-stage OS analysis, respectively. The 3-year OS for AJCC-7 among pathologically staged patients was: stage IA 97%, stage IB 95%, stage IIA 87%, stage IIB 76%, stage IIC 57%, stage IIIA 86%, stage IIIB 69%, stage IIIC 50%, and stage IV 24%. The 3-year OS for AJCC-8 patients was similar but was 56% for stage IIIC and 30% for stage IIID. Stage IV individuals with an elevated LDH had worse OS and CSS at all measured time-points up to 60 months compared to those with a normal LDH. The discriminatory ability of AJCC-8 and AJCC-7 appear comparable. Changes in AJCC-8 identified stage IIID as a poor prognostic subgroup among stage III patients and elevated LDH in stage IV. However, patients with advanced T-stage, node-negative tumors experienced worse survival compared to those with earlier T-stage, node-positive tumors, and the results of ongoing trials should inform adjuvant therapy in this subset of patients.

Supervised machine learning model to predict oncotype DX risk category in patients over age 50.

Routine use of the oncotype DX recurrence score (RS) in patients with early-stage, estrogen receptor-positive, HER2-negative (ER+/HER2-) breast cancer is limited internationally by cost and availability. We created a supervised machine learning model using clinicopathologic variables to predict RS risk category in patients aged over 50years. From January 2012 to December 2018, we identified patients aged over 50years with T1-2, ER+/HER2-, node-negative tumors. Clinicopathologic data and RS results were randomly split into training and validation cohorts. A random forest model with 500 trees was developed on the training cohort, using age, pathologic tumor size, histology, progesterone receptor (PR) expression, lymphovascular invasion (LVI), and grade as predictors. We predicted risk category (low: RS ≤ 25, high: RS > 25) using the validation cohort. Of the 3880 tumors identified, 1293 tumors comprised the validation cohort in patients of median (IQR) age 62years (56-68) with median (IQR) tumor size 1.2cm (0.8-1.7). Most tumors were invasive ductal (80.3%) of low-intermediate grade (80.5%) without LVI (80.9%). PR expression was ≤ 20% in 27.3% of tumors. Specificity for identifying RS ≤ 25 was 96.3% (95% CI 95.0-97.4) and the negative predictive value was 92.9% (95% CI 91.2-94.4). Sensitivity and positive predictive value for predicting RS > 25 was lower (48.3 and 65.1%, respectively). Our model was highly specific for identifying eligible patients aged over 50years for whom chemotherapy can be omitted. Following external validation, it may be used to triage patients for RS testing, if predicted to be high risk, in resource-limited settings.

Can Multigene Testing Provide Additional Risk Stratification for Patients Considered Eligible for Accelerated Partial Breast Irradiation?

Following breast conserving surgery, the risk of ipsilateral in-breast recurrence is equivalent between whole breast radiation therapy (WBRT) and accelerated partial breast irradiation (APBI) in patients with low-risk tumors according to ASTRO guidelines. The Oncotype DX Recurrence Score (RS) is prognostic for both local and distant recurrence in ER+/HER2- breast cancer. Whether the RS can identify patients at increased risk for local recurrence among those considered eligible for APBI is unclear.We retrospectively identified consecutive patients with clinical T1-2, ER+/HER2-, node-negative tumors with an available RS, and who were treated with APBI from 2010-2019 at a single institution. RS testing was performed for all patients with ER+/HER2-, invasive cancers ≥ 0.5 cm who were candidates for chemotherapy. Patients were considered for APBI based on the 2009 ASTRO guidelines. Characteristics were compared between patients with RS ≤ 25 and RS > 25 using Fisher's exact test for categorical variables and the Wilcoxon rank sum test for continuous variables. The 6-year cumulative incidence rate (CIR) of local recurrence was estimated using Kaplan-Meier methods and was compared between groups using the log-rank test.223 patients were identified; the median (IQR) age was 63 years (57-68) and median (IQR) tumor size was 1.0 cm (0.8-1.4). 201 patients (90%) had RS ≤ 25 and 22 patients (10%) had RS > 25. Nine patients aged ≤ 50 years were included, all of whom had RS ≤ 25. Compared with the RS ≤ 25 group, patients with RS > 25 more frequently had tumors that were progesterone receptor negative (55% vs. 9%; P < 0.001), grade III (50% vs. 11%; P < 0.001) and were more likely to have received chemotherapy (73% vs. 5%; P < 0.001). Uptake of endocrine therapy was similar in the RS ≤ 25 group compared with RS > 25 group (97% vs. 95%; P = 0.39), as was median (IQR) duration of endocrine therapy at 3 years (2-5) for both groups (P = 0.9). The median (range) follow-up was 3.6 years (0.1-10.2) and was similar between groups (P = 0.64). Overall, 4 ipsilateral in-breast recurrences occurred during follow-up, with 2 events (1.0%) in the RS ≤ 25 group and 2 events (9.1%) in the RS > 25 group (P = 0.05). The 6-year CIR of local recurrence was higher among patients with RS > 25 compared with RS ≤ 25 (6-year CIR [95% CI] 0.01 [0-0.04] vs. 0.08 [0-0.21]; P = 0.006). Due to a low number of events, a multivariable analysis of factors associated with local recurrence could not be performed.The overall risk of local recurrence following APBI in patients with early-stage, ER+ tumors is low, but our findings suggest that the RS may identify patients at increased risk for local failure among a favorable risk population. Prospective studies are needed to assess whether genomic profiling can be used for additional risk stratification for patients considered eligible for APBI, to identify patients for whom de-escalation of WBRT may not be advisable.

The Evolving Landscape of Treatment Paradigms for Locally Advanced Rectal Cancer: A Survey Study of Gastrointestinal Radiation Oncology Experts

To assess current practice patterns in the treatment of locally advanced rectal cancer among radiation oncologists specializing in gastrointestinal (GI) malignancies.Radiation oncologists specialized in GI malignancies at an ACGME affiliated institution were invited to complete an online survey and select management recommendations for seven locally advanced rectal cancer clinical vignettes, consisting of variable T and N staging, tumor location and high-risk features (presence of enlarged lateral lymph nodes, mesorectal fascia involvement and extramural vascular invasion). Answer choices representing the diversity of current treatment paradigms for rectal cancer included variable sequences of chemotherapy (CHT), radiation (long-course chemoradiation [LC-CRT] or short-course radiation [SCRT]), surgery or non-operative management (NOM). Participation was voluntary and all responses remained anonymous. The survey was open from January to February 2021.Of 207 GI experts invited to participate, 36 replied, resulting in a response rate of 17.4% (36/207). For low rectal tumors (cT3N2) without threatened margins, 80.6% (29/36) recommended total neoadjuvant therapy (TNT) of which 41.4% (12/29) preferred NOM if a clinical complete response was achieved upon restaging. Of those who chose TNT and surgery (17/29), 76.5% preferred LC-CRT (consolidation CHT [53.8%] vs. induction CHT [46.2%]) and 23.5% preferred SCRT. For mid to upper rectal tumors (cT3N1-2) without threatened margins, 66.6% (24/36) recommended TNT and surgery with 38.9% (14/36) electing for SCRT then consolidation CHT, and 22.2% (8/36) for induction CHT then LC-CRT. After TNT, neoadjuvant LC-CRT (16.7%, 6/36) or neoadjuvant SCRT (11.1%, 4/36) followed by surgery and adjuvant CHT were most favored. In patients with mid to upper rectal tumors and threatened margins, SCRT with consolidation CHT and surgery remained the most accepted treatment paradigm (44.4%, 16/36). LC-CRT followed by consolidation CHT was the preferred choice to maximize likelihood of NOM. For a clinical node negative upper rectal tumor (cT3N0), 38.9% (14/36) recommended SCRT, then surgery with adjuvant CHT, 19.4% (7/36) recommended induction CHT then surgery, and 16.7% (6/36) recommended LC-CRT, then surgery with adjuvant CHT.Total neoadjuvant therapy has been widely adopted in the management of locally advanced rectal cancer. For mid to upper rectal tumors, most GI experts recommended SCRT, consolidation CHT and surgery. For low rectal tumors, LC-CRT was preferred with significant variability between consolidation versus induction CHT. As compared to mid and upper rectal tumors, clinicians were more likely to recommend NOM following a clinical complete response for low rectal tumors.

Epithelial\u2013mesenchymal transition (EMT) in vulvar cancer with and without inguinal lymph node involvement

PurposeEpithelial-mesenchymal transition (EMT) is associated with increased metastatic spread and poor prognosis. Data on vulvar carcinoma are limited.MethodsThirty-two cases of squamous cell carcinoma of the vulva (16 with and 16 without inguinal lymph node metastases) and their lymph node deposits were evaluated for immunohistochemical expression of EMT markers (vimentin, cyclin D1, e-cadherin), p16, p53 and Ki-67. Results of EMT-immunostainings were compared to lymph node involvement and expression of p53 and p16. The micro-anatomical staining pattern for EMT markers comparing the tumor center with the front of invasion was analysed in each tumor.ResultsThere was no difference in the expression of EMT markers between node negative and node positive tumors. Staining for vimentin and cyclin D1 was seen within tumor cells at the front of invasion in 100 and 84.4% of the tumors, respectively. The majority of cases (68.7%) showed negative or reduced staining for e-cadherin in this micro-anatomical localization. Tumor cells within the lymph node metastases showed positive staining for e-cadherin in 75% and for cyclin D1 in 49% of the cells but were negative for vimentin in 13 out of 16 cases (81.3%). Tumors with aberrant p53 staining represented a non-significant higher vimentin but significantly higher cyclin D1 expression at the front of invasion than those with p53 wild-type pattern.ConclusionThe present study shows no differences in the expression of EMT markers between node positive and node negative vulvar cancers. The evaluation of immunostaining within the micro-anatomical context indicates that an EMT-phenotype is restricted to the tumor cells at the front of invasion. Paired analyses of vulvar carcinomas and their lymph node deposits suggest mesenchymal-epithelial transition (MET) in the metastatic deposits. Immunohistochemical staining results may suggest that EMT is more prevalent in vulvar cancer with aberrant p53 staining.

Epithelial-mesenchymal plasticity and lymph node metastases in invasive breast carcinoma of no special type

Background: Breast cancer is the commonest cancer among women with distant metastases being the leading cause of mortality. Epithelial-mesenchymal plasticity (EMP) is a proposed mechanism involved in establishment of metastasis. E-cadherin and vimentin can be used as epithelial and mesenchymal markers, respectively, to identify EMP. Aims: To compare E-cadherin and vimentin expressions between node-negative and node-positive invasive breast carcinoma–no special type (IBC-NST) and their lymph node metastases. Methods: Forty node negative tumours and 44 axillary node positive tumours of IBC-NST with their metastatic lymph nodes were retrieved from patients who had undergone mastectomy at the Teaching Hospital, Peradeniya. Samples were subjected to dual immunohistochemical staining with anti-E-cadherin and anti-vimentin primary antibodies. Any cytoplasmic staining for vimentin and 70% or more of membranous staining for E-cadherin were taken as positive and cells counted in 10 high power fields. Intensity of staining was graded as high=3, moderate=2, low=1 and absent=0 by comparing with internal controls. Percentage of positive cells was multiplied by the intensity to obtain the immuno-score (IS) for both protein expressions. IS was compared using independent and paired t-test. Results and conclusions: A lower E-cadherin (p=0.001) and higher vimentin (p=0.008) expression was seen in node positive group compared to node negative group. A higher E-cadherin (p<0.001) and lower vimentin (p<0.001) expression was seen in lymph nodes compared to the corresponding primary tumours. A significant loss of epithelial properties and acquisition of mesenchymal properties in the node positive group indicates epithelial to mesenchymal transition of tumour cells, contributing to metastasis. In the lymph nodes, higher E-cadherin and lower vimentin expression suggests a reverse mechanism, i.e., mesenchymal to epithelial transition. These Results are suggestive of epithelial-mesenchymal plasticity of tumour cells in establishment of metastasis in IBC-NST.

Local excision and treatment of early node-negative anal squamous cell carcinomas in a highly HIV prevalent population

BackgroundAnal squamous cell carcinoma (ASCC) is an uncommon cancer associated with human immunodeficiency virus (HIV) infection. There has been increasing interest in providing organ-sparing treatment in small node-negative ASCC’s, however, there is a paucity of evidence about the use of local excision alone in people living with HIV (PLWH). The aim of this study was to evaluate the efficacy of local excision alone in this patient population.MethodsWe present a case series of stage 1 and stage 2 ASCC in PLWH and HIV negative patients. Data were extracted from a 20-year retrospective cohort study analysing the treatment and outcomes of patients with primary ASCC in a cohort with a high prevalence of HIV.ResultsNinety-four patients were included in the analysis. Fifty-seven (61%) were PLWH. Thirty-five (37%) patients received local excision alone as treatment for ASCC, they were more likely to be younger (p = 0.037, ANOVA) and have either foci of malignancy or well-differentiated tumours on histology (p = 0.002, Fisher’s exact test).There was no statistically significant difference in 5-year disease-free survival and recurrence between treatment groups, however, patients who had local excision alone and PLWH were both more likely to recur later compared to patients who received other treatments for ASCC. (72.3 months vs 27.3 months, p = 0.06, ANOVA, and 72.3 months vs 31.8 months, p = 0.035, ANOVA, respectively).ConclusionsWe recommend that local excision be considered the sole treatment for stage 1 node-negative tumours that have clear margins and advantageous histology regardless of HIV status. However, PLWH who have local excision alone must have access to an expert long-term surveillance programme after treatment to identify late recurrences.

Nodal status in luminal A invasive breast cancer: relationships with cytotoxic CD8\u2009+\u2009and regulatory FOXP3\u2009+\u2009cells tumor-associated infiltrate and other prognostic factors

Luminal A breast cancers are generally associated with low metastatic potential and good prognosis. However, there is a proportion of patients, who present with metastases in lymph nodes. The aim of our study was to determine the association between the number of positive lymph nodes and infiltrates of tumor-associated cytotoxic CD8 + (CTLs), regulatory FOXP3 + T cells (Tregs), as well as other prognostic factors. Immunohistochemistry (IHC) for CD8 + and FOXP3 + was performed in 87 formalin-fixed paraffin-embedded primary breast cancer tissues, and cell infiltrate was assessed under light microscope. We observed that node-positive cases were associated with higher numbers of Treg cells and lower CTL/Treg ratio. There was also an inverse correlation between the CTL/Treg ratio and the number of metastatic lymph nodes. Similar relationships were found between the number of metastatic lymph nodes and Treg density or CTL/Treg ratio in pT1 BC. An elevated intratumoral CTL/Treg ratio was associated with pN0 stage. The relationship between lymphovascular invasion (LVI) and Treg density was also noted in node-negative tumors. In addition, more advanced nodal stage was related to LVI, higher pT, and lower PR expression. The numbers of CD8 + and FOXP3 + were also associated with tumor size, histologic grade, PR expression, and mitotic index. The results of our study suggested that the levels of tumor-infiltrating regulatory and cytotoxic cells as well as the balance between them play a role in lymphovascular spread of luminal A breast cancers.

Abstract PS11-01: Outcome without adjuvant systemic treatment in breast cancer patients included in the MINDACT trial

Abstract Background: Adjuvant systemic treatments have played an important role in the decline of breast cancer mortality over the years. Because of the extensive short- and long-term toxicities associated with these treatments, careful selection of patients likely to benefit from them is needed. Studies have shown excellent survival in subgroups of patients receiving no adjuvant systemic treatments. Some national guidelines advise no adjuvant systemic treatments in specific groups of patients with clinical low risk breast cancer. The aim of this study is to investigate the survival of breast cancer patients who received no adjuvant treatment (chemotherapy nor endocrine therapy) using data from the EORTC 10041/BIG 3-04 MINDACT trial. Material and methods: Of the 6693 patients enrolled in the MINDACT trial, accrued 2007-2011, 509 patients with hormone receptor positive, HER2 negative, lymph node negative tumors &amp;lt;2cm received no adjuvant systemic treatment, mostly following local recommendations. Median follow-up was 8.7 years. Using propensity score matching and exact matching, we will identify groups of patients treated with adjuvant endocrine therapy and/or chemotherapy with similar tumor characteristics to the untreated patients. We will use the Kaplan-Meier method to estimate distant metastasis free interval and overall survival at 5 and 8 years for each group. Differences between groups will be evaluated using the log-rank test, and hazard ratios with 95% CI derived from Cox proportional hazards models. Planned analyses: The long-term data of the MINDACT trial has recently become available. The date of planned analysis is August 10th 2020.For this study, the primary clinical endpoint will be distant metastasis free interval, which will be assessed in the matched groups of untreated patients, patients who received endocrine therapy only, and patients who received chemotherapy with or without endocrine therapy. Kaplan-Meier estimates will be provided at 5 years, and at 8 years to assess the long-term outcomes in this population. A statistical plan for this analysis was specifically developed and approved prior to performing any analysis. Citation Format: Josephine MN Lopes Cardozo, Danalyn Byng, Caroline A Drukker, Marjanka K Schmidt, Laura J van 't Veer, Fatima Cardoso, Martine Piccart, Coralie Poncet, Emiel JTh Rutgers. Outcome without adjuvant systemic treatment in breast cancer patients included in the MINDACT 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 PS11-01.

In modern times, how important are breast cancer stage, grade and receptor subtype for survival: a population-based cohort study

BackgroundIn breast cancer, immunohistochemistry (IHC) subtypes, together with grade and stage, are well-known independent predictors of breast cancer death. Given the immense changes in breast cancer treatment and survival over time, we used recent population-based data to test the combined influence of IHC subtypes, grade and stage on breast cancer death.MethodsWe identified 24,137 women with invasive breast cancer aged 20 to 74 between 2005 and 2015 in the database of the Cancer Registry of Norway. Kaplan-Meier curves, mortality rates and adjusted hazard ratios for breast cancer death were estimated by IHC subtypes, grade, tumour size and nodal status during 13 years of follow-up.ResultsWithin all IHC subtypes, grade, tumour size and nodal status were independent predictors of breast cancer death. When combining all prognostic factors, the risk of death was 20- to 40-fold higher in the worst groups compared to the group with the smallest size, low grade and ER+PR+HER2− status. Among node-negative ER+HER2− tumours, larger size conferred a significantly increased breast cancer mortality. ER+PR−HER2− tumours of high grade and advanced stage showed particularly high breast cancer mortality similar to TNBC. When examining early versus late mortality, grade, size and nodal status explained most of the late (> 5 years) mortality among ER+ subtypes.ConclusionsThere is a wide range of risks of dying from breast cancer, also across small breast tumours of low/intermediate grade, and among node-negative tumours. Thus, even with modern breast cancer treatment, stage, grade and molecular subtype (reflected by IHC subtypes) matter for prognosis.

Association of Race/Ethnicity and the 21-Gene Recurrence Score With Breast Cancer–Specific Mortality Among US Women

Given the widespread use of the 21-gene recurrence score for identifying candidates for adjuvant chemotherapy, it is important to examine the performance of the Oncotype DX Breast Recurrence Score test in diverse patient populations to validate this approach for tailoring treatment in women in racial/ethnic minority groups. To examine whether breast cancer-specific mortality for women with hormone-dependent breast cancer differs by race/ethnicity across risk categories defined by the Oncotype DX Breast Recurrence Score test and whether the prognostic accuracy of the 21-gene recurrence score differs by race/ethnicity. This retrospective, population-based cohort study used the Surveillance, Epidemiology, and End Results Oncotype DX 2004-2015 database to obtain breast cancer-specific survival data on US women 18 years and older who were diagnosed with first primary stage I to III, estrogen receptor-positive breast cancer between January 1, 2004, and December 31, 2015, and had tumor testing through the Genomic Health Clinical Laboratory. Data were analyzed from April 20 to September 27, 2020. The primary outcome was breast cancer-specific mortality among women from different racial/ethnic groups stratified by the 21-gene recurrence score risk categories. Secondary analyses compared the prognostic accuracy of the recurrence score among the different racial/ethnic groups. A total of 86 033 patients with breast cancer (mean [SD] age, 57.6 [10.6] years) with Oncotype DX Breast Recurrence Score test information were available for the analysis, including 64 069 non-Hispanic White women (74.4%), 6719 non-Hispanic Black women (7.8%), 7944 Hispanic women (9.2%), 6950 Asian/Pacific Islander women (8.0%), and 351 American Indian/Alaska Native women (0.4%). Black women were significantly more likely than non-Hispanic White women to have a recurrence score greater than 25 (17.7% vs 13.7%; P < .001). Among women with axillary node-negative tumors, competing risk models adjusted for age, tumor characteristics, and treatment found higher breast cancer-specific mortality for Black compared with non-Hispanic White women within each recurrence score risk stratum, with subdistribution hazard ratios of 2.54 (95% CI, 1.44-4.50) for Black women with recurrence scores of 0 to 10, 1.64 (95% CI, 1.23-2.18) for Black women with recurrence scores of 11 to 25, and 1.48 (95% CI, 1.10-1.98) for Black women with scores greater than 25. The prognostic accuracy of the recurrence score was significantly lower for Black women, with a C index of 0.656 (95% CI, 0.592-0.720) compared with 0.700 (95% CI, 0.677-0.722) (P = .002) for non-Hispanic Whites. In this cohort study, Black women in the US were more likely to have a high-risk recurrence score and to die of axillary node-negative breast cancer compared with non-Hispanic White women with comparable recurrence scores. The Oncotype DX Breast Recurrence Score test has lower prognostic accuracy in Black women, suggesting that genomic assays used to identify candidates for adjuvant chemotherapy may require model calibration in populations with greater racial/ethnic diversity.

Deregulation of extracellular matrix modeling with molecular prognostic markers revealed by transcriptome sequencing and validations in Oral Tongue squamous cell carcinoma

Oral Tongue Squamous Cell Carcinoma (OTSCC), a distinct sub-group of head and neck cancers, is characteristically aggressive in nature with a higher incidence of recurrence and metastasis. Recent advances in therapeutics have not improved patient survival. The phenomenon of occult node metastasis, even among the purportedly good prognosis group of early-stage and node-negative tongue tumors, leads to a high incidence of locoregional failure in OTSCC which needs to be addressed. In the current study, transcriptome analysis of OTSCC patients identified the key genes and deregulated pathways. A panel of 26 marker genes was shortlisted and validated using real-time PCR in a prospective cohort of 100 patients. The gene expression was correlated with clinicopathological features including occult node metastasis, survival, and therapeutic outcome. The up-regulation of a panel of 6 genes namely, matrix metalloproteinase 9 (MMP9), Laminin subunit Gamma 2 (LAMC2), Desmoglein 2 (DSG2), Plasminogen Activator Urokinase (PLAU), Forkhead Box M1 (FOXM1), and Myosin 1B (MYO1B) was associated with failure of treatment in the early stage (T1, T2). Up-regulation of Tenacin C (TNC) and Podoplanin (PDPN) was significantly correlated with occult node positivity. Immunohistochemical analysis of LAMC2, MMP9, and E-Cadherin (ECAD) confirmed these markers to be indicators of poor prognosis. We propose this panel of valuable prognostic markers can be clinically useful to identify poor prognosis and occult node metastasis in OTSCC patients.

Clinical significance of HER2 status in T1bN0 breast cancer: a nationwide study from the Korean Breast Cancer Society.

The prognosis of patients with node-negative T1b tumors according to human epidermal growth factor receptor 2 (HER2) status is not known. This group of patients has not been studied in the available randomized trials. The objective of this study was to evaluate the survival of patients in a monoethnic group diagnosed with T1b lymph node-negative breast cancer depending on HER2 status. We analyzed 3110 patients with T1bN0M0 breast cancer whose data were deposited into the Korean Breast Cancer Society Registry database between 2000 and 2009. Overall survival (OS) and breast cancer-specific survival (BCSS) were compared according to HER2 status. Among all patients, 494 (15.9%) had HER2-positive breast cancer. At a mean follow-up of 93months, 108 deaths and 86 breast cancer-specific deaths were noted among all patients. There was no significant difference in OS between the HER2-negative and HER2-positive groups (p = 0.103). The same result was observed for BCSS. However, in the subgroup of estrogen receptor (ER)-positive women, HER2-negative patients had a better BCSS prognosis than HER2-positive patients (p = 0.025). Multivariate analysis also indicated a significant difference in BCSS in the ER-positive subgroup (HR 2.60; 95% CI 1.15-5.87; p = 0.021). This study analyzed a large nationwide and monoethnic cohort and found a significant difference only in BCSS in the ER-positive subgroup according to HER2 status. Anti-HER2 therapy may be considered in HER2-positive and ER-positive patients with small, node-negative breast cancer.

Diagnostic ipsilateral central neck dissection may reduce undertreatment of initially low-risk papillary thyroid cancer.

Although small papillary thyroid cancer (PTC) patients are considered as low-risk population, approximately 5-20% of these patients relapse after surgery. The objective of this single-center retrospective study was to identify risk factors, which could help to distinguish patients who would need additional treatment after surgery. A total of 268 patients (39 men, 229 women, median age 49 years) underwent surgery between 2007-2015, and fulfilled inclusion criteria: tumor size ≤20 mm, absence of metastatic lymph nodes (LN) in the lateral neck compartment (LC), and absence of local invasion. Total thyroidectomy was performed in 252 cases, in 221 cases with central neck compartment (CC) dissection. The outcome - a more aggressive disease - was defined as the presence of metastases in the LNLC or in distant organs found during follow-up. A median follow-up was 117 months. Overall, 41 patients experienced the outcome with a median time-to-event of 18 months. Male gender (OR=2.2, p=0.049), extra-thyroidal extension ETE (OR=2.61, p=0.015), and metastases in LNCC (OR=4.21, p<0.001) were associated with worse outcome. Multivariable analysis and stratification according to ETE revealed an effect modification with a higher effect of the positive LNCC on the outcome among patients without ETE than in those with ETE. Our findings advocate placing greater emphasis on the role of LNCC metastases in the absence of ETE. In clinically node-negative tumors intraoperative examination of CC on the side of the tumor followed by CC dissection if metastatic lymphadenopathy is present could play an important role in the stratification of patients with small-size PTC.

Insights for the application of TILs and AR in the treatment of TNBC in routine clinical practice

Triple negative breast cancer (TNBC), usually presenting with a very aggressive phenotype, is a heterogeneous entity. We aim to discuss new biomarkers, suitable for prognostic and predictive purposes. We retrospectively collected clinical variables and immunohistochemical characteristics of early TNBCs, specifically focusing on the prognostic and predictive significance of tumor infiltrating lymphocytes (TILs) and androgen receptor (AR) expression, assessing their correlation with clinical variables. Among 159 patients, TILs were significantly higher in younger patients and with lower BMI, and in tumors with higher ki-67 and greater nodal involvement; conversely, AR was significantly higher in older patients and in tumors with lower ki-67. Interestingly and in line with literature, both TILs level and ARs expression were lower within metastatic sites, in patients who developed distant metastases, compared to those found in the primary site. Small (pT1) and node negative tumors were highly represented and no correlation of either TILs or AR with prognosis could be observed. Our findings support the use of stromal TILs to identify a more aggressive, but chemo-sensitive phenotype, mostly represented in younger women, while AR may identify a less aggressive, slow-growing luminal TNBC subtype, more common among older patients. TILs and AR are worth implementing in routine clinical practice to refine prognosis even if, in our case series, we couldn’t identify a significant correlation of the two variables with either disease-free and overall survival.

How Different Are the Molecular Mechanisms of Nodal and Distant Metastasis in Luminal A Breast Cancer?

Simple SummaryLymph node status is one of the best prognostic factors in breast cancer, however, its association with distant metastasis is not straightforward. Here we compare molecular mechanisms of nodal and distant metastasis in molecular subtypes of breast cancer, with major focus on luminal A patients. Our results indicate that lymph node positivity is associated with NF-κB and Src pathways and is related to high risk of distant metastasis in luminal A patients. Distant metastasis of lymph node negative tumors is related to cell proliferation control and thrombolysis, whereas distant metastasis of lymph node positive tumors is associated mostly to immune response. These mechanisms vary in other molecular subtypes. Our data indicate that the management of breast cancer and prevention of distant metastasis requires stratified approach based on targeted strategies.Lymph node status is one of the best prognostic factors in breast cancer, however, its association with distant metastasis is not straightforward. Here we compare molecular mechanisms of nodal and distant metastasis in molecular subtypes of breast cancer, with major focus on luminal A patients. We analyze a new cohort of 706 patients (MMCI_706) as well as an independent cohort of 836 primary tumors with full gene expression information (SUPERTAM_HGU133A). We evaluate the risk of distant metastasis, analyze targetable molecular mechanisms in Gene Set Enrichment Analysis and identify relevant inhibitors. Lymph node positivity is generally associated with NF-κB and Src pathways and is related to high risk (OR: 5.062 and 2.401 in MMCI_706 and SUPERTAM_HGU133A, respectively, p < 0.05) of distant metastasis in luminal A patients. However, a part (≤15%) of lymph node negative tumors at the diagnosis develop the distant metastasis which is related to cell proliferation control and thrombolysis. Distant metastasis of lymph node positive patients is mostly associated with immune response. These pro-metastatic mechanisms further vary in other molecular subtypes. Our data indicate that the management of breast cancer and prevention of distant metastasis requires stratified approach based on targeted strategies.