Persistent EGFR/K-RAS/SIAH pathway activation drives chemo-resistance and early tumor relapse in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. It disproportionately affects BRCA mutation carriers and young women, especially African American (AA) women. Chemoresistant TNBC is a heterogeneous and molecularly unstable disease that challenges our ability to apply personalized therapies. With the approval of immune checkpoint blockade (ICB) for TNBC, the addition of pembrolizumab to systemic chemotherapy has become standard of care (SOC) in neoadjuvant systemic therapy (NST) for high-risk early-stage TNBC. Pembrolizumab plus chemotherapy significantly increased the pathologic complete response (pCR) and improved event-free survival in TNBC. However, clinical uncertainties remain because similarly treated TNBC partial responders with comparable tumor responses to neoadjuvant therapy often experience disparate clinical outcomes. Current methods fall short in accurately predicting which high-risk patients will develop chemo-resistance and tumor relapse. Therefore, novel treatment strategies and innovative new research initiatives are needed. We propose that the EGFR-K-RAS-SIAH pathway activation is a major tumor driver in chemoresistant TNBC. Persistent high expression of SIAH in residual tumors following NACT/NST reflects that the EGFR/K-RAS pathway remains activated (ON), indicating an ineffective response to treatment. These chemoresistant tumor clones persist in expressing SIAH (SIAHHigh/ON) and are linked to early tumor relapse and poorer prognosis. Conversely, the loss of SIAH expression (SIAHLow/OFF) in residual tumors post-NACT/NST reflects EGFR/K-RAS pathway inactivation (OFF), indicating effective therapy and chemo-sensitive tumor cells. SIAHLow/OFF signal is linked to tumor remission and better prognosis post-NACT/NST. Therefore, SIAH is well-positioned to become a novel tumor-specific, therapy-responsive, and prognostic biomarker. Potentially, this new biomarker (SIAHHigh/ON) could be used to quantify therapy response, predict chemo-resistance, and identify those patients at the highest risk for tumor relapse and poor survival in TNBC.

Combined modality therapy including cytoreductive surgery and heated intraperitoneal chemotherapy for synchronous low volume peritoneal carcinomatosis from adenocarcinoma of the tail of pancreas in a BRCA-2 carrier resulting in long-term disease-free survival: A case report.

INTRODUCTION: A BRCA-2 mutation carrier with a metachronous pancreatic adenocarcinoma (PC) and established peritoneal metastases is presented. Combined modality therapy including Cytoreductive Surgery (CS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) was associated with long-term disease-free survival. CASE PRESENTATION: A 62-yr. old female underwent successful treatment for stage IIIa carcinoma of the right breast at age 48. 11 years later a cystic adenocarcinoma of the tail of the pancreas with peritoneal metastases was diagnosed. Platin based neoadjuvant chemotherapy followed by definitive resection of the pancreatic mass with cytoreductive surgery (CS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with mitomycin C was performed. Postoperatively, a retro-gastric fluid collection developed from a pancreatic duct leak, successfully managed non-operatively. Maintenance poly ADP ribose polymerase (PARP) inhibitor therapy was initiated after recovery from surgery. The patient experienced a 30-month disease free survival and was subsequently found to have oligometastases to the brain. DISCUSSION: CR and HIPEC have not been reported to be efficacious in patients with pancreatic carcinomatosis. However, PC arising in BRCA-2 carriers has a DNA repair defect, which is sensitive to platin based chemotherapy and mitomycin C. HIPEC has more severe postoperative complications following distal pancreatectomy. Isolated brain metastases from PC are rare. BRCA-2 mutation carriers are at significantly increased risk for PC. CONCLUSION: Leveraging the DNA Repair defect in BRCA-2 pancreatic adenocarcinoma, including CS and HIPEC, led to long-term disease-free survival and good locoregional control in this patient. Complications from HIPEC are more severe. BRCA-2 carriers should undergo annual pancreatic cancer screening.

TARGIT-R (Retrospective): 5-Year Follow-Up Evaluation of Intraoperative Radiation Therapy (IORT) for Breast Cancer Performed in North America.

BACKGROUND: Intraoperative radiation therapy (IORT) has been investigated for patients with low-risk, early-stage breast cancer. The The North American experience was evaluated by TARGIT-R (retrospective) to provide outcomes for patients treated in "real-world" clinical practice with breast IORT. This analysis presents a 5-year follow-up assessment. METHODS: TARGIT-R is a multi-institutional retrospective registry of patients who underwent lumpectomy and IORT between the years 2007 and 2013. The primary outcome of the evaluation was ipsilateral breast tumor recurrence (IBTR). RESULTS: The evaluation included 667 patients with a median follow-up period of 5.1 years. Primary IORT (IORT at the time of lumpectomy) was performed for 72%, delayed IORT (after lumpectomy) for 3%, intended boost for 8%, and unintended boost (primary IORT followed by whole-breast radiation) for 17% of the patients. At 5 years, IBTR was 6.6% for all the patients, with 8% for the primary IORT cohort and 1.7% for the unintended-boost cohort. No recurrences were identified in the delayed IORT or intended-boost cohorts. Noncompliance with endocrine therapy (ET) was associated with higher IBTR risk (hazard ratio [HR], 3.67). Patients treated with primary IORT who were complaint with ET had a 5-year IBTR rate of 3.9%. CONCLUSION: The local recurrence rates in this series differ slightly from recent results of randomized IORT trials and are notably higher than in previous published studies using whole-breast radiotherapy for similar patients with early-stage breast cancer. Understanding differences in this retrospective series and the prospective trials will be critical to optimizing patient selection and outcomes going forward.

Perspectives on Triple-Negative Breast Cancer: Current Treatment Strategies, Unmet Needs, and Potential Targets for Future Therapies.

Triple-negative breast cancer (TNBC), characterized by the absence or low expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), is the most aggressive subtype of breast cancer. TNBC accounts for about 15% of breast cancer cases in the U.S., and is known for high relapse rates and poor overall survival (OS). Chemo-resistant TNBC is a genetically diverse, highly heterogeneous, and rapidly evolving disease that challenges our ability to individualize treatment for incomplete responders and relapsed patients. Currently, the frontline standard chemotherapy, composed of anthracyclines, alkylating agents, and taxanes, is commonly used to treat high-risk and locally advanced TNBC. Several FDA-approved drugs that target programmed cell death protein-1 (Keytruda) and programmed death ligand-1 (Tecentriq), poly ADP-ribose polymerase (PARP), and/or antibody drug conjugates (Trodelvy) have shown promise in improving clinical outcomes for a subset of TNBC. These inhibitors that target key genetic mutations and specific molecular signaling pathways that drive malignant tumor growth have been used as single agents and/or in combination with standard chemotherapy regimens. Here, we review the current TNBC treatment options, unmet clinical needs, and actionable drug targets, including epidermal growth factor (EGFR), vascular endothelial growth factor (VEGF), androgen receptor (AR), estrogen receptor beta (ERß), phosphoinositide-3 kinase (PI3K), mammalian target of rapamycin (mTOR), and protein kinase B (PKB or AKT) activation in TNBC. Supported by strong evidence in developmental, evolutionary, and cancer biology, we propose that the K-RAS/SIAH pathway activation is a major tumor driver, and SIAH is a new drug target, a therapy-responsive prognostic biomarker, and a major tumor vulnerability in TNBC. Since persistent K-RAS/SIAH/EGFR pathway activation endows TNBC tumor cells with chemo-resistance, aggressive dissemination, and early relapse, we hope to design an anti-SIAH-centered anti-K-RAS/EGFR targeted therapy as a novel therapeutic strategy to control and eradicate incurable TNBC in the future.

Unmet Clinical Need: Developing Prognostic Biomarkers and Precision Medicine to Forecast Early Tumor Relapse, Detect Chemo-Resistance and Improve Overall Survival in High-Risk Breast Cancer.

Chemo-resistant breast cancer is a major barrier to curative treatment for a significant number of women with breast cancer. Neoadjuvant chemotherapy (NACT) is standard first- line treatment for most women diagnosed with high-risk TNBC, HER2+, and locally advanced ER+ breast cancer. Current clinical prognostic tools evaluate four clinicopathological factors: Tumor size, LN status, pathological stage, and tumor molecular subtype. However, many similarly treated patients with identical residual cancer burden (RCB) following NACT experience distinctly different tumor relapse rates, clinical outcomes and survival. This problem is particularly apparent for incomplete responders with a high-risk RCB classification following NACT. Therefore, there is a pressing need to identify new prognostic and predictive biomarkers, and develop novel curative therapies to augment current standard of care (SOC) treatment regimens to save more lives. Here, we will discuss these unmet needs and clinical challenges that stand in the way of precision medicine and personalized cancer therapy.

Intraoperative Radiation "Boost" to the Surgical Resection Bed following Pancreaticoduodenectomy for a Borderline Resectable Pancreatic Carcinoma: A Case Report.

Neoadjuvant therapy including chemotherapy alone or concurrent chemotherapy with external bream radiation is a standard treatment strategy for borderline resectable pancreatic adenocarcinoma and is also used routinely for primary operable cancers at some institutions (1). The use of intraoperative radiation therapy (IORT) has been limited largely because of the logistical issues in delivery of radiation during surgery (2). This is the first reported case of a borderline resectable pancreas cancer patient who underwent neoadjuvant chemo-radiation therapy followed by resection with the use of IORT using the mobile IntraBeam device to boost the resection bed and improve local control by dose escalation.

Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma.

BACKGROUND: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. METHODS: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. RESULTS: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).

SIAH and EGFR, Two RAS Pathway Biomarkers, are Highly Prognostic in Locally Advanced and Metastatic Breast Cancer.

BACKGROUND: Metastatic breast cancer exhibits diverse and rapidly evolving intra- and inter-tumor heterogeneity. Patients with similar clinical presentations often display distinct tumor responses to standard of care (SOC) therapies. Genome landscape studies indicate that EGFR/HER2/RAS "pathway" activation is highly prevalent in malignant breast cancers. The identification of therapy-responsive and prognostic biomarkers is paramount important to stratify patients and guide therapies in clinical oncology and personalized medicine. METHODS: In this study, we analyzed matched pairs of tumor specimens collected from 182 patients who received neoadjuvant systemic therapies (NST). Statistical analyses were conducted to determine whether EGFR/HER2/RAS pathway biomarkers and clinicopathological predictors, alone and in combination, are prognostic in breast cancer. FINDINGS: SIAH and EGFR outperform ER, PR, HER2 and Ki67 as two logical, sensitive and prognostic biomarkers in metastatic breast cancer. We found that increased SIAH and EGFR expression correlated with advanced pathological stage and aggressive molecular subtypes. Both SIAH expression post-NST and NST-induced changes in EGFR expression in invasive mammary tumors are associated with tumor regression and increased survival, whereas ER, PR, and HER2 were not. These results suggest that SIAH and EGFR are two prognostic biomarkers in breast cancer with lymph node metastases. INTERPRETATION: The discovery of incorporating tumor heterogeneity-independent and growth-sensitive RAS pathway biomarkers, SIAH and EGFR, whose altered expression can be used to estimate therapeutic efficacy, detect emergence of resistant clones, forecast tumor regression, differentiate among partial responders, and predict patient survival in the neoadjuvant setting, has a clear clinical implication in personalizing breast cancer therapy. FUNDING: This work was supported by the Dorothy G. Hoefer Foundation for Breast Cancer Research (A.H. Tang); Center for Innovative Technology (CIT)-Commonwealth Research Commercialization Fund (CRCF) (MF14S-009-LS to A.H. Tang), and National Cancer Institute (CA140550 to A.H. Tang).

TARGIT-R (Retrospective): North American Experience with Intraoperative Radiation Using Low-Kilovoltage X-Rays for Breast Cancer.

BACKGROUND: Single-dose intraoperative radiotherapy (IORT) is an emerging treatment for women with early stage breast cancer. The objective of this study was to define the frequency of IORT use, patient selection, and outcomes of patients treated in North America. METHODS: A multi-institutional retrospective registry was created, and 19 institutions using low-kilovoltage IORT for the treatment of breast cancer entered data on patients treated at their institution before July 31, 2013. Patient selection, IORT treatment details, complications, and recurrences were analyzed. RESULTS: From 2007 to July 31, 2013, a total of 935 women were identified and treated with lumpectomy and IORT. A total of 822 patients had at least 6 months' follow-up documented and were included in the analysis. The number of IORT cases performed increased significantly over time (p < 0.001). The median patient age was 66.8 years. Most patients had disease that was <2 cm in size (90 %) and was estrogen positive (91 %); most patients had invasive ductal cancer (68 %). Of those who had a sentinel lymph node procedure performed, 89 % had negative sentinel lymph nodes. The types of IORT performed were primary IORT in 79 %, secondary IORT in 7 %, or planned boost in 14 %. Complications were low. At a median follow-up of 23.3 months, crude in-breast recurrence was 2.3 % for all patients treated. CONCLUSIONS: IORT use for the treatment of breast cancer is significantly increasing in North America, and physicians are selecting low-risk patients for this treatment option. Low complication and local recurrence rates support IORT as a treatment option for selected women with early stage breast cancer.

RAS pathway biomarkers for breast cancer prognosis.

Metastatic breast cancer is a highly heterogeneous, rapidly evolving and devastating disease that challenges our ability to find curative therapies. RAS pathway activation is an understudied research area in breast cancer. EGFR/RAS pathway activation is prevalent in breast cancer with poor prognosis. The prognostic RAS pathway biomarkers can be used to identify resistant tumour clones, stratify patients and guide therapies.

Accelerated partial breast irradiation: a review and description of an early North American surgical experience with the intrabeam delivery system.

BACKGROUND: Targeted intraoperative radiation therapy (IORT) as an alternative to whole breast irradiation (WBI) has been described for patients with early-stage breast cancer. The randomized phase III TARGiT trial demonstrated similar recurrence rates to WBI and a lower overall toxicity profile on short-term follow-up. We report on our early North American surgical experience using the Intrabeam radiotherapy delivery system and review the current literature. METHODS: Prospectively gathered estrogen receptor-positive, clinically node-negative patients with invasive breast cancer < 3 cm receiving IORT using the Intrabeam system were reviewed. IORT-related effects and early postoperative outcome were assessed. A literature review was also performed. RESULTS: Forty-two patients (median age 71 years) underwent lumpectomy, sentinel lymph node (SLN) biopsy, and concurrent IORT from January 2011 to July 2011. Ninety-one percent of patients had invasive ductal histology with a median tumor size of 1.0 cm. This review highlights the patient selection criteria, describes commercially available accelerated partial breast irradiation (APBI) treatment options, and discusses outcomes for the variety of APBI techniques currently utilized in clinical practice as well as an institutional review of our early surgical experience using the Intrabeam radiotherapy delivery system. CONCLUSIONS: While a variety of APBI techniques are currently available for clinical use, our early North American operative experience with IORT shows it is well tolerated with low morbidity. Delivery of IORT adds moderate operative time and may require creating subcutaneous tissue fl aps. The addition of WBI may be necessary in situations for positive residual margins or microscopic nodal disease in patients who do not undergo additional surgery.