Patient with Lobular Carcinoma of the Breast and Activating AKT1 E17K Variant.

OBJECTIVE: To present the characteristics of the AKT1E117K gene variant and a description of the clinical application in a patient with metastatic breast cancer. RESULTS: 63 y/o woman with Stage IV Invasive lobular carcinoma at diagnosis was treated with Palbociclib and aromatase inhibitors (AI). At progression, tissue was sent for comprehensive genomic profiling to Foundation Medicine (FM) which revealed AKT1E17K mutation. In lieu of available clinical data within the patient's tumor type (HR+ HER2- breast cancer), extrapolated data from the Flatiron Health-FM (FH-FMI) Clinico-genomic Database (CGDB) was discussed at our Molecular Tumor Board (MTB). After multidisciplinary discussion, the consensus recommendation was to start treatment with the combination of mTOR inhibitor everolimus, and AI, exemestane. Patient tolerated treatment without major side effects. By the second clinical visit the patient's breast showed signs of improvement. PET/CT showed diminished left axillary uptake, decreased right paratracheal lymph node PET avidity, and stable bone disease consistent with a partial response. The most recent office visit in January 2021, breast exam revealed a normal-appearing skin with only faint erythema. All other skin lesions have resolved. Although, the role of AKT1 variant described here is not well defined and therapeutic significance of M-Tor inhibitors not established in metastatic breast cancers, comprehensive approach to this case unraveled new and successful therapeutic option in this patient. CONCLUSION: This demonstrates that applying available Precision Medicine tools like MTB and real world data sets from patient populations with similar clinical and genomic profiles may provide more options for treatment.

Changing Landscape of Clinical-Genomic Oncology Practice.

The current paper discusses the use of genomics in the context of the changing landscape of clinical practice and modern medicine. Medical practice has shifted considerably over the past few decades, from empirical to evidence-based to personalized medicine, and the transition from reliance on observation to measureable parameters. Scientific innovation is required to collect an ever-increasing number and variety of data points and sophisticated analyses capable of distilling vast datasets into meaningful information. The next phase of innovation seeks to personalize disease management, in particular through genomics in oncology. With expanding use of genomics in medicine, and several initiatives collecting genomic data at the population level, education of patients and physicians is critical for data utility. By combining genomic and clinical data, bioinformatics approaches can be applied to developing individualized or targeted therapies. Breast cancer provides an example through which to understand the evolution of genomic data from pure science to clinical utility. From intrinsic subtype classification to development of multigene panels estimating recurrence risk, new studies, such as the FLEX trial, will expand to evaluate the whole transcriptome of tumours. This approach will enable discovery of novel gene signatures and ultimately pave the way toward a personalized approach to breast cancer management. CONCLUSION: Despite the potential for genomics to personalize treatments, a number of challenges remain to fully integrate these types of large datasets in a manner that provides clinicians and patients with meaningful, actionable information. However, if challenges are addressed, precision medicine has the capacity to transform patient care.

Prospective Validation of a Genomic Assay in Breast Cancer: The 70-gene MammaPrint Assay and the MINDACT Trial.

MammaPrint was the first genomic assay in breast cancer to be validated with a prospective randomized trial, the MINDACT trial. The 70 gene MammaPrint assay was developed to determine the risk of distant metastasis in early stage breast cancer through gene expression analysis and was the first FDA cleared genomic assay for breast cancer. The assay identifies primary breast cancers likely to metastasize within the first five years of diagnosis and has clinical utility for helping to determine the expected benefit from adjuvant chemotherapy. The MINDACT Trial was the first trial of a genomic assay in breast cancer to provide prospective, randomized evidence of clinical utility for this important clinical question, identifying a significant proportion of patients who could safely forgo chemotherapy within a cohort of patients with high risk clinical characteristics. Nearly half of all patients (46%) who would have been advised chemotherapy according to clinical guidelines were identified genomically by MammaPrint as being low risk and found to have equivalent rates of freedom from metastasis at 5 years with or without chemotherapy. Based upon the MINDACT trial, the ASCO Biomarker Guidelines now approve the use of MammaPrint to inform decisions regarding chemotherapy for women with clinically high-risk ER+ breast cancer, and as the only approved assay for use in women with 1-3 involved lymph nodes. Recent studies suggest information obtained from the 70-gene assay may also help inform decisions regarding endocrine therapy, as well as chemotherapy, targeted therapy and immunotherapy. CONCLUSION: The power of gene expression analysis in breast cancer, effectively illustrated with MammaPrint in the MINDACT trial, is now being explored through examination of the full transcriptome in breast cancer.

Implementation and Outcomes of a Molecular Tumor Board at Herbert-Herman Cancer Center, Sparrow Hospital.

OBJECTIVE: This paper describes our experience and outcomes from 54 cases presented to the (Molecular tumor board) MTB. METHODS: 54 Cases presented between July 2017 and April 2018 were included in this analysis. These patients had different types of cancers that had either failed standard therapy or were expected to fail and physicians were looking for future options for anticipated progression. Patients who had obvious mutations and were candidates for Targeted Agent and Profiling Utilization Registry or Molecular Analysis for Treatment Choice clinical trials were not included. Oncologists presented the cases virtually and Foundation Medicine scientific and clinical team discussed the molecular pathways to find targeted options or trials. Tumor board attendees included oncologists, nurses, pharmacists, mid-level providers, residents and staff of the Cancer Center. RESULTS: Amongst the 54 cases presented 81% had one or more potentially actionable alteration. 12 (22%) patients received genomically matched therapy as per MTB recommendations. Additional 13 (24%) patients have options available when they progress. Out of 12 patients who got treatment six are alive at the time of this analysis. Genomically matched therapy or Clinical Trials option were offered to the 46% of patients based on the MTB discussion. CONCLUSION: More widespread use of molecular diagnostics, better physician education and multidisciplinary collaboration between the staff involved in diagnosis and treatment, as well as third party payers are necessary for consensus on treatment and care of oncology patients.

Prognostic factors of overall survival for patients with stage II colon cancer.

OBJECTIVE: To analyze factors influencing survival of patients with stage II colon cancer treated at our cancer center (Sparrow Hospital) from February 1996 through December 2006. PATIENTS AND METHODS: Survival analyses on 197 patients' age 71.1±0.9 years (29 to 97) were done using SAS system (V9.3, Cary NC). Analysis included age, gender, stage, surgery type, number of examined lymph nodes, pathological grade, tumor size and the use of adjuvant chemotherapy. RESULTS: Mean follow up length was 48.1±2.3 months (0.1-133) and 56±3.3 (0.2-133) for survivors. The average number of removed lymph nodes was 18±13 (1-103). Adjuvant chemotherapy treatment (5-FU± leucovorin) was given to 49 patients, while others (148) were followed expectantly. There were 90 deaths during follow up. Only age exhibits a statistically significant relationship to survival (Hazard Ratio (HR) =1.06, 95% CI=1.03-1.08, p<0.001). Adjuvant chemotherapy possibly reduced the risk of death by 42% approaching a borderline advantage for survival (HR=0.58, CI=0.33-1.03, p=0.06. The number of removed lymph nodes also showed a possible relationship to survival (HR=0.98, CI= 0.62-1.56, p=0.07). Other investigated factors (gender, type of surgery, etc.) were not significant correlates. CONCLUSION: In this study we found that the most important factor for survival of patients with Stage II colon cancer is the patient's age. Adjuvant chemotherapy showed a borderline significance while the number of resected lymph nodes seemed to be an important survival factor. However, in our study statistical significance was not achieved.

A phase II trial of BAY 43-9006 (sorafenib) (NSC-724772) in patients with relapsing and resistant multiple myeloma: SWOG S0434.

The authors assessed the overall response rate, including confirmed complete response (CR) and partial response, in patients with relapsed/refractory multiple myeloma treated with sorafenib. Qualitative and quantitative toxicities associated with this regimen were evaluated. Patients were eligible if they had a confirmed diagnosis of refractory or relapsed (RR) multiple myeloma (MM) with measurable monoclonal protein. Patients had to have adequate renal, hepatic, hematologic, and cardiac function with a Zubrod performance status of 0-2. Patients were given 400 mg sorafenib by mouth twice daily for 28-day treatment cycles. These patients were followed up for a maximum of 3 years to assess responses and adverse events. Twenty-three patients were enrolled. Of these, five were found to be ineligible for the following reasons: four had insufficient documentation of the baseline disease and one patient did not have measurable disease. All eighteen eligible patients were evaluable for toxicities. Three patients experienced grade 4 toxicities: one with thrombocytopenia, one with anemia, and one with renal failure. Four of the eighteen eligible patients were not assessable for response due to removal from protocol treatment prior to adequate disease assessment. Specifically, three were removed for either grade 4 toxicity or progression of disease and one was removed per patient choice (due to reasons unrelated to treatment). Of the 18 patients who were assessed for toxicities, 5 (27.8%) received at least one fully dosed cycle, 2 (11.1%) of whom had all cycles fully dosed. No responses were observed on this study of the 14 patients who were assessable for response. All patients have discontinued protocol treatment as of August 2008. Overall survival at 12 months was 50% (95% CI 27-73%) and median progression-free survival was 1.2 months (95% CI 1.0-5.4). The trial did not exhibit activity by the International Uniform Response Criteria for MM. Further research should focus on combination therapy of sorafenib with standard treatments in selected patients with RR MM.