Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer.

Circulating IL-6, an activator of JAK/STAT signaling, is associated with poor prognosis and aromatase inhibitor (AI) resistance in hormone-receptor positive (HR+) breast cancer. Here we report the results of a phase 2 single-arm Simon 2-stage trial combining Ruxolitinib, an oral selective inhibitor of JAK1/2, with exemestane, a steroidal AI, in patients with HR+ metastatic breast cancer (MBC) after progression on non-steroidal AI (NSAI). Safety and efficacy were primary objectives, and analysis of inflammatory markers as predictors of response was a key secondary objective. Twenty-five subjects enrolled. The combination of ruxolitinib and exemestane was safe, though anemia requiring transfusion in 5/15 (33%) at the 25 mg dose in stage 1 led to a reduction to 15 mg twice daily in stage 2 (with no additional transfusions). Clinical benefit rate (CBR) in the overall study population was 24% (95% CI 9.4-45.1); 6/25 patients demonstrated stable disease for ≥6 months. Median progression-free survival was 2.8 months (95% CI 2.6-3.9). Exploratory biomarkers revealed high levels of systemic inflammation and 60% harbored a high-risk IL-6 genotype. Pharmacodynamics demonstrated modest on-target inhibition of phosphorylated-STAT3 by ruxolitinib at a tolerable dose. Thus, ruxolitinib combined with exemestane at a tolerable dose was safe but minimally active in AI-resistant tumors of patients with high levels of systemic inflammation. These findings highlight the need for more potent and specific therapies targeting inflammation in MBC.

Refining the indications for neoadjuvant chemotherapy for patients with HER2+ breast cancer: A single institution experience.

BACKGROUND: We aim to compare the clinical outcomes of patients with early-stage HER2+ breast cancer treated with adjuvant chemotherapy (AC) and neoadjuvant chemotherapy (NAC). METHODS: Patients with non-metastatic HER2+ breast cancer treated from 2009 to 2018 at our institution comprised our study cohort (n = 1254). Pathologic complete response (pCR) was defined as the absence of invasive disease in the breast and axilla after NAC. Log-rank, Kaplan-Meier, and inverse probability of treatment weighting were used to assess differences in disease-free and overall survival between groups stratified by AC vs. NAC and pCR vs. non-pCR. RESULTS: The majority received AC (n = 787 or 62.8%) while 467 (37.2%) patients received NAC. Median follow up for AC and NAC groups was 46 and 28 months, respectively. The crude disease-free survival and overall survival of our study cohort were 92.2% and 89.1% for AC, 89.1% and 82.2% for NAC pCR, and 68.1% and 60.0% for NAC non-pCR, respectively. For clinical stage ≥IIB patients, NAC conferred a positive but statistically nonsignificant treatment effect over AC in multivariate analysis. CONCLUSIONS: After adjusting for imbalances in our subgroups, we found that, regardless of the sequence of chemotherapy (AC vs. NAC), patients with early-stage HER2+ breast cancer had excellent outcomes.

Does time to adjuvant chemotherapy (TTC) affect outcomes in patients with triple-negative breast cancer?

PURPOSE: A recent study reported that time to adjuvant chemotherapy (TTC) > 30 days was significantly associated with worse OS and DFS in triple-negative breast cancer (TNBC). Earlier studies, however, found that worse outcomes were associated with TTC > 60 days or > 90 days. As the trend for mastectomy with reconstruction continues to rise, TTC of < 30 days is often not feasible due to wound-healing issues in some of these patients. To elucidate the impact of TTC, we sought to evaluate the clinical outcomes associated with TTC in a contemporary cohort treated for TNBC at a single institution. METHODS: A single-institution database was queried to identify nonmetastatic TNBC patients who received adjuvant chemotherapy from 2009 to 2018. TTC was defined as interval between date of surgery and adjuvant chemotherapy start date. Median TTC was used to divide our cohort into four quartiles; ≤ 31, 32-42, 43-56, and > 56 days. Logrank, Kaplan-Meier, and inverse probability weighting (IPW) tests were used to analyze disease-free (DFS) and overall survival (OS). RESULTS: The mean TTC of our study cohort (n = 724) was 48 days (median TTC = 42 days). Black race, mastectomy without adjuvant radiation, and mastectomy with immediate reconstruction were associated with delayed TTC (all p-values < 0.01). In multivariate IPW analysis, TTC > 56 (n = 173) days did not impact DFS or OS compared to TTC ≤ 31 (n = 198) days (p = 0.27 and p = 0.21, respectively). Similar results were seen during subgroup analysis for groups identified as higher risk for delayed TTC. CONCLUSION: Our results demonstrated that TTC was not significant or significantly associated with DFS or OS in patient receiving chemotherapy for operable TNBC. Our results were reassuring for patients electing mastectomy with immediate reconstruction, who may experience a longer TTC.

Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer.

Chimeric antigen receptors (CAR) are synthetic molecules that provide new specificities to T cells. Although successful in treatment of hematologic malignancies, CAR T cells are ineffective for solid tumors to date. We found that the cell-surface molecule c-Met was expressed in ∼50% of breast tumors, prompting the construction of a CAR T cell specific for c-Met, which halted tumor growth in immune-incompetent mice with tumor xenografts. We then evaluated the safety and feasibility of treating metastatic breast cancer with intratumoral administration of mRNA-transfected c-Met-CAR T cells in a phase 0 clinical trial (NCT01837602). Introducing the CAR construct via mRNA ensured safety by limiting the nontumor cell effects (on-target/off-tumor) of targeting c-Met. Patients with metastatic breast cancer with accessible cutaneous or lymph node metastases received a single intratumoral injection of 3 × 107 or 3 × 108 cells. CAR T mRNA was detectable in peripheral blood and in the injected tumor tissues after intratumoral injection in 2 and 4 patients, respectively. mRNA c-Met-CAR T cell injections were well tolerated, as none of the patients had study drug-related adverse effects greater than grade 1. Tumors treated with intratumoral injected mRNA c-Met-CAR T cells were excised and analyzed by immunohistochemistry, revealing extensive tumor necrosis at the injection site, cellular debris, loss of c-Met immunoreactivity, all surrounded by macrophages at the leading edges and within necrotic zones. We conclude that intratumoral injections of mRNA c-Met-CAR T cells are well tolerated and evoke an inflammatory response within tumors. Cancer Immunol Res; 5(12); 1152-61. ©2017 AACR.

Identifying patients at high risk of breast cancer recurrence: strategies to improve patient outcomes.

Identifying patients at high risk of breast cancer recurrence has important implications not only for enabling the ability to provide accurate information to patients but also the potential to improve patient outcomes. Patients at high recurrence risk can be offered appropriate treatment to improve the overall survival. However, the major challenge is identifying patients with early-stage breast cancer at lower risk who may be spared potentially toxic therapy. The successful integration of molecular assays into clinical practice may address the problem of overtreatment and improve overall patient outcomes.

Inflammatory breast cancer management in the national comprehensive cancer network: the disease, recurrence pattern, and outcome.

BACKGROUND: Inflammatory breast cancer (IBC) is an uncommon clinicopathologic entity characterized by rapid progression and aggressive behavior. We used the National Comprehensive Cancer Network (NCCN) Outcomes Database to characterize recurrence patterns and outcomes. METHODS: Patients with newly diagnosed IBC treated between 1999 and 2009 at 12 NCCN institutions were identified, and baseline characteristics were obtained. Patients had multimodality therapy if they received 2 of 3 treatments: surgery, perioperative (neoadjuvant or adjuvant) chemotherapy, or perioperative radiation. The first site of recurrence/metastatic diagnosis was identified. Overall survival was calculated on the basis of stage at diagnosis and receipt of multimodality therapy. RESULTS: We identified 673 patients, of whom 195 (29%) had metastatic disease at presentation. Median follow-up was 29 months. Of patients in stage III, 82% received > 1 treatment modality. Among 203 patients in stage III with recurrence, the most frequent sites of first recurrence were bone (28%), central nervous system (CNS), lung, and liver (all 21%). Human epidermal growth factor receptor 2 positive and triple negative subtypes had higher rates of CNS recurrence (P = .001). Median survival was 66 months (95% confidence interval [CI], 54-107) for stage III and 26 months (95% CI, 22-33) for stage IV. Among 82% of patients in stage III receiving multimodality therapy, the median survival was 107 months (95% CI, 71 to not reached). CONCLUSIONS: This large, retrospective, multi-institutional study confirms the aggressive clinical features, unique recurrence patterns, and adverse prognosis of IBC. The high rate of CNS recurrence among high-risk subtypes, despite the inflammatory nature of the breast cancer, suggests that new strategies are needed for earlier detection or prevention of brain metastases to improve long-term prognosis.

Cost sharing and hereditary cancer risk: predictors of willingness-to-pay for genetic testing.

Increasing use of predictive genetic testing to gauge hereditary cancer risk has been paralleled by rising cost-sharing practices. Little is known about how demographic and psychosocial factors may influence individuals' willingness-to-pay for genetic testing. The Gastrointestinal Tumor Risk Assessment Program Registry includes individuals presenting for genetic risk assessment based on personal/family cancer history. Participants complete a baseline survey assessing cancer history and psychosocial items. Willingness-to-pay items include intention for: genetic testing only if paid by insurance; testing with self-pay; and amount willing-to-pay ($25-$2,000). Multivariable models examined predictors of willingness-to-pay out-of-pocket (versus only if paid by insurance) and willingness-to-pay a smaller versus larger sum (≤$200 vs. ≥$500). All statistical tests are two-sided (α = 0.05). Of 385 evaluable participants, a minority (42%) had a personal cancer history, while 56% had ≥1 first-degree relative with colorectal cancer. Overall, 21.3% were willing to have testing only if paid by insurance, and 78.7% were willing-to-pay. Predictors of willingness-to-pay were: 1) concern for positive result; 2) confidence to control cancer risk; 3) fewer perceived barriers to colorectal cancer screening; 4) benefit of testing to guide screening (all p < 0.05). Subjects willing-to-pay a higher amount were male, more educated, had greater cancer worry, fewer relatives with colorectal cancer, and more positive attitudes toward genetic testing (all p < 0.05). Individuals seeking risk assessment are willing-to-pay out-of-pocket for genetic testing, and anticipate benefits to reducing cancer risk. Identifying factors associated with willingness-to-pay for genetic services is increasingly important as testing is integrated into routine cancer care.

How do I follow patients with early breast cancer after completing adjuvant therapy.

OPINION STATEMENT: With improvements in the detection and treatment of breast cancer, more women are surviving after diagnosis. Patients who complete adjuvant therapy require ongoing follow-up to manage toxicities, to detect recurrences early, and to provide ongoing physical and psychosocial support. Routine surveillance should be implemented, with attention to educating patients about symptoms of recurrence, such as weight loss, cough, and bone pain. An intensive surveillance strategy with the routine use of laboratory and radiographic studies does not improve outcomes and raises the cost of follow-up. Patients should have annual mammograms in conjunction with physical exam and history at appropriate intervals that increase the farther out patients are from treatment. Attention also should be focused on other routine health maintenance and cancer screening, such as colonoscopy, gynecologic examinations, and bone health/DEXA scans. In the early posttreatment period, medical oncologists are best equipped to follow these patients. However, as women live longer after a breast cancer diagnosis and treatment, transitioning care to a primary care physician or nurse practitioner is appropriate, provided these practitioners are educated about late treatment effects and managing side effects of treatment, which may continue as long as a decade. A multidisciplinary follow-up strategy with excellent communication between providers can ensure safe, convenient, and quality care to the growing population of breast cancer survivors. As the treatment of breast cancer evolves into personalized strategies based on the biologic characteristics of individual tumors, future studies will be needed to determine if a single surveillance strategy is sufficient or if individualized surveillance based on risk can improve outcomes and costs of long-term follow-up care.

Recombinant, live-attenuated tetravalent dengue virus vaccine formulations induce a balanced, broad, and protective neutralizing antibody response against each of the four serotypes in rhesus monkeys.

Three tetravalent vaccine (TV) formulations of previously described monovalent dengue (DEN) virus vaccine candidates were compared to a tetravalent formulation of wild-type DEN viruses (T-wt) for replication in SCID mice transplanted with human liver cells (SCID-HuH-7) or for replication and immunogenicity in rhesus monkeys. TV-1 consists of recombinant DEN1, -2, -3, and -4, each with a 30-nucleotide deletion in the 3' untranslated region (Delta30). TV-2 consists of rDEN1Delta30, rDEN4Delta30, and two antigenic chimeric viruses, rDEN2/4Delta30 and rDEN3/4Delta30, both also bearing the Delta30 mutation. TV-3 consists of rDEN1Delta30, rDEN2Delta30, rDEN4Delta30, and a 10-fold higher dose of rDEN3/4Delta30. TV-1 and TV-2 were attenuated in SCID-HuH-7 mice with minimal interference in replication among the virus components. TV-1, -2, and -3 were attenuated in rhesus monkeys as measured by duration and peak of viremia. Each monkey immunized with TV-1 and TV-3 seroconverted to the four DEN components by day 28 with neutralization titers ranging from 1:52 to 1:273 and 1:59 to 1:144 for TV-1 and TV-3, respectively. TV-2 induced low antibody titers to DEN2 and DEN3, but a booster immunization after 4 months increased the neutralizing antibody titers to greater than 1:100 against each serotype and elicited broad neutralizing activity against 19 of 20 DEN subtypes. A single dose of TV-2 induced protection against wild-type DEN1, DEN3, and DEN4 challenge, but not DEN2. However, two doses of TV-2 or TV-3 induced protection against DEN2 challenge. Two tetravalent formulations, TV-2 and TV-3, possess properties of a successful DEN vaccine and can be considered for evaluation in clinical trials.