There has been little consideration of genomic risk of recurrence by breast cancer subtype despite evidence of racial disparities in breast cancer outcomes.
To evaluate associations between clinical ...trial end points, namely pathologic complete response (pCR) and distant recurrence-free survival (DRFS), and race and examine whether gene expression signatures are associated with outcomes by race.
This retrospective cohort study used data from the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2 (I-SPY 2) multicenter clinical trial of neoadjuvant chemotherapy with novel agents and combinations for patients with previously untreated stage II/III breast cancer. Analyses were conducted of associations between race and short- and long-term outcomes, overall and by receptor subtypes, and their association with 28 expression biomarkers. The trial enrolled 990 female patients between March 30, 2010, and November 5, 2016, with a primary tumor size of 2.5 cm or greater and clinical or molecular high risk based on MammaPrint or hormone receptor (HR)-negative/ERBB2 (formerly HER2 or HER2/neu)-positive subtyping across 9 arms. This data analysis was performed between June 10, 2021, and October 20, 2022.
Race, tumor receptor subtypes, and genomic biomarker expression of early breast cancer.
The primary outcomes were pCR and DRFS assessed by race, overall, and by tumor subtype using logistic regression and Cox proportional hazards regression models. The interaction between 28 expression biomarkers and race, considering pCR and DRFS overall and within subtypes, was also evaluated.
The analytic sample included 974 participants (excluding 16 self-reporting as American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or multiple races due to small sample sizes), including 68 Asian (7%), 120 Black (12%), and 786 White (81%) patients. Median (range) age at diagnosis was 47 (25-71) years for Asian, 49 (25-77) for Black, and 49 (23-73) years for White patients. The pCR rates were 32% (n = 22) for Asian, 30% for Black (n = 36), and 32% for White (n = 255) patients (P = .87). Black patients with HR-positive/ERBB2-negative tumors not achieving pCR had significantly worse DRFS than their White counterparts (hazard ratio, 2.28; 95% CI, 1.24-4.21; P = .01), with 5-year DRFS rates of 55% (n = 32) and 77% (n = 247), respectively. Black patients with HR-positive/ERBB2-negative tumors, compared with White patients, had higher expression of an interferon signature (mean SD, 0.39 0.87 and -0.10 0.99; P = .007) and, compared with Asian patients, had a higher mitotic score (mean SD, 0.07 1.08 and -0.69 1.06; P = .01) and lower estrogen receptor/progesterone receptor signature (mean SD, 0.31 0.90 and 1.08 0.95; P = .008). A transforming growth factor β signature had a significant association with race relative to pCR and DRFS, with a higher signature associated with lower pCR and worse DRFS outcomes among Black patients only.
The findings show that women with early high-risk breast cancer who achieve pCR have similarly good outcomes regardless of race, but Black women with HR-positive/ERBB2-negative tumors without pCR may have worse DRFS than White women, highlighting the need to develop and test novel biomarker-informed therapies in diverse populations.
Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 single mutants in Philadelphia chromosome-positive (Ph+) leukemia, including the recalcitrant ...BCR-ABL1T315I mutant. However, emergence of compound mutations in a BCR-ABL1 allele may confer ponatinib resistance. We found that clinically reported BCR-ABL1 compound mutants center on 12 key positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib, and bosutinib. T315I-inclusive compound mutants confer high-level resistance to TKIs, including ponatinib. In vitro resistance profiling was predictive of treatment outcomes in Ph+ leukemia patients. Structural explanations for compound mutation-based resistance were obtained through molecular dynamics simulations. Our findings demonstrate that BCR-ABL1 compound mutants confer different levels of TKI resistance, necessitating rational treatment selection to optimize clinical outcome.
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•BCR-ABL1 compound mutations can lead to clinical failures of ponatinib and other TKIs•Nearly all non-T315I compound mutants are sensitive to at least one approved TKI•T315I-inclusive compound mutants confer resistance to all TKIs, including ponatinib•Structural modeling provides a basis for design of TKIs targeting compound mutants
Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that can inhibit all clinical BCR-ABL1 single mutations. Zabriskie et al. show that T315I-inclusive BCR-ABL1 compound mutants confer resistance to all clinical TKIs, including ponatinib, and provide structural explanations for the resistance.
Gross inequities in disease burden between developed and developing countries are now the subject of intense global attention. Public and private donors have marshaled resources and created ...organizational structures to accelerate the development of new health products and to procure and distribute drugs and vaccines for the poor. Despite these encouraging efforts directed primarily from and funded by industrialized countries, sufficiency and sustainability remain enormous challenges because of the sheer magnitude of the problem. Here we highlight a complementary and increasingly important means to improve health equity: the growing ability of some developing countries to undertake health innovation.
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Background: Soft tissue sarcomas (STSs) are a heterogeneous group of cancers with high unmet need. Trabectedin (T) is an FDA-approved chemotherapy that blocks cell cycling and DNA repair ...pathways. Combination T and conventional radiation (XRT) in STS nonrandomized phase 1/2 trials demonstrated objective response rates (ORR) of 36-72% in localized and low burden metastatic disease, while pre-treated metastatic STS treated with T alone has an ORR of 10-14%. We hypothesize that the combination of T and hypofractionated radiation (hXRT) will exhibit a tolerable safety profile and improve ORR relative to historical outcomes with T or hXRT alone. Here we report our experience in the treatment of oligometastatic STS with combined T and hXRT. Methods: We reviewed our institutional experience to identify patients treated with T and XRT. We included patients with high risk localized or metastatic STS (majority of patients had metastatic disease at time of treatment). All patients received at least 1 cycle of T and concurrent XRT to at least 1 lesion. ORR and local control rate (LCR) were determined for irradiated lesions by RECIST 1.1. Results: Between 2020 – 2021, 9 STS patients with 21 tumors were treated at the University of Colorado with XRT and concurrent T. The median age was 39.2 (range 26.0 – 64.6) years. 8 patients had metastatic disease at the time of treatment. Treated tumor sites included 1 lung,1 extremity, 2 liver, 2 retroperitoneal, 5 bone, and 10 peritoneal. The following histologic subtypes were included: myxoid liposarcoma (3), uterine leiomyosarcoma (2), non-uterine leiomyosarcoma (1), dedifferentiated liposarcoma (1), undifferentiated pleomorphic sarcoma (1), and synovial sarcoma (1). All metastatic patients were pre-treated with a median of 3 lines of systemic therapy. The median number of T cycles delivered was 5 (range 1 – 20). The median XRT prescription dose was 3000cGy (range 2000cGy – 5000cGy), with 8 patients having received hXRT (5 -10 fractions) and 1 having received conventionally fractionated XRT. 8 patients underwent 1 course of XRT, while 1 received 3 courses in combination with T. All patients had a Karnofsky performance status equal to or greater than 60. After a median follow-up 5.4 months, the LCR of treated lesions was 90.5%. The ORR (CR or PR) was 57.1% and median decrease in tumor diameter at time of maximum response was 52.0%. The median time until maximum response was 3.7 months. 2 patients experienced grade 3 toxicity (LFT elevation) attributable to T, and 2 patients experienced grade 3 toxicity due to XRT. There were no grade 4 or 5 toxicities. Conclusions: T in combination with hXRT appears to be safe and feasible in this patient population. Based on these data, a phase 1/2 prospective clinical trial is being planned in oligometastatic and high risk localized STS. Table: see text
Since most patients with Hodgkin lymphoma survive their disease, long-term issues such as development of second primary malignancies arise, especially in patients treated with multimodal therapy ...including radiation therapy plus chemotherapy. The risk of breast cancer is significantly elevated in women exposed to high-dose ionizing radiation to the chest before age 40. The case of a 48-year-old patient with a lump in her right breast is presented as a clinical scenario in this article. We review available strategies for screening and risk reduction through chemoprevention or risk-reducing surgery, as well as challenges for management of breast cancer in patients with prior exposure to radiation for Hodgkin lymphoma. The Children's Oncology Group clinical practice guidelines for long-term follow-up care of pediatric cancer survivors provide recommendations that have been endorsed by American and European oncologists.
Southwest Oncology Group (SWOG)/Intergroup study 9623 was undertaken to compare treatment with an anthracycline-based adjuvant chemotherapy regimen followed by high-dose chemotherapy (HDC) with ...autologous hematopoietic progenitor cell support (AHPCS) with a modern dose-dense dose-escalated (nonstandard) regimen including both an anthracycline and a taxane.
Participants in this phase III randomized study had operable breast cancer involving four or more axillary lymph nodes and had completed mastectomy or breast-conserving surgery. Patients were randomly assigned to receive four cycles of doxorubicin and cyclophosphamide followed by HDC with AHPCS or to receive sequential dose-dense and dose-escalated chemotherapy with doxorubicin, paclitaxel, and cyclophosphamide. The primary end point of this study was disease-free survival (DFS).
Among 536 eligible patients, there was no significant difference between the two arms for DFS or overall survival (OS). Estimated five-year DFS was 80% (95% CI, 76% to 85%) for dose-dense therapy and 75% (95% CI, 69% to 80%) for transplantation. Estimated 5-year OS was 88% (95% CI, 84% to 92%) for dose-dense therapy and 84% (95% CI, 79% to 88%) for transplantation.
There is no evidence that transplantation was superior to dose-dense dose-escalated therapy. Transplantation was associated with an increase in toxicity and a possibly inferior outcome, although the hazard ratios were not significantly different from 1.
Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of ...lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients.
ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and--in absence of available stem cells from earlier harvesting--undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3(rd) (arm A + B) and the 5(th) lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS.
This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients.
ISRCTN16345835 (date of registration 2010-08-24).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Advances in the surgical management of the axilla in patients treated with neoadjuvant chemotherapy, especially those with node positive disease at diagnosis, have led to changes in practice and more ...judicious use of axillary lymph node dissection that may minimize morbidity from surgery. However, there is still significant confusion about how to optimally manage the axilla, resulting in variation among practices. From the viewpoint of drug development, assessment of response to neoadjuvant chemotherapy remains paramount and appropriate assessment of residual disease-the primary endpoint of many drug therapy trials in the neoadjuvant setting-is critical. Therefore decreasing the variability, especially in a multicenter clinical trial setting, and establishing a minimum standard to ensure consistency in clinical trial data, without mandating axillary lymph node dissection, for all patients is necessary. The key elements which include proper staging and identification of nodal involvement at diagnosis, and appropriately targeted management of the axilla at the time of surgical resection are presented. The following protocols have been adopted as standard procedure by the I-SPY2 trial for management of axilla in patients with node positive disease, and present a framework for prospective clinical trials and practice.
During the last 25 years, National Cancer Institute (NCI) cooperative trial groups have extended trial networks from academic centers to include certain community and Veterans Health Administration ...(VHA) centers. We compared trial patients' attributes and outcomes by these enrollment settings.
Studying 2,708 patients on one of 10 cooperative group, randomized lung trials at 272 institutions, we compared patient attributes by enrollment setting (ie, academic, community, and VHA affiliates). We used adjusted Cox regression to evaluate for survival differences by setting.
Main member institutions enrolled 44% of patients; community affiliates enrolled 44%; and VHAs enrolled 12%. Patient attributes (ie, case-mix) of age, ethnicity, sex, and performance status varied by enrollment setting. After analysis was adjusted for patient case-mix, no mortality differences by enrollment setting were noted.
Although trial patients with primarily advanced-stage lung cancer from nonacademic centers were older and had worse performance statuses than those from academic centers, survival did not differ by enrollment setting after analysis accounted for patient heterogeneity. An answer for whether long-term outcomes for patients at community and VHA centers affiliated with cooperative trial groups are equivalent to those at academic centers when care is delivered through NCI trials requires additional research among patients with longer survival horizons.
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