Clinical Treatment Score Post-5 Years (CTS5) and Late Recurrence Risk in Hormone Receptor-Positive, HER2-Positive Breast Cancer.

BACKGROUND: The Clinical Treatment Score post-5 years (CTS5) is a risk stratification tool used to determine the risk of late recurrence in hormone receptor-positive (HR+), HER2-negative breast cancer (BC). Limited data exist on its use in HR+, HER2-positive (HER2+) BC. PATIENTS AND METHODS: CTS5 was evaluated in HR+, HER2+ BC in the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) and NSABP B-31 (NRG) trials. RESULTS: A total of 1,862 patients with HR+, HER2+ BC without recurrence 5 years after enrollment were included. Overall, the CTS5 score was significantly associated with recurrence-free survival (RFS), with a hazard ratio (HR) of 1.35 (95% CI, 1.12-1.63; P=.002), but did not reach statistical significance in patients who received trastuzumab (n=829; HR, 1.29; 95% CI, 0.98-1.71; P=.07). CTS5 risk category was not significantly associated with RFS. In patients who received trastuzumab, other variables used in CTS5, including patient age and tumor size, were not significantly associated with RFS. N3 was significantly associated with worse outcomes (HR, 1.86; 95% CI, 1.09-3.17; P=.02) compared with N0-N1. Paradoxically, higher tumor grade was associated with better outcomes after 5 years in the multivariate analysis (HR, 0.71; 95% CI, 0.50-1.00; P=.05). The incidence of recurrences or deaths between years 5 to 10 was 10.6% in the CTS5 low-risk category, 5.6% in the intermediate-risk category, and 9.8% in the high-risk category. CONCLUSIONS: The CTS5 model does not accurately predict the risk of late recurrence in HR+, HER2+ BC treated with adjuvant trastuzumab in the N9831 and B-31 trials. This study underlines the need to develop a new prognostic model to better delineate the risk of late recurrence in patients with HR+, HER2+ BC receiving adjuvant trastuzumab. CLINICALTRIALS: gov identifiers: NCT00005970 (NCCTG N9831) and NCT00004067 (NRG/NSABP B-31).

A randomized phase III double-blind placebo-controlled trial of first-line chemotherapy and trastuzumab with or without bevacizumab for patients with HER2/neu-positive metastatic breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1105).

BACKGROUND: In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the pre-clinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC. FINDINGS: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43-1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61-1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab. CONCLUSIONS: In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time. CLINICAL TRIAL INFORMATION: NCT00520975.

Tailoring neoadjuvant systemic therapy in breast cancer: "The advent of a personalized approach"-The Breast-Gynecological and Immuno-Oncology International Cancer Conference (BGICC) consensus and recommendations.

BACKGROUND: The management of early breast cancer (BC) has witnessed an uprise in the use of neoadjuvant therapy and a remarkable reshaping of the systemic therapy postneoadjuvant treatment in the last few years, with the evolution of many controversial clinical situations that require consensus. METHODS: During the 14th Breast-Gynecological and Immuno-Oncology International Cancer Conference held in Egypt in 2022, a panel of 44 BC experts from 13 countries voted on statements concerning debatable challenges in the neo/adjuvant treatment setting. The recommendations were subsequently updated based on the most recent data emerging. A modified Delphi approach was used to develop this consensus. A consensus was achieved when ≥75% of voters selected an answer. RESULTS AND CONCLUSIONS: The consensus recommendations addressed different escalation and de-escalation strategies in the setting of neoadjuvant therapy for early BC. The recommendations recapitulate the available clinical evidence and expert opinion to individualize patient management and optimize therapy outcomes. Consensus was reached in 63% of the statements (52/83), and the rationale behind each statement was clarified.

Adjunctive Statistical Standardization of Adjuvant Estrogen Receptor and Progesterone Receptor in Canadian Cancer Trials Group MA.27 Postmenopausal Breast Cancer Trial of Exemestane Versus Anastrozole.

PURPOSE: ASCO/College of American Pathologists guidelines recommend reporting estrogen receptor (ER) and progesterone receptor (PgR) as positive with (1%-100%) staining. Statistically standardized quantitated positivity could indicate differential associations of positivity with breast cancer outcomes. METHODS: MA.27 (ClinicalTrials.gov identifier: NCT00066573) was a phase III adjuvant trial of exemestane versus anastrozole in postmenopausal women with early-stage breast cancer. Immunochemistry ER and PgR HSCORE and % positivity (%+) were centrally assessed by machine image quantitation and statistically standardized to mean 0 and standard deviation (SD) 1 after Box-Cox variance stabilization transformations of square for ER; for PgR, (1) natural logarithm (0.1 added to 0 HSCOREs and 0%+) and (2) square root. Our primary end point was MA.27 distant disease-free survival (DDFS) at a median 4.1-year follow-up, and secondary end point was event-free survival (EFS). Univariate survival with cut points at SDs about a mean of 0 (≤-1; (-1, 0]; (0, 1]; >1) was described with Kaplan-Meier plots and examined with Wilcoxon (Peto-Prentice) test statistic. Adjusted Cox multivariable regressions had two-sided Wald tests and nominal significance P < .05. RESULTS: Of 7,576 women accrued, 3,048 women's tumors had machine-quantitated image analysis results: 2,900 (95%) for ER, 2,726 (89%) for PgR, and 2,582 (85% of 3,048) with both ER and PgR. Higher statistically standardized ER and PgR HSCORE and %+ were associated with better univariate DDFS and EFS (P < .001). In multivariable assessments, ER HSCORE and %+ were not significantly associated (P = .52-.88) with DDFS in models with PgR, whereas higher PgR HSCORE and %+ were significantly associated with better DDFS (P = .001) in models with ER. CONCLUSION: Adjunctive statistical standardization differentiated quantitated levels of ER and PgR. Patients with higher ER- and PgR-standardized units had superior DDFS compared with those with HSCOREs and %+ ≤-1.

A randomized phase III double-blind placebo-controlled trial of first line chemotherapy and trastuzumab with or without bevacizumab for patients with HER2/neu-positive metastatic breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1105).

Background: In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the preclinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC. Findings: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43-1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61-1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab. Conclusions: In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time.

Age, Body Mass Index, Tumor Subtype, and Racial and Ethnic Disparities in Breast Cancer Survival.

Importance: Black women in the United States have higher breast cancer (BC) mortality rates than White women. The combined role of multiple factors, including body mass index (BMI), age, and tumor subtype, remains unclear. Objective: To assess the association of race and ethnicity with survival among clinical trial participants with early-stage BC (eBC) according to tumor subtype, age, and BMI. Design, Setting, and Participants: This cohort study analyzed survival data, as of November 12, 2021, from participants enrolled between 1997 and 2010 in 4 randomized adjuvant chemotherapy trials: Cancer and Leukemia Group B (CALGB) 9741, 49907, and 40101 as well as North Central Cancer Treatment Group (NCCTG) N9831, legacy groups of the Alliance of Clinical Trials in Oncology. Median follow-up was 9.8 years. Exposures: Non-Hispanic Black and Hispanic participants were compared with non-Hispanic White participants within subgroups of subtype (hormone receptor positive [HR+]/ERBB2 [formerly HER2] negative [ERBB2-], ERBB2+, and HR-/ERBB2-), age (<50, 50 to <65, and ≥65 years), and BMI (<18.5, 18.5 to <25.0, 25.0 to <30.0, and ≥30.0). Main Outcomes and Measures: Recurrence-free survival (RFS) and overall survival (OS). Results: Of 9479 participants, 436 (4.4%) were Hispanic, 871 (8.8%) non-Hispanic Black, and 7889 (79.5%) non-Hispanic White. The median (range) age was 52 (19.0-89.7) years. Among participants with HR+/ERBB2- tumors, non-Hispanic Black individuals had worse RFS (hazard ratio [HR], 1.49; 95% CI, 1.04-2.12; 5-year RFS, 88.5% vs 93.2%) than non-Hispanic White individuals, although the global test for association of race and ethnicity with RFS was not significant within any tumor subtype. There were no OS differences by race and ethnicity in any subtype. Race and ethnicity were associated with OS in young participants (age <50 years; global P = .008); young non-Hispanic Black participants (HR, 1.34; 95% CI, 1.04-1.71; 5-year OS, 86.6% vs 92.0%) and Hispanic participants (HR, 1.62; 95% CI, 1.16-2.29; 5-year OS, 86.2% vs 92.0%) had worse OS than young non-Hispanic White participants. Race and ethnicity were associated with RFS in participants with BMIs of 25 to less than 30, with non-Hispanic Black participants having worse RFS (HR, 1.81; 95% CI, 1.23-2.68; 5-year RFS, 83.2% vs 87.3%) than non-Hispanic White participants. Conclusions and Relevance: In this cohort study, racial and ethnic survival disparities were identified in patients with eBC receiving standardized initial care, and potentially at-risk subgroups, for whom focused interventions may improve outcomes, were found.

Osseointegration of Dental Implants in Patients with Congenital and Degenerative Bone Disorders: A Literature Review.

Aims and Objectives: The aim of this study was to describe the mechanism of dental implants osseointegration in patients with congenital and degenerative genetic bone disorders. Materials and Methods: A PubMed and Scopus documents search was carried out between November 2021 in the, using words such as "osseointegration," "degenerative disease," "congenital disease," and "dental implants." Results: The thirteen articles selected dealt with dental implants osseointegration in patients with congenital and degenerative bone disorders. The influence and repercussion of these diseases on the bone system, as well as the osseointegration process were described from healing to bone remodeling. In addition, certain articles described some considerations to improve the osseointegration process in patients suffering from these types of conditions. Conclusions: Within the limitations of this literature review we can conclude that osseointegration in patients with ectodermal dysplasia and osteoporosis could be achieved. However, the planning process for dental implant placement in these patients should be more meticulous and individualized considering the degree of tissue involvement as well as the patient's age and skeletal development compared to systemically healthy patients.

Replication of genetic associations of chemotherapy-related cardiotoxicity in the adjuvant NSABP B-31 clinical trial.

Background: The cardiotoxic effects of doxorubicin, trastuzumab, and other anticancer agents are well known, but molecular genetic testing is lacking for the early identification of patients at risk for therapy-related cardiac toxicity. Methods: Using the Agena Bioscience MassARRAY system, we genotyped TRPC6 rs77679196, BRINP1 rs62568637, LDB2 rs55756123, RAB22A rs707557, intergenic rs4305714, LINC01060 rs7698718, and CBR3 rs1056892 (V244M) (previously associated with either doxorubicin or trastuzumab-related cardiotoxicity in the NCCTG N9831 trial of anthracycline-based chemotherapy ± trastuzumab) in 993 patients with HER2+ early breast cancer from the NSABP B-31 trial of adjuvant anthracycline-based chemotherapy ± trastuzumab. Association analyses were performed with outcomes of congestive heart failure (N = 29) and maximum decline in left ventricular ejection fraction (LVEF) using logistic and linear regression models, respectively, under an additive model with age, baseline LVEF, and previous use of hypertensive medications as covariates. Results: Associations of maximum decline in LVEF in the NCCTG N9831 patients did not replicate in the NSABP B-31 patients. However, TRPC6 rs77679196 and CBR3 rs1056892 were significantly associated with congestive heart failure, p < 0.05, with stronger associations observed in patients treated with chemotherapy only (no trastuzumab) or in the combined analysis of all patients relative to those patients treated with chemotherapy + trastuzumab. Conclusions: TRPC6 rs77679196 and CBR3 rs1056892 (V244M) are associated with doxorubicin-induced cardiac events in both NCCTG N9831 and NSABP B-31. Other variants previously associated with trastuzumab-related decline in LVEF failed to replicate between these studies.

Distinct spatial immune microlandscapes are independently associated with outcomes in triple-negative breast cancer.

The utility of spatial immunobiomarker quantitation in prognostication and therapeutic prediction is actively being investigated in triple-negative breast cancer (TNBC). Here, with high-plex quantitative digital spatial profiling, we map and quantitate intraepithelial and adjacent stromal tumor immune protein microenvironments in systemic treatment-naïve (female only) TNBC to assess the spatial context in immunobiomarker-based prediction of outcome. Immune protein profiles of CD45-rich and CD68-rich stromal microenvironments differ significantly. While they typically mirror adjacent, intraepithelial microenvironments, this is not uniformly true. In two TNBC cohorts, intraepithelial CD40 or HLA-DR enrichment associates with better outcomes, independently of stromal immune protein profiles or stromal TILs and other established prognostic variables. In contrast, intraepithelial or stromal microenvironment enrichment with IDO1 associates with improved survival irrespective of its spatial location. Antigen-presenting and T-cell activation states are inferred from eigenprotein scores. Such scores within the intraepithelial compartment interact with PD-L1 and IDO1 in ways that suggest prognostic and/or therapeutic potential. This characterization of the intrinsic spatial immunobiology of treatment-naïve TNBC highlights the importance of spatial microenvironments for biomarker quantitation to resolve intrinsic prognostic and predictive immune features and ultimately inform therapeutic strategies for clinically actionable immune biomarkers.

Miz1 promotes KRAS-driven lung tumorigenesis by repressing the protocadherin Pcdh10.

Targeting KRAS-mutated non-small-cell lung cancer (NSCLC) remains clinically challenging. Here we show that loss of function of Miz1 inhibits lung tumorigenesis in a mouse model of oncogenic KRAS-driven lung cancer. In vitro, knockout or silencing of Miz1 decreases cell proliferation, clonogenicity, migration, invasion, or anchorage-independent growth in mutant (MT) KRAS murine or human NSCLC cells but has unremarkable impact on non-tumorigenic cells or wild-type (WT) KRAS human NSCLC cells. RNA-sequencing reveals Protocadherin-10 (Pcdh10) as the top upregulated gene by Miz1 knockout in MT KRAS murine lung tumor cells. Chromatin immunoprecipitation shows Miz1 binding on the Pcdh10 promoter in MT KRAS lung tumor cells but not non-tumorigenic cells. Importantly, silencing of Pcdh10 rescues cell proliferation and clonogenicity in Miz1 knockout/knockdown MT KRAS murine or human tumor cells, and rescues allograft tumor growth of Miz1 knockout tumor cells in vivo. Miz1 is upregulated in MT KRAS lung tumor tissues compared with adjacent non-involved tissues in mice. Consistent with this, Miz1 is upregulated while Pcdh10 is downregulated in human lung adenocarcinomas (LUAD) compared with normal tissues, and high Miz1 levels or low Pcdh10 levels are associated with poor survival in lung cancer patients. Furthermore, the Miz1 signature is associated with worse survival in MT but not WT KRAS LUAD, and Pcdh10 is downregulated in MT compared to WT KRAS LUAD. Taken together, our studies implicate the Miz1/Pcdh10 axis in oncogenic KRAS-driven lung tumorigenesis.

La hipertensión arterial como causa de muerte: causa básica vs causas múltiples. Cuba, 2013-2019 / Arterial hypertension as a cause of death: basic cause vs multiple causes. Cuba, 2013-2019

Introducción: Las tasas de mortalidad "por" hipertensión arterial subestiman el impacto de esta causa en la mortalidad. Objetivo: Determinar el cambio de la contribución de la hipertensión arterial como causa de muerte, al involucrar todas sus menciones en el certificado de defunción en Cuba en el periodo 2013-2019. Material y Métodos: Se realizó un estudio observacional descriptivo de las defunciones ocurridas en Cuba entre enero de 2013 y diciembre de 2019. Se calcularon las Tasas de Mortalidad "por" (causa básica) y "con" hipertensión arterial (causas múltiples). Además, se determinaron las causas básicas más asociadas a la mención de esta afección. Resultados: Los riesgos de morir "por" y "con" hipertensión arterial evidencian un ascenso. El segundo es, como promedio, cuatro veces mayor que el primero; lo que significa que el análisis de mortalidad "por· HTA continúa infravalorando el papel de esta afección dentro de los procesos que causan muerte. Ambos riesgos son mayores para hombres y para los adultos de 85 años y más. Como promedio, en 15,7 por ciento de las defunciones se mencionó a la HTA en alguna de las partes del certificado; sin embargo, solo en 3,8 por ciento fue declarada como causa básica. Las enfermedades cerebrovasculares y las del corazón son las dos causas básicas en las que la HTA es más frecuentemente causa asociada. Conclusiones: La contribución de la hipertensión arterial a la mortalidad es mayor a lo que traduce el análisis tradicional. Disponer de estimaciones de causas múltiples fortalecería la planificación en salud y potenciaría los análisis de carga de enfermedad(AU)

Introduction: Mortality rates "due to" arterial hypertension underestimate the impact of this cause on mortality. Objective: To determine the change in the contribution of arterial hypertension to the cause of death, by analyzing all its mentions in the death certificates in Cuba in the period 2013-2019. Material and Methods: A descriptive observational study of deaths that occurred in Cuba between January 2013 and December 2019 was carried out. Mortality rates "due to" (basic cause) and "with" arterial hypertension (multiple causes) were calculated. In addition, the most common underlying causes associated with the mention of this condition were determined. Results: The risks of dying "due to" and "with" arterial hypertension show an increase. The second risk is, on average, four times higher than the first one, which means that the analysis of mortality "due to" arterial hypertension continues to underestimate the role of this condition within the processes causing death. Both risks are higher for men and adults aged 85 years and older. On average, arterial hypertension was mentioned in some parts of the certificates in 15,7 percent of the deaths registered during the period; however, it was declared as the basic cause only in 3,8 percent of them. Cerebrovascular and heart diseases are the two underlying causes in which arterial hypertension is the most frequently associated cause. Conclusions: The contribution of arterial hypertension to mortality is greater than that identified in the traditional analysis. Having estimates of multiple causes would strengthen health planning and enhance the analyses of disease burden(AU)

Incidence of adverse events with therapies targeting HER2-positive metastatic breast cancer: a literature review.

PURPOSE: Human epidermal growth factor receptor 2 (HER2)-targeted therapies improve survival for patients with HER2-positive breast cancer but carry risks of hematologic, cardiopulmonary, gastro-hepatobiliary, and other adverse events (AEs). In this review, we describe published AE incidences for HER2-targeted therapies for metastatic breast cancer (mBC). METHODS: We searched PubMed and Embase to identify studies on HER2-targeted therapies in HER2-positive mBC, reporting on AEs of special interest, and published between January 1, 2009, and February 6, 2020. Treatment regimens were categorized into mutually exclusive therapy-based categories, with primary therapy determined by worldwide approval date. RESULTS: One hundred and fifty-three included articles assessed a combined 29,238 patients treated with the following therapy-based regimens: trastuzumab or biosimilars (78 studies), lapatinib (40), T-DM1 (ado-trastuzumab emtansine) (20), pertuzumab (14), neratinib (8), MM-302 (1), T-DXd (2), tucatinib (3), and pyrotinib (3). While direct comparisons of AE incidence are not warranted owing to study heterogeneity, proportions of patients experiencing any Grade 3 + AE ranged across therapy-based regimens from 39.4% (lapatinib) to 66.3% (neratinib). The most common hematologic AE of special interest, of any grade and regardless of causality, was leukopenia/white blood cells decreased [21.4% (T-DXd)-46.2% (pyrotinib)]. Cardiopulmonary AEs of special interest included interstitial lung disease [2.7% (trastuzumab)-5.2% (T-DXd)], pneumonitis [0.2% (lapatinib)-7.4% (trastuzumab)], and decreased ejection fraction [1% (T-DXd)-13.6% (trastuzumab)]. Gastro-hepatobiliary AEs of special interest included nausea [33.9% (trastuzumab)-78.3% (T-DXd)], vomiting [19.2% (T-DM1)-48.2% (T-DXd)], diarrhea [19.6% (T-DM1)-96.9% (pyrotinib)], and hepatotoxicity [5.9% (lapatinib)-53.6% (T-DM1)]. CONCLUSION: Differing AE profiles for anti-HER2 therapies should be considered when assessing benefit-risk profile for treatment options.

Adaptive immune signature in HER2-positive breast cancer in NCCTG (Alliance) N9831 and NeoALTTO trials.

Trastuzumab acts in part through the adaptive immune system. Previous studies showed that enrichment of immune-related gene expression was associated with improved outcomes in HER2-positive (HER2+) breast cancer. However, the role of the immune system in response to lapatinib is not fully understood. Gene expression analysis was performed in 1,268 samples from the North Central Cancer Treatment Group (NCCTG) N9831 and 244 samples from the NeoALTTO trial. In N9831, enrichment of CD45 and immune-subset signatures were significantly associated with improved outcomes. We identified a novel 17-gene adaptive immune signature (AIS), which was found to be significantly associated with improved RFS among patients who received adjuvant trastuzumab (HR 0.66, 95% CI 0.49-0.90, Cox regression model p = 0.01) but not in patients who received chemotherapy alone (HR 0.96, 95% CI 0.67-1.40, Cox regression model p = 0.97). This result was validated in NeoALTTO. Overall, AIS-low patients had a significantly lower pathologic complete response (pCR) rate compared with AIS-high patients (χ2 p < 0.0001). Among patients who received trastuzumab alone, pCR was observed in 41.7% of AIS-high patients compared with 9.8% in AIS-low patients (OR of 6.61, 95% CI 2.09-25.59, logistic regression model p = 0.003). More importantly, AIS-low patients had a higher pCR rate with an addition of lapatinib (51.1% vs. 9.8%, OR 9.65, 95% CI 3.24-36.09, logistic regression model p < 0.001). AIS-low patients had poor outcomes, despite receiving adjuvant trastuzumab. However, these patients appear to benefit from an addition of lapatinib. Further studies are needed to validate the significance of this signature to identify patients who are more likely to benefit from dual anti-HER2 therapy. ClinicalTrials.gov Identifiers: NCT00005970 (NCCTG N9831) and NCT00553358 (NeoALTTO).

Randomized Phase II Study of Two Doses of Pixantrone in Patients with Metastatic Breast Cancer (NCCTG N1031, Alliance).

BACKGROUND: Anthracycline use in metastatic breast cancer (MBC) is hindered by cumulative exposure limits and risk of cardiotoxicity. Pixantrone, a novel aza-anthracenedione with structural similarities to mitoxantrone and anthracyclines, is theorized to exhibit less cardiotoxicity, mainly due to lack of iron binding. We conducted a randomized phase II study to evaluate the efficacy and safety of 2 dosing schedules of pixantrone in patients with refractory HER2-negative MBC. METHODS: Intravenous pixantrone was administered at 180 mg/m2 every 3 weeks (group A) versus 85 mg/m2 on days 1, 8, and 15 of a 28-day cycle (group B). Primary endpoint was objective response rate (ORR) and secondary endpoints included progression-free survival (PFS), median 6-month PFS, overall survival (OS), safety, quality of life, and serial assessment of circulating tumor cells. A 20% ORR was targeted as sufficient for further testing of pixantrone in this patient population. RESULTS: Forty-five patients were evaluable, with 2 confirmed partial responses in group A and 1 in group B. The trial was terminated due to insufficient activity. Overall median PFS and OS were 2.8 (95% confidence interval [CI]: 2.0-4.1) and 16.8 (95% CI: 8.9-21.6) months, respectively. Notable overall grade 3-4 adverse events were the following: neutrophil count decrease (62%), fatigue (16%), and decrease in ejection fraction (EF) (4%). CONCLUSION: Pixantrone has insufficient activity in the second- and third-line MBC setting. It appears, however, to have limited cardiotoxicity. (ClinicalTrials.gov ID: NCT01086605).

GSK-3ß Localizes to the Cardiac Z-Disc to Maintain Length Dependent Activation.

BACKGROUND: Altered kinase localization is gaining appreciation as a mechanism of cardiovascular disease. Previous work suggests GSK-3ß (glycogen synthase kinase 3ß) localizes to and regulates contractile function of the myofilament. We aimed to discover GSK-3ß's in vivo role in regulating myofilament function, the mechanisms involved, and the translational relevance. METHODS: Inducible cardiomyocyte-specific GSK-3ß knockout mice and left ventricular myocardium from nonfailing and failing human hearts were studied. RESULTS: Skinned cardiomyocytes from knockout mice failed to exhibit calcium sensitization with stretch indicating a loss of length-dependent activation (LDA), the mechanism underlying the Frank-Starling Law. Titin acts as a length sensor for LDA, and knockout mice had decreased titin stiffness compared with control mice, explaining the lack of LDA. Knockout mice exhibited no changes in titin isoforms, titin phosphorylation, or other thin filament phosphorylation sites known to affect passive tension or LDA. Mass spectrometry identified several z-disc proteins as myofilament phospho-substrates of GSK-3ß. Agreeing with the localization of its targets, GSK-3ß that is phosphorylated at Y216 binds to the z-disc. We showed pY216 was necessary and sufficient for z-disc binding using adenoviruses for wild-type, Y216F, and Y216E GSK-3ß in neonatal rat ventricular cardiomyocytes. One of GSK-3ß's z-disc targets, abLIM-1 (actin-binding LIM protein 1), binds to the z-disc domains of titin that are important for maintaining passive tension. Genetic knockdown of abLIM-1 via siRNA in human engineered heart tissues resulted in enhancement of LDA, indicating abLIM-1 may act as a negative regulator that is modulated by GSK-3ß. Last, GSK-3ß myofilament localization was reduced in left ventricular myocardium from failing human hearts, which correlated with depressed LDA. CONCLUSIONS: We identified a novel mechanism by which GSK-3ß localizes to the myofilament to modulate LDA. Importantly, z-disc GSK-3ß levels were reduced in patients with heart failure, indicating z-disc localized GSK-3ß is a possible therapeutic target to restore the Frank-Starling mechanism in patients with heart failure.

Behavioral and health outcomes from the NRG Oncology/NSABP B-36 trial comparing two different adjuvant therapy regimens for early-stage node-negative breast cancer.

BACKGROUND: The NSABP B-36 compared four cycles of doxorubicin and cyclophosphamide (AC) with six cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC-100) in node-negative early-stage breast cancer. A sub-study within B-36, focusing on symptoms, quality of life (QOL), menstrual history (MH), and cardiac function (CF) was conducted. PATIENTS AND METHODS: Patients completed the QOL questionnaire at baseline, during treatment, and every 6 months through 36 months. FACT-B Trial Outcome Index (TOI), symptom severity, and SF-36 Vitality and Physical Functioning (PF) scales scores were compared between the two groups using a mixed model for repeated measures analysis. MH was collected at baseline and subsequently assessed if menstrual bleeding occurred within 12 months prior to randomization. Post-chemotherapy amenorrhea outcome was examined at 18 months and was defined as lack of menses in the preceding year. Logistic regression was used to test for association of amenorrhea and treatment. CF assessment was done at baseline and 12 months. Correlation analysis was used to address associations between changes in baseline and 12-month PF and concurrent CF changes measured by LVEF. RESULTS: FEC-100 patients had statistically significantly lower TOI scores during chemotherapy (P = 0.02) and at 6 months (P < 0.001); lower Vitality score at 6 months (P < 0.01), and lower PF score during the first year than AC patients. There were no statistically significant QOL score differences between the two groups beyond 12 months. No significant differences in symptom severity between the two groups were observed. Rates of amenorrhea were significantly different between FEC-100 and AC (67.4% vs. 59.1%, P < 0.001). There was no association between changes in LVEF and PF (P = 0.38). CONCLUSIONS: Statistically significant QOL differences between the two groups favored AC; however, the magnitude was small and unlikely to be clinically meaningful. There was a clinical and statistically significant difference in risk for amenorrhea, favoring AC. TRIAL REGISTRY: NCT00087178; Date of registration: 07/08/2004.

Beta-2 Adrenergic Receptor Gene Expression in HER2-Positive Early-Stage Breast Cancer Patients: A Post-hoc Analysis of the NCCTG-N9831 (Alliance) Trial.

BACKGROUND: Beta-2 adrenergic receptor (ß2AR) modulates immune activation and may enhance trastuzumab activity. We assessed the impact of ß2AR gene (ADRB2) expression on the outcomes of patients with HER2-positive early-stage breast cancer enrolled on the NCCTG-N9831 trial. PATIENTS AND METHODS: This is a post-hoc analysis of the NCCTG-N9831 trial, which compared chemotherapy (arm A) versus chemotherapy plus trastuzumab (arms B&C) as adjuvant treatment of patients with HER2-positive early-stage breast cancer, with disease-free survival (DFS) as primary endpoint. Gene expression levels retrieved by DASL assay were used to classify patients as ADRB2-high or ADRB2-low. Hazard ratios (HRs) were calculated by a Cox proportional model adjusted for prognostic variables and ADRB2 expression. Correlations between ADRB2 expression and stromal tumor-infiltrating lymphocyte (TIL) levels were assessed with Pearson coefficient. A multivariable Cox regression model with interaction term was performed to assess the interaction between ADRB2 expression and treatment arm; and ADRB2 expression and a 8-gene signature previously shown to predict trastuzumab benefit. RESULTS: Overall, 1,282 patients were included (ADRB2-high [N = 944] / ADRB2-low [N = 338]). A high expression of ADRB2 was associated with a longer DFS (P = .01) in the overall population. The addition of trastuzumab to chemotherapy improved DFS only in patients with ADRB2-high tumors (P < .01). ADRB2 expression was correlated with TIL levels (r = 0.24, P < .001). No association between ADRB2 expression and the 8-gene trastuzumab benefit signature was observed (P = .32). CONCLUSION: Our findings suggest that a high ADRB2 expression is a favorable prognostic factor and may identify patients with HER2-positive early-stage breast cancer who benefit from adjuvant trastuzumab. TRIAL REGISTRATION: clinicaltrials.gov NCT00005970.

21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer.

BACKGROUND: The recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary lymph-node-negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear. METHODS: In a prospective trial, we randomly assigned women with hormone-receptor-positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease-free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse-free survival. RESULTS: A total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease-free survival differed according to menopausal status (P = 0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease-free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer [breast cancer or another type], or death, 1.02; 95% confidence interval [CI], 0.82 to 1.26; P = 0.89). Among premenopausal women, invasive disease-free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P = 0.002), with a similar increase in distant relapse-free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P = 0.009). The relative chemotherapy benefit did not increase as the recurrence score increased. CONCLUSIONS: Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease-free survival and distant relapse-free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037.).

The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group.

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.