Predicting the clinical outcomes and benefit from letrozole after 5 years of treatment with aromatase inhibitors for early breast cancer: analysis from CCTG MA.17R.

PURPOSE: Women with hormone receptor positive breast cancer may receive 5 years of treatment with aromatase inhibitors but the magnitude of benefit was relatively small. Our goal was to develop a tool for identification of women with limited treatment benefit. METHODS: Regression analyses were applied to women treated by placebo in CCTG MA.17R trial (NCT00754845) to identify important prognostic factors associated with distant recurrence and develop a nomogram for predicting 5-year likelihood of distant recurrence, which was internally validated using bootstrap resampling method. Differential treatment effects between risk categories derived from the nomogram were evaluated among all women enrolled through interaction test between treatment and risk category. RESULTS: A total of 1735 women were included and the final model from 866 women treated by placebo identified the following three factors associate with distant recurrence: tumor size, nodal status, and presence of cardiovascular disease. The nomogram derived from the final model exhibited good discrimination power with a bootstrap-corrected concordance index of 0.71 and, importantly, identified 64% of low risk patients in whom extended treatment has limited benefit. Interaction between treatment and risk category derived from the nomogram was significant (p = 0.04). CONCLUSION: A nomogram with good performance may be used to accurately predict distant recurrence risk and also benefits with extended treatment after 5 years of aromatase inhibitors. Future independent validation of the proposed nomogram is warranted. TRIAL REGISTRATION NUMBER: NCT00754845.

Single-nucleotide polymorphism biomarkers of adjuvant anastrozole-induced estrogen suppression in early breast cancer.

OBJECTIVES: Based on our previous findings that postmenopausal women with estrone (E1) and estradiol (E2) concentrations at or above 1.3 pg/ml and 0.5 pg/ml, respectively, after 6 months of adjuvant anastrozole therapy had a three-fold risk of recurrence, we aimed to identify a single-nucleotide polymorphism (SNP)-based model that would predict elevated E1 and E2 and then validate it in an independent dataset. PATIENTS AND METHODS: The test set consisted of 322 women from the M3 study and the validation set consisted of 152 patients from MA.27. All patients were treated with adjuvant anastrozole, had on-anastrozole E1 and E2 concentrations and genome-wide genotyping. RESULTS: SNPs were identified from the M3 genome-wide association study. The best model to predict the E1-E2 phenotype with high balanced accuracy was a support vector machine model using clinical factors plus 46 SNPs. We did not have an independent cohort that is similar to the M3 study with clinical, E1-E2 phenotypes and genotype data to test our model. Hence, we chose a nested matched case-control cohort (MA.27 study) for testing. Our E1-E2 model was not validated but we found the MA.27 validation cohort was both clinically and genomically different. CONCLUSIONS: We identified a SNP-based model that had excellent performance characteristics for predicting the phenotype of elevated E1 and E2 in women treated with anastrozole. This model was not validated in an independent dataset but that dataset was clinically and genomically substantially different. The model will need validation in a prospective study.

Patient Navigation to Improve Early Access to Supportive Care for Patients with Advanced Cancer in Resource-Limited Settings: A Randomized Controlled Trial.

BACKGROUND: The early integration of supportive care in oncology improves patient-centered outcomes. However, data are lacking regarding how to achieve this in resource-limited settings. We studied whether patient navigation increased access to multidisciplinary supportive care among Mexican patients with advanced cancer. MATERIALS AND METHODS: This randomized controlled trial was conducted between August 2017 and April 2018 at a public hospital in Mexico City. Patients aged ≥18 years with metastatic tumors ≤6 weeks from diagnosis were randomized (1:1) to a patient navigation intervention or usual care. Patients randomized to patient navigation received personalized supportive care from a navigator and a multidisciplinary team. Patients randomized to usual care obtained supportive care referrals from treating oncologists. The primary outcome was the implementation of supportive care interventions at 12 weeks. Secondary outcomes included advance directive completion, supportive care needs, and quality of life. RESULTS: One hundred thirty-four patients were randomized: 67 to patient navigation and 67 to usual care. Supportive care interventions were provided to 74% of patients in the patient navigation arm versus 24% in usual care (difference 0.50, 95% confidence interval [CI] 0.34-0.62; p < .0001). In the patient navigation arm, 48% of eligible patients completed advance directives, compared with 0% in usual care (p < .0001). At 12 weeks, patients randomized to patient navigation had less moderate/severe pain (10% vs. 33%; difference 0.23, 95% CI 0.07-0.38; p = .006), without differences in quality of life between arms. CONCLUSION: Patient navigation improves access to early supportive care, advance care planning, and pain for patients with advanced cancer in resource-limited settings. IMPLICATIONS FOR PRACTICE: The early implementation of supportive care in oncology is recommended by international guidelines, but this might be difficult to achieve in resource-limited settings. This randomized clinical trial including 134 Mexican patients with advanced cancer demonstrates that a multidisciplinary patient navigation intervention can improve the early access to supportive and palliative care interventions, increase advance care planning, and reduce symptoms compared with usual oncologist-guided care alone. These results demonstrate that patient navigation represents a potentially useful solution to achieve the adequate implementation of supportive and palliative care in resource-limited settings globally.

Breast cancer in Colombia: a growing challenge for the healthcare system.

AIM: To provide a comprehensive overview of breast cancer in Colombia. METHODS: Data on breast cancer in Colombia are scarce. We present incidence data from population-based cancer registries that represent 4 distinct regions of the country. Other data originate from non-governmental institutions and healthcare providers within Colombia, official sources, expert opinion, Colombian legislation, and the Cancer Mortality Atlas publishes by Colombian National Cancer Institute. RESULTS: In Colombia, the age-standardized incidence rate remained relatively stable between 2012 and 2020 (43.1 to 47.8 cases per 100,000 women-years); Additionally, survival since 1995 has presented a substantial improvement from 65.7 to 72.1. In 33% of cases, the diagnosis of breast cancer was made in advanced stages, stage III or higher. The health demography survey conducted in 2015 showed that the participation in mammography screening in women aged 40 to 69 remains low 48.1%. Some limitations regarding access to early detection and diagnosis include economic strata, health insurance coverage, origin, and accessibility. On average, a 90-day period was reported from onset of symptoms to diagnosis of breast cancer. CONCLUSION: The first action towards improving outcomes in breast cancer should be to improve stage at diagnosis and timely access to care.

Phase II trial of veliparib and temozolomide in metastatic breast cancer patients with and without BRCA1/2 mutations.

PURPOSE: We evaluated the efficacy and safety of poly-(adenosine diphosphate-ribose) polymerase (PARP) 1 and 2 inhibitor veliparib and temozolomide in metastatic breast cancer patients with and without germline BRCA1/2 mutations. METHODS: In this single-arm phase II trial, patients with metastatic breast cancer received veliparib 30 to 40 mg twice daily on days 1 to 7 with concurrent temozolomide 150 mg/m2 on days 1 to 5 of a 28-day cycle. The primary cohort was unselected for BRCA mutation status, and an expansion cohort enrolled only BRCA1/2 carriers. The primary endpoint was objective response rate (ORR) in each cohort. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), and evaluation of safety and tolerability. RESULTS: In the primary cohort of 41 unselected patients, which included 9 BRCA mutation carriers, the ORR was 10% and clinical benefit rate at 4 months (CBR) was 27%. In the expansion cohort of 21 BRCA1/2 carriers, the ORR was 14% and CBR was 43%. Among all 30 BRCA1/2 carriers, the ORR was 23% versus 0% among non-carriers. In the subset of BRCA1/2 carriers, the ORR was 32% among platinum-naïve patients versus 9% among platinum-exposed patients. The median PFS was 3.3 months among BRCA1/2 carriers compared to 1.8 months among non-carriers (HR: 0.48, p = 0.006). A longer median PFS of 6.2 months was observed among BRCA1/2 carriers who had no prior platinum therapy. The most common grade 3 and 4 toxicities were thrombocytopenia (32%) and neutropenia (21%) that generally improved with dose modifications. CONCLUSION: Veliparib and temozolomide demonstrated clinical activity in platinum-naïve BRCA-associated metastatic breast cancer with manageable toxicity at doses of veliparib well below the single-agent active dose. Although the study did not meet its primary endpoint in unselected nor BRCA-associated breast cancer, this regimen was further evaluated in the BROCADE 2 study. TRIAL REGISTRATION: NCT01009788 (ClinicalTrials.gov), November 9, 2009.

Deep sequencing across germline genome-wide association study signals relating to breast cancer events in women receiving aromatase inhibitors for adjuvant therapy of early breast cancer.

OBJECTIVE: To identify additional genetic variants beyond those observed in a previous genome-wide association study (GWAS) in women treated on the MA.27 clinical trial in which women were randomized to 5 years of adjuvant therapy with anastrozole or exemestane. PATIENTS AND METHODS: We performed a matched case-control study in 234 women who had a recurrence of breast cancer (cases) and 649 women who had not (controls). The analysis was restricted to White women with an estrogen receptor-positive breast cancer. Multiplex PCR-based targeted deep sequencing was performed of the MIR2052HG region on chromosome 8 between positions 75.4 and 75.7, a span of 300 kb, in an attempt to identify additional functional single nucleotide polymorphisms (SNPs). RESULTS: A total of 4677 unique variants were identified that had not been identified in the previous GWAS. Clinical Annotation of Variants analysis revealed 10 variants, including eight SNPs and two insertion-deletion mutations with moderate or high impact. However, none of the common and variant regions was significant after adjustment for the most significant SNP (rs13260300) identified in our previous GWAS. We performed haplotype analysis that revealed two regions in which the haplotypes lost significance when adjusted for this prior GWAS SNP and one region with two significant haplotypes (P = 0.046 and 0.031) after adjusting for the GWAS SNP. CONCLUSION: We were unable to identify common or rare variant regions that added value to the findings from our previous GWAS. We did find two haplotypes that were significant after adjusting for our top GWAS SNP but these were considered to be of marginal value.

Patient Navigation to Enhance Access to Care for Underserved Patients with a Suspicion or Diagnosis of Cancer.

BACKGROUND: Interventions aimed at improving access to timely cancer care for patients in low- and middle-income countries (LMIC) are urgently needed. We aimed to evaluate a patient navigation (PN) program to reduce referral time to cancer centers for underserved patients with a suspicion or diagnosis of cancer at a public general hospital in Mexico City. MATERIALS AND METHODS: From January 2016 to March 2017, consecutive patients aged >18 years with a suspicion or diagnosis of cancer seen at Ajusco Medio General Hospital in Mexico City who required referral to a specialized center for diagnosis or treatment were enrolled. A patient navigator assisted patients with scheduling, completing paperwork, obtaining results in a timely manner, transportation, and addressing other barriers to care. The primary outcome was the proportion of patients who obtained a specialized consultation at a cancer center within the first 3 months after enrollment. RESULTS: Seventy patients (median age 54, range 19-85) participated in this study. Ninety-six percent (n = 67) identified >1 barrier to cancer care access. The most commonly reported barriers to health care access were financial burden (n = 50) and fear (n = 37). Median time to referral was 7 days (range 0-49), and time to specialist appointment was 27 days (range 1-97). Ninety-one percent of patients successfully obtained appointments at cancer centers in <3 months. CONCLUSION: Implementing PN in LMIC is feasible, and may lead to shortened referral times for specialized cancer care by helping overcome barriers to health care access among underserved patients. IMPLICATIONS FOR PRACTICE: A patient navigation program for patients with suspicion or diagnosis of cancer in a second-level hospital was feasible and acceptable. It reduced patient-reported barriers, and referral time to specialized appointments and treatment initiation were within international recommended limits. Patient navigation may improve access to care for underserved patients in developing countries.

Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years.

BACKGROUND: Treatment with an aromatase inhibitor for 5 years as up-front monotherapy or after tamoxifen therapy is the treatment of choice for hormone-receptor-positive early breast cancer in postmenopausal women. Extending treatment with an aromatase inhibitor to 10 years may further reduce the risk of breast-cancer recurrence. METHODS: We conducted a double-blind, placebo-controlled trial to assess the effect of the extended use of letrozole for an additional 5 years. Our primary end point was disease-free survival. RESULTS: We enrolled 1918 women. After a median follow-up of 6.3 years, there were 165 events involving disease recurrence or the occurrence of contralateral breast cancer (67 with letrozole and 98 with placebo) and 200 deaths (100 in each group). The 5-year disease-free survival rate was 95% (95% confidence interval [CI], 93 to 96) with letrozole and 91% (95% CI; 89 to 93) with placebo (hazard ratio for disease recurrence or the occurrence of contralateral breast cancer, 0.66; P=0.01 by a two-sided log-rank test stratified according to nodal status, prior adjuvant chemotherapy, the interval from the last dose of aromatase-inhibitor therapy, and the duration of treatment with tamoxifen). The rate of 5-year overall survival was 93% (95% CI, 92 to 95) with letrozole and 94% (95% CI, 92 to 95) with placebo (hazard ratio, 0.97; P=0.83). The annual incidence rate of contralateral breast cancer in the letrozole group was 0.21% (95% CI, 0.10 to 0.32), and the rate in the placebo group was 0.49% (95% CI, 0.32 to 0.67) (hazard ratio, 0.42; P=0.007). Bone-related toxic effects occurred more frequently among patients receiving letrozole than among those receiving placebo, including a higher incidence of bone pain, bone fractures, and new-onset osteoporosis. No significant differences between letrozole and placebo were observed in scores on most subscales measuring quality of life. CONCLUSIONS: The extension of treatment with an adjuvant aromatase inhibitor to 10 years resulted in significantly higher rates of disease-free survival and a lower incidence of contralateral breast cancer than those with placebo, but the rate of overall survival was not higher with the aromatase inhibitor than with placebo. (Funded by the Canadian Cancer Society and others; ClinicalTrials.gov numbers, NCT00003140 and NCT00754845.).

Discrepancy in risk assessment of hormone receptor positive early-stage breast cancer patients using breast cancer index and recurrence score.

PURPOSE: A recent comparison of the prognostic accuracy of Breast Cancer Index (BCI) and the Recurrence Score (RS) showed that BCI was more precise than RS. BCI identified a subset of RS low and intermediate risk patients with clinically relevant elevated rates of distant recurrences (DR). The current study analyzed the correlation of BCI and RS risk classification to clinical and pathological parameters and further examined the re-categorization between the two risk group indices in a multi-institutional cohort of hormone receptor positive (HR+) breast cancer patients. METHODS: 560 women with HR+, lymph node-negative breast cancer who underwent testing with RS as part of their routine clinical care were included in the final analysis. Individual risk was assessed using predefined categories of RS and BCI (Low, Intermediate and High, respectively). Correlations between BCI, RS, and standard clinical-pathological prognostic factors were examined, and re-categorization of risk groups between BCI and RS was analyzed. RESULTS: An overall significant association between histological tumor grade and RS or BCI was observed with high-grade tumors more prevalent among RS and BCI high-risk patients. The invasive ductal carcinoma histologic subtype was associated with 98% and 93% of high-risk RS and BCI cases, respectively. The invasive lobular subtype accounted for 0% and 6% of high-risk RS and BCI cases, respectively. A poor agreement between the two biomarker risk group indices was demonstrated with more than 51% of the total cohort stratified differently between BCI and RS. As compared with RS, BCI stratified fewer patients into the intermediate-risk group (29% vs. 39%, BCI and RS, respectively) and more patients into the high-risk group (19% vs. 7%, BCI and RS, respectively). Subsets of both RS low- and intermediate-risk patients were identified by BCI as high risk. CONCLUSIONS: In this clinical series, BCI and RS risk groups demonstrated a significant association with histological tumor grade. BCI showed a modest correlation with tumor size and no correlation with age, while RS showed no correlation with tumor size or age. Compared with RS, BCI classifies fewer intermediate risk patients, identifies subsets of low and intermediate RS risk patients as high-risk, and provides distinct individualized risk assessment for patients with early-stage breast cancer.

Patient-reported predictors of early treatment discontinuation: treatment-related symptoms and health-related quality of life among postmenopausal women with primary breast cancer randomized to anastrozole or exemestane on NCIC Clinical Trials Group (CCTG) MA.27 (E1Z03).

PURPOSE: Aromatase inhibitors are the most commonly prescribed adjuvant endocrine therapy for hormone-dependent early breast cancer in postmenopausal women. Among Canadian Cancer Trials Group MA.27 participants, anastrozole and exemestane had comparable 5-year event-free survival. This companion study examined differences in patient-reported treatment-related symptoms (TRS) and health-related quality of life (HRQL) among postmenopausal women randomized to anastrozole or exemestane. METHODS: MA.27 participants (N = 686, of 7576) randomized to 5 years of anastrozole (1 mg/day, n = 371, Arm A) or exemestane (25 mg/day, n = 315, Arm E) completed the 56-item Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) questionnaire to assess TRS and HRQL. The FACT-ES was completed at baseline, 3, 6, 12, and 24 months. RESULTS: No significant differences in FACT-ES median scores measuring TRS and HRQL were observed between treatment arms at any time point. Change in TRS from baseline was statistically significant at 3, 6, 12, and 24 months. HRQL was stable over time in both arms. Greater TRS burden was associated with poorer HRQL (coefficient = 0.57, p < 0.001). Twenty percent of patients discontinued AI therapy by month 24 and 32% discontinued AIs at 4 years. In both arms, patients reporting more side effect bother prior to initiating study treatment had a higher risk of discontinuing treatment before completing protocol therapy (hazard ratio [HR] 1.29, 95% CI 1.08-1.55, p = 0.01). CONCLUSIONS: TRS and HRQL were comparable between anastrozole and exemestane. TRS negatively affect HRQL. Women who report being bothered by treatment side effects prior to initiating an AI are at increased risk for early treatment discontinuation.

TCL1A, a Novel Transcription Factor and a Coregulator of Nuclear Factor κB p65: Single Nucleotide Polymorphism and Estrogen Dependence.

T-cell leukemia 1A (TCL1A) single-nucleotide polymorphisms (SNPs) have been associated with aromatase inhibitor-induced musculoskeletal adverse events. We previously demonstrated that TCL1A is inducible by estradiol (E2) and plays a critical role in the regulation of cytokines, chemokines, and Toll-like receptors in a TCL1A SNP genotype and estrogen-dependent fashion. Furthermore, TCLIA SNP-dependent expression phenotypes can be "reversed" by exposure to selective estrogen receptor modulators such as 4-hydroxytamoxifen (4OH-TAM). The present study was designed to comprehensively characterize the role of TCL1A in transcriptional regulation across the genome by performing RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) assays with lymphoblastoid cell lines. RNA-seq identified 357 genes that were regulated in a TCL1A SNP- and E2-dependent fashion with expression patterns that were 4OH-TAM reversible. ChIP-seq for the same cells identified 57 TCL1A binding sites that could be regulated by E2 in a SNP-dependent fashion. Even more striking, nuclear factor-κB (NF-κB) p65 bound to those same DNA regions. In summary, TCL1A is a novel transcription factor with expression that is regulated in a SNP- and E2-dependent fashion-a pattern of expression that can be reversed by 4OH-TAM. Integrated RNA-seq and ChIP-seq results suggest that TCL1A also acts as a transcriptional coregulator with NF-κB p65, an important immune system transcription factor.

TCL1A Single-Nucleotide Polymorphisms and Estrogen-Mediated Toll-Like Receptor-MYD88-Dependent Nuclear Factor-κB Activation: Single-Nucleotide Polymorphism- and Selective Estrogen Receptor Modulator-Dependent Modification of Inflammation and Immune Response.

In a previous genome-wide association study (GWAS) for musculoskeletal adverse events during aromatase inhibitor therapy for breast cancer, we reported that single nucleotide polymorphisms (SNPs) near the TCL1A gene were associated with this adverse drug reaction. Functional genomic studies showed that TCL1A expression was induced by estradiol, but only in cells with the variant sequence for the top GWAS SNP (rs11849538), a SNP that created a functional estrogen response element. In addition, TCL1A genotype influenced the downstream expression of a series of cytokines and chemokines and had a striking effect on nuclear factor κB (NF-κB) transcriptional activity. Furthermore, this SNP-dependent regulation could be reversed by selective ER modulators (SERMs). The present study was designed to pursue mechanisms underlying TCL1A SNP-mediated, estrogen-dependent NF-κB activation. Functional genomic studies were performed using a panel of 300 lymphoblastoid cell lines for which we had generated genome-wide SNP and gene expression data. It is known that toll-like receptors (TLRs) can regulate NF-κB signaling by a process that requires the adaptor protein MYD88. We found that TLR2, TLR7, TLR9, and TLR10 expression, as well as that of MYD88, could be modulated by TCL1A in a SNP and estrogen-dependent fashion and that these effects were reversed in the presence of SERMs. Furthermore, MYD88 inhibition blocked the TCL1A SNP and estrogen-dependent NF-κB activation, as well as protein-protein interaction between TCL1A and MYD88. These observations greatly expand the range of pathways influenced by TCL1A genotype and raise the possibility that this estrogen- and SNP-dependent regulation might be altered pharmacologically by SERMs.

Improving access to high-cost cancer drugs in Latin America: Much to be done.

Lack of access to high-cost medications is a complex issue at the intersection of economics, medicine, politics, and ethics, and it poses a significant threat to global health care. The problem is even more significant in low- and middle-income countries, such as those in Latin America, where governments and individuals struggle to pay for products that are priced at several times the level of their per capita gross domestic product. In this review, we examine the determinants for increasing drug costs and how Latin American countries face this burgeoning crisis. We emphasize that a number of opportunities and strategies to reduce costs and improve access exist and should be identified and implemented, ideally within a regional approach with multiple stakeholders involved and based on systematic and transparent cost-effectiveness analyses. Cancer 2017;123:1313-1323. © 2016 American Cancer Society.

Osteoporosis therapy and outcomes for postmenopausal patients with hormone receptor-positive breast cancer: NCIC CTG MA.27.

BACKGROUND: Breast cancer patients in the MA.27 trial had similar outcomes with steroidal aromatase inhibitor (AI) exemestane and nonsteroidal anastrozole. AIs increase the risk of osteoporosis. This study examined the effects of self-reported osteoporosis and osteoporosis therapy (OPT) on outcomes. METHODS: The MA.27 phase 3 adjuvant trial enrolled 7576 postmenopausal women. The primary outcome was event-free survival (EFS), and the secondary outcome was distant disease-free survival (DDFS). Patients were permitted bisphosphonates to prevent or treat osteopenia/osteoporosis. In a multivariate, stratified Cox regression, factors were significant with a 2-sided Wald test P value ≤ .05. RESULTS: Osteoporosis was reported at the baseline by 654 of the 7576 women (8.6%) and in total by 1294 patients. Oral OPT was received at the baseline by 815 of the 7576 women (10.8%) and in total by 2711 patients (36%). With a median follow-up of 4.1 years, 693 EFS events (9.15%) and 321 DDFS events (4.2%) occurred. Osteoporosis was not associated with EFS or DDFS. Few EFS events occurred before the initiation of OPT, with no substantive evidence of a time-differing effect on outcomes (nonproportional hazards). OPT (yes vs no) was significantly associated with improved EFS (hazard ratio [HR] for yes vs no, 0.67; 95% confidence interval [CI], 0.57-0.80; P < .001) and DDFS (HR, 0.57; 95% CI, 0.44-0.73; P <. 001). Time-differing (time-dependent) OPT was not (EFS; P = .45). OPT did not alter the incidence of visceral-only metastasis (P = .31). CONCLUSIONS: Oral OPT, administered to postmenopausal breast cancer patients receiving adjuvant AI therapy, was associated with improved EFS and DDFS; the time of OPT initiation (a time-dependent effect) did not affect the outcome. OPT did not alter the risk of visceral metastasis. Cancer 2017;123:2444-51. © 2017 American Cancer Society.

Barriers to Primary Debulking Surgery for Advanced Ovarian Cancer in Latin America.

Ovarian cancer is gynecologic tumor with particularly high mortality because it is usually diagnosed in advanced stages. In Latin America and the Caribbean, it is the eighth most common malignancy in women, with an estimated 18,000 new cases and 11,500 deaths annually. Standard of care for women diagnosed with advanced ovarian cancer (AOC) is primary cytoreductive surgery followed by systemic chemotherapy using a combination of paclitaxel plus carboplatin. To pursue upfront surgery, highly specialized and well-trained gynecologic oncologists are required, in addition with well-equipped hospitals. Neoadjuvant chemotherapy (NACT) has been gaining greater acceptance in the past decade for patients with AOC. Two phase III randomized clinical trials have demonstrated that NACT is noninferior to primary cytoreductive surgery for women with stages III and IV epithelial ovarian cancer, and since publication of these results, NACT is more commonly used. Apart from medical reasons of inoperability and unresectability, there may be nonmedical barriers to upfront debulking surgery in clinical practice. These barriers include inadequate expertise of the surgeon, inadequate resources, and/or barriers to access. The aim of this article was to discuss patterns of care and barriers to upfront ovarian debulking surgery, as well as a possible shift toward overuse of NACT as the primary approach for patients with AOC (stages III and IV) in Latin America.

Assessment of the prognostic and predictive utility of the Breast Cancer Index (BCI): an NCIC CTG MA.14 study.

BACKGROUND: Biomarkers that can be used to accurately assess the residual risk of disease recurrence in women with hormone receptor-positive breast cancer are clinically valuable. We evaluated the prognostic value of the Breast Cancer Index (BCI), a continuous risk index based on a combination of HOXB13:IL17BR and molecular grade index, in women with early breast cancer treated with either tamoxifen alone or tamoxifen plus octreotide in the NCIC MA.14 phase III clinical trial (ClinicalTrials.gov Identifier NCT00002864; registered 1 November 1999). METHODS: Gene expression analysis of BCI by real-time polymerase chain reaction was performed blinded to outcome on RNA extracted from archived formalin-fixed, paraffin-embedded tumor samples of 299 patients with both lymph node-negative (LN-) and lymph node-positive (LN+) disease enrolled in the MA.14 trial. Our primary objective was to determine the prognostic performance of BCI based on relapse-free survival (RFS). MA.14 patients experienced similar RFS on both treatment arms. Association of gene expression data with RFS was evaluated in univariate analysis with a stratified log-rank test statistic, depicted with a Kaplan-Meier plot and an adjusted Cox survivor plot. In the multivariate assessment, we used stratified Cox regression. The prognostic performance of an emerging, optimized linear BCI model was also assessed in a post hoc analysis. RESULTS: Of 299 samples, 292 were assessed successfully for BCI for 146 patients accrued in each MA.14 treatment arm. BCI risk groups had a significant univariate association with RFS (stratified log-rank p = 0.005, unstratified log-rank p = 0.007). Adjusted 10-year RFS in BCI low-, intermediate-, and high-risk groups was 87.5 %, 83.9 %, and 74.7 %, respectively. BCI had a significant prognostic effect [hazard ratio (HR) 2.34, 95 % confidence interval (CI) 1.33-4.11; p = 0.004], although not a predictive effect, on RFS in stratified multivariate analysis, adjusted for pathological tumor stage (HR 2.22, 95 % CI 1.22-4.07; p = 0.01). In the post hoc multivariate analysis, higher linear BCI was associated with shorter RFS (p = 0.002). CONCLUSIONS: BCI had a strong prognostic effect on RFS in patients with early-stage breast cancer treated with tamoxifen alone or with tamoxifen and octreotide. BCI was prognostic in both LN- and LN+ patients. This retrospective study is an independent validation of the prognostic performance of BCI in a prospective trial.

Prolactin and breast cancer: The need to avoid undertreatment of serious psychiatric illnesses in breast cancer patients: A review.

Hyperprolactinemia, defined as a sustained elevation of prolactin (PRL) levels greater than 530 mIU/L in women and greater than 424 mIU/L in men, has been implicated for a long time in breast cancer etiology and prognosis. Elevated PRL values (approximately 2-3 times higher than the reference values) are a common adverse effect of antipsychotic medications, especially with first-generation drugs, and most antipsychotics carry a standard warning regarding PRL elevations on their US product labels. These associations foster undertreatment of serious psychiatric illnesses in both otherwise healthy patients and cancer patients. This review assesses both the preclinical and clinical evidence that has led to the hypothesis of PRL's role in breast cancer risk or breast cancer progression. It is concluded that taken together, the published data are unconvincing and insufficient to deprive cancer patients in general and breast cancer patients specifically of potentially effective antipsychotic or antidepressant medications for serious psychiatric indications. We thus call on revised medication guidelines to avoid the existing undertreatment of serious psychiatric illnesses among cancer patients based on an unproven contraindication to psychiatric medications. Cancer 2016;122:184-188. © 2015 American Cancer Society.

Cervical cancer control in Latin America: A call to action.

Cervical cancer (CC) is second most common cause of cancer in Latin America and is a leading cause of cancer mortality among women. In 2015, an estimated 74,488 women will be diagnosed with CC in Latin America and 31,303 will die of the disease. CC mortality is projected to increase by 45% by 2030 despite human papillomavirus (HPV) vaccination and screening efforts. In this setting, the goal was of the current study was to examine CC control efforts in Latin America and identify deficiencies in these efforts that could be addressed to reduce CC incidence and mortality. The authors found that HPV vaccination has been introduced in the majority of Latin American countries, and there is now a need to monitor the success (or shortcomings) of these programs and to ensure that these programs are sustainable. This topic was also reviewed in light of emerging data demonstrating that visual inspection with acetic acid and HPV DNA testing without Papanicolaou tests have efficacy from a screening perspective and are good alternatives to cytology-based screening programs. Overall, there is a need to build capacity for CC control in Latin America and the best strategy will depend on the country/region and must be tailored to meet the needs of the population as well as available resources.

Competing risks of death in women treated with adjuvant aromatase inhibitors for early breast cancer on NCIC CTG MA.27.

Baseline patient and tumor characteristics differentially affected type of death in the MA.17 placebo-controlled letrozole trial where cardiovascular death was not separately identified. The MA.27 trial allowed competing risks analysis of breast cancer (BC), cardiovascular, and other type (OT) of death. MA.27 was a phase III adjuvant breast cancer trial of exemestane versus anastrozole. Effects of baseline patient and tumor characteristics were tested for whether factors were associated with (1) all cause mortality and (2) cause-specific mortality. We also fit step-wise forward cause-specific-adjusted models. 7576 women (median age 64 years; 5417 (72 %) < 70 years and 2159 (28 %) ≥ 70 years) were enrolled and followed for median 4.1 years. The 432 deaths comprised 187 (43 %) BC, 66 (15 %) cardiovascular, and 179 (41 %) OT. Five baseline factors were differentially associated with type of death. Older patients had greater BC (p = 0.03), cardiovascular (p < 0.001), and other types (p < 0.001) of mortality. Patients with pre-existing cardiovascular history had worse cardiovascular mortality (p < 0.001); those with worse ECOG performance status had worse OT mortality (p < 0.001). Patients with T1 tumors (p < 0.001) and progesterone receptor positive had less BC mortality (p < 0.001). Fewer BC deaths occurred with node-negative disease (p < 0.001), estrogen receptor-positive tumors (p = 0.001), and without adjuvant chemotherapy (p = 0.005); worse cardiovascular mortality (p = 0.01), with trastuzumab; worse OT mortality, for non-whites (p = 0.03) and without adjuvant radiotherapy (p = 0.003). Overall, 57 % of deaths in MA.27 AI-treated patients were non-breast cancer related. Baseline patient and tumor characteristics differentially affected type of death with women 70 or older experiencing more non-breast cancer death.

Relapse-free survival of statistically standardized continuous RT-PCR estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2): NCIC CTG MA.14.

Recent ASCO/CAP guidelines focus on decision making associated with the presence/absence of continuous breast biomarkers. Statistical standardization (SS) is demonstrated as a method to evaluate the effects of continuous RT-PCR biomarker expression levels on breast cancer outcomes. MA.14 allocated 667 postmenopausal patients to tamoxifen based on locally determined ER/PR. Of 299 available patient tumor samples, 292 passed internal quality control. All tumors were centrally assessed by RT-PCR ER/PR/HER2 with each biomarker's z-scores categorized: ≥1.0 standard deviation (SD) below mean; <1.0 SD below mean; ≤1.0 SD above mean; >1.0 SD above mean. Log-rank statistics tested univariate differences in breast cancer relapse-free survival (RFS). Continuous SS-ER/PR/HER2 were assessed in multivariate Cox step-wise forward regression, adding a factor if p ≤ 0.05. Sensitivity analyses examined an external HER2+ cut-point of 1.32. Patients whose tumors were tested were representative of the MA.14 population (p values = 0.18-0.90). At 9.8 years median follow-up, SS-ER did not univariately impact RFS (p = 0.31). SS-PR values above the mean (z ≥ 0.0) had the best univariate RFS (p = 0.03). SS-HER2 also univariately impacted RFS (p = 0.004) with lowest (z-scores ≤ -1.0) and highest (z-scores > 1.0) having shortest RFS. Multivariate stratified/unstratified Cox models indicated patients with T1 tumors (p = 0.02/p = 0.0002) and higher SS-PR (p = 0.02/p = 0.01) had longer RFS; node-negative patients had better RFS (in unstratified analysis, p < 0.0001). Local ER/PR status did not impact RFS (p > 0.05). Patients with SS HER2+ ≥ 1.32 had worse RFS (univariate, p = 0.05; multivariate, p = 0.06). We demonstrated that higher SS-PR, and SS HER2 levels, measured by RT-PCR impacted breast cancer RFS outcomes. Evaluation in other trials may provide support for this methodology.