Genomic Landscape of Advanced Solid Tumors in Middle East and North Africa Using Circulating Tumor DNA (ctDNA) in Routine Clinical Practice.

INTRODUCTION: Next-generation sequencing (NGS) of tumor DNA can detect actionable drivers and help guide therapy for patients with advanced-stage cancers. While tissue-based genotyping is considered standard of care, blood-based genotyping is emerging as a valid alternative. Tumor genomic profiles may vary by region, and data from the Middle East and North Africa (MENA) are not widely available. This study elucidates the genomic landscape of advanced solid cancers in patients from the MENA region by retrospectively analyzing results from NGS ctDNA testing. METHODS: In routine clinical practice, 926 plasma samples from 767 patients with advanced cancers from the MENA region were profiled using a comprehensive NGS assay (Guardant360®). We conducted a pan-cancer analysis and sub-analyses focusing on lung, breast, and colorectal cancers. RESULTS: In the pan-cancer group, TP53 (58.5%), EGFR (20.4%), and KRAS (18.9%) were the most frequently mutated genes. EGFR (10.2%), FGFR1 (4.9%), and PIK3CA (4.9%) showed the most amplifications, while fusions were observed in 2.7% of patients, including ALK, FGFR2, and RET. For lung adenocarcinoma, EGFR (30.5%), KRAS (19.3%), and ERBB2 (4.6%) were the most frequently identified alterations among the genes recommended for evaluation by the National Comprehensive Cancer Network (NCCN). In patients with breast cancer, PIK3CA (35.3%), ESR1 (21.7%), and BRCA1/2 (13.3%) had the most prevalent alterations among NCCN-recommended genes. In colorectal cancer, KRAS (39.0%), NRAS (8.0%), and BRAF (V600E, 4.0%) were the most observed mutations among genes recommended by the NCCN. Comparing this cohort to publicly available Western and Eastern datasets also indicated similarities (including PIK3CA in breast cancer) and variances (including EGFR in lung adenocarcinoma) in key genes of interest in the analyzed cancer types. CONCLUSION: Overall, our findings provide insight into the genomic landscape of individuals with advanced solid organ malignancies from the MENA region and support the role of ctDNA in guiding therapeutic decisions.

Practical notes on the current ESMO consensus guidelines for the management of patients with metastatic colorectal cancer in resource-constrained environments of low- to middle-income countries.

Letter (no abstract).

Understanding the benefits and challenges of first-line cyclin-dependent kinases 4 and 6 inhibitors in advanced breast cancer among postmenopausal women.

Endocrine therapy (ET) has been regarded for many years as the standard treatment for patients with hormone receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer (ABC) without visceral crisis. However, the efficacy of single-agent ET is constrained by the development of resistance, attributed to alterations in several intracellular signaling pathways, including those related to cell cycle dysregulation. The cyclin-dependent kinases 4 and 6 (CDK4/6) are principal regulators of cell cycle progression from the G1-phase into the DNA synthesis (S)-phase. In vitro inhibition of CDK4/6 activity has potent antiproliferative properties against luminal breast cancer cell lines, which are enhanced when combined with traditional ET. This has led to a substantial interest in targeting this pathway to overcome endocrine resistance in the clinic. Three selective CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) have been approved as first-line therapy in combination with an aromatase inhibitor, or fulvestrant in the case of ribociclib in patients with ER+/HER2- ABC. To date, there is no clue as to which subgroup of patients might benefit most from these combinations. Here, we outline some of the established approaches to overcome endocrine resistance, with special emphasis on the unique mechanism of action of CDK4/6 inhibitors.

Ten-year survival in women with primary stage IV breast cancer.

PURPOSE: To evaluate breast cancer-specific survival at 10 years in patients who present with primary stage IV breast cancer, and to determine whether survival varies with age of diagnosis. METHODS: We retrieved the records of 25,323 women diagnosed with primary stage IV breast cancer in the surveillance, epidemiology, and end results 18 registries database from 1990 to 2012. For each case, we extracted information on age at diagnosis, tumour size, nodal status, oestrogen receptor status, progesterone receptor status, ethnicity, cause of death and date of death. The Cox proportional hazards model was used to estimate the unadjusted and adjusted hazard ratio (HR) of death due to stage IV breast cancer, according to age group. RESULTS: Among 25,323 women with stage IV breast cancer, 2542 (10.0 %) were diagnosed at age 40 or below, 5562 (22.0 %) were diagnosed between ages 41 and 50 and 17,219 (68.0 %) were diagnosed between ages 51 and 70. After a mean follow-up of 2.2 years, 16,387 (64.7 %) women died of breast cancer (median survival 2.3 years). The ten-year actuarial breast cancer-specific survival rate was 15.7 % for women ages 40 and below, 14.9 % for women ages 41-50 and 11.7 % for women ages 51 to 70 (p < 0.0001). In an adjusted analysis, the risk of death from breast cancer at 10 years was significantly lower for women ages 40 and below (HR 0.78; 95 % CI 0.74-0.82; p < 0.0001) and for women ages 41-50 (HR 0.82; 95 % CI 0.79-0.85; p < 0.0001), compared to women ages 51-70. CONCLUSIONS: Approximately 13 % of women with primary stage IV breast cancer survive 10 years after diagnosis. Women diagnosed with stage IV breast cancer before age 50 have better survival at 10 years compared to older women.

Circulating tumor cells in newly diagnosed inflammatory breast cancer.

INTRODUCTION: Circulating tumor cells (CTCs) are an independent prognostic factor for progression-free survival (PFS) and overall survival (OS) in patients with metastatic breast cancer. Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. The prognostic value of a CTC count in newly diagnosed IBC has not been established. The aim of this study was to assess the prognostic value of a baseline CTC count in patients with newly diagnosed IBC. METHODS: This retrospective study included 147 patients with newly diagnosed IBC (77 with locally advanced and 70 with metastatic IBC) treated with neoadjuvant therapy or first-line chemotherapy during the period from January 2004 through December 2012 at The University of Texas MD Anderson Cancer Center. CTCs were detected and enumerated by using the CellSearch system before patients were started with chemotherapy. RESULTS: The proportion of patients with ≥1 CTC was lower among patients with stage III than among patients with metastatic IBC (54.5% versus 84.3%; P=0.0002); the proportion of patients with ≥5 CTCs was also lower for stage III than for metastatic IBC (19.5% versus 47.1%; P=0.0004). Patients with fewer than five CTCs had significantly better progression-free survival (PFS) (hazard ratio (HR)=0.60; P=0.02) and overall survival (HR=0.59; P=0.03) than patients with five or more CTCs. Among patients with stage III IBC, there was a nonsignificant difference in PFS (HR=0.66; 95% confidence interval (CI), 0.31 to 1.39; P=0.29) and OS (HR=0.54; 95% CI, 0.24 to 1.26; P=0.48) in patients with no CTCs compared with patients with one or more CTCs. In multivariate analysis, CTC was prognostic for PFS and OS independent of clinical stage. CONCLUSIONS: CTCs can be detected in a large proportion of patients with newly diagnosed IBC and are a strong predictor of worse prognosis in patients with newly diagnosed IBC.

Is the Proportion of Patients Diagnosed with Synchronous Stage IV Breast Cancer Who Survive More than Two Years Increasing over Time?

BACKGROUND: Studies have shown a moderate increase in survival over time among patients with stage IV breast cancer. Median survival is approximately 2 years. The aim of this study was to evaluate trends over time in survival of >2 years of patients with synchronous stage IV disease. METHODS: Using the SEER (Surveillance, Epidemiology and End Results) registry, we identified patients with synchronous stage IV breast cancer diagnosed between 1990 and 2007. Patients were divided into 3 groups according to the year of diagnosis (1990-1995, 1996-2000, and 2001-2007). The probability of survival of >2 years was computed within each group of diagnosis years. A multivariate logistic regression model was then fit to determine the association between year of diagnosis and probability of surviving >2 years after adjusting for important prognostic factors. RESULTS: 22,601 patients were identified, of whom 9,435 (41.7%) had an overall survival of >2 years. The probability of breast cancer-specific survival (BCSS) of >2 years was 40.1, 44, and 48.1% among patients diagnosed in the periods 1990-1995, 1996-2000, and 2001-2007, respectively (p < 0.001). In the multivariate model, the probability of BCSS of >2 years increased with the more recent year of diagnosis (OR 1.058, 95% CI 1.046-1.069, p < 0.001). Other factors significantly associated with an increased probability of surviving >2 years included surgery of the primary tumor, lower grade, younger age, hormone receptor-positive disease, and noninflammatory disease. CONCLUSION: Our results indicate that among the patients with synchronous stage IV breast cancer, the probability of BCSS of >2 years in the US has increased over time. Attributable factors may be the increasing number of efficacious agents and improved palliative care services over time.

Pertuzumab: a new anti-HER2 drug in the management of women with breast cancer.

Pertuzumab is a humanized monoclonal antibody targeting HER2 that is different from trastuzumab in that it binds to a different domain of HER2; hence, combining the two drugs leads to a more comprehensive blockade of the receptor. This is the first drug to receive fast-track approval from US FDA based on the pathologic complete response (as the primary end point) attained in patients treated with neoadjuvant chemotherapy for breast cancer. Pertuzumab is approved in first-line treatment in metastatic setting both by FDA and EMA in combination with trastuzumab and docetaxel. Combining two targeted therapies ('dual blockade') will certainly escalate treatment costs and it remains to be seen if this strategy will find its way in to the clinic for all patients.

Buparlisib in breast cancer.

Buparlisib (formerly BKM 120), an oral 2,6-dimorpholino pyrimidine derivative is a potent pan-PI3K inhibitor causing inhibition of PI3K downstream signaling including downregulation of p-Akt and p-S6R and apoptosis of cancer cells. Buparlisib is rapidly absorbed, has more than 90% bioavailability, good blood-brain barrier penetration and half-life of 40 h. Phase I trials have shown good disease control rate with tolerable toxicity profile at the recommended doses of 100 mg. The most common adverse events noted with buparlisib are rash, hyperglycemia, derangement of liver functions and psychiatric events. Several clinical trials with buparlisib alone or in combination with chemotherapy and targeted therapies are underway. Buparlisib has not yet been approved for regular use. Further randomized trials are required before buparlisib is approved for treatment of breast cancer.

Use of gemcitabine-platinum in Indian patients with advanced gall bladder cancer.

BACKGROUND: Gemcitabine-platinum (Gem-P) is the current standard for patients with advanced gall bladder cancer. MATERIALS & METHODS: This is retrospective analysis of a prospectively maintained database of 210 patients with advanced gall bladder cancer treated with Gem-P between January 2012 and September 2013. RESULTS: Median age was 53 years, 65.2% females. In total,158 patients had metastatic and 52 had locoregional disease. Median number of cycles was 5 (1-12). At a median follow-up of 10 months, median overall survival/progression-free survival was 10/5 months, respectively. On multivariate analysis, patients who underwent prior surgery for primary and locoregional disease had a significantly better progression-free survival and those with locoregional disease had a significantly better overall survival. A total of 45.7% received second-line chemotherapy. CONCLUSION: Use of Gem-P in Indian patients leads to slightly worse outcomes suggesting an aggressive biology.

Cancer stem cells: implications for cancer therapy.

The survival of patients with cancer has improved significantly, primarily because of multidisciplinary care, improved chemotherapeutic agents in both the adjuvant and metastatic settings, the introduction of targeted biologic agents, and the incorporation of palliative care services into the management scheme. However, despite these advances, a significant proportion of patients continue to experience recurrence after adjuvant treatment, and survival associated with stage IV solid tumors still remains low. A primary or acquired resistance to chemotherapeutic and biologic agents is responsible for the failure of many of the agents used to treat patients with a malignancy. This can be explained by the presence of intratumoral heterogeneity and the molecular complexity of many cancers. Factors contributing to intratumoral heterogeneity include genetic mutations, interactions with the microenvironment-and the presence of cancer stem cells. Cancer stem cells have been identified in a number of solid tumors, including breast cancer, brain tumors, lung cancer, colon cancer, and melanoma. Cancer stem cells have the capacity to self-renew, to give rise to progeny that are different from them, and to utilize common signaling pathways. Cancer stem cells may be the source of all the tumor cells present in a malignant tumor, the reason for the resistance to the chemotherapeutic agent used to treat the malignant tumor, and the source of cells that give rise to distant metastases. This review will focus on properties of cancer stem cells; will compare and contrast the cancer stem cell model with the clonal evolution model of tumorigenesis; will discuss the role of cancer stem cells in the development of resistance to chemotherapy; and will review the therapeutic implications and challenges of targeting cancer stem cells, with an assessment of the potential such an approach holds for improving outcomes for patients with cancer.

Comprehensive molecular profiling identifies actionable biomarkers for patients from Thailand and the United Arab Emirates with advanced malignancies.

Background: Comprehensive molecular profiling of tissue samples that can help guide therapy management is not widely available across the globe. Methods: Comprehensive molecular profiling through Caris Molecular Intelligence involves the analysis of DNA through next-generation sequencing, chromogenic or fluorescent in situ hybridization, pyrosequencing, and copy number alterations; RNA through whole-transcriptome sequencing and multiplex PCR of RNA; and protein through immunohistochemistry. Results: Here we describe the experience of molecular profiling of tumor tissue samples from patients diagnosed with advanced solid tumors and treated in two countries, the United Arab Emirates and Thailand. Tumor cancer cases submitted to Caris Life Sciences (Phoenix, Arizona, USA) for molecular profiling from the UAE and Thailand were retrospectively analyzed (data accessed between 2019 and 2020) for their molecular alterations and clinical biomarkers, without regard to ethnicity. A total of 451 samples from 35 distinct types of advanced cancers were examined for mutations, amplifications, overexpression, exon copy number alterations, microsatellite instability, deficient mismatch repair, tumor mutational burden, and fusions. Interrogating each step of the biological pathway, from DNA to RNA to distinct protein, identified an alteration with an associated therapy for 75% of these tumor samples. The most common alterations identified included elevated PDL-1 that can be targeted with an immune checkpoint inhibitors and amplification of HER2 for which a variety of anti HER2 therapies are available. Conclusion: Comprehensive molecular profiling in patients with advanced malignancies can help optimize therapeutic management allowing for improved prognostic outcome.

Utilization of tissue-free minimal residual disease testing in colorectal cancer patients from Asia and Middle East.

Introduction: The presence of minimal residual disease (MRD) after curative-intent surgery for early-stage cancers is associated with disease recurrence. Circulating tumour deoxyribonucleic acid (ctDNA) has emerged as a promising biomarker for MRD assessment in patients with colorectal cancer (CRC) who have undergone surgery or completed adjuvant therapy. MRD tests are already available for use in clinics; however, treatment decisions following MRD results obtained in routine practice are infrequently described. Methods: In this observational study, we report on the real-world clinical use of Guardant Reveal, a validated tissue-free MRD assay, in the first 215 consecutive patients (279 samples) with CRC tested in Asia and the Middle East. Results: Overall, 22% of patients had ctDNA detected in their first MRD test, and the frequency of ctDNA positivity increased with increasing tumour stage. 132 samples were tested with an earlier version of Guardant Reveal, one that assessed both genomic and epigenomic features. An updated version of the assay assesses only ctDNA methylation data and was used for the remaining 147 samples. In patients with stage II CRC, 71% of tests were ordered within 12 weeks after tumour resection, while for patients with stage III disease, 69% of tests were ordered after completion of all curative-intent treatment. Discussion: Clinical cases utilizing tissue-free MRD assessment are described.

Discordance in Recommendation Between Next-Generation Sequencing Test Reports and Molecular Tumor Boards in India.

PURPOSE: Accurate understanding of the genomic and transcriptomic data provided by next-generation sequencing (NGS) is essential for the effective utilization of precision oncology. Molecular tumor boards (MTBs) aim to translate the complex data in NGS reports into effective clinical interventions. Often, MTB treatment recommendations differ from those in the NGS reports. In this study, we analyze the discordance between these recommendations and the rationales behind the discordances, in a non-high-income setting, with international input to evaluate the necessity of MTB in clinical practice. METHODS: We collated data from MTB that were virtually hosted in Chennai, India. We included patients with malignancies who had NGS reports on solid tissue or liquid biopsies, and excluded those with incomplete data. MTB forms and NGS reports of each clinical case were analyzed and evaluated for recommendation concordance. Concordance was defined as an agreement between the first recommendation in the MTB forms and the therapeutic recommendations suggested in the NGS report. Discordance was the absence of the said agreement. The rationales for discordance were identified and documented. RESULTS: Seventy MTB reports were analyzed with 49 cases meeting the inclusion criteria. The recommendation discordance was 49% (24 of 49). Discordant recommendations were mainly due to low level of evidence for the drug (75% of cases). CONCLUSION: The discordance between MTB and NGS vendor recommendations highlights the clinical utility of MTB. The educational experiences provided by this initiative are an example of how virtual academic collaborations can enhance patient care and provider education across geographic borders.

Progress in the biological understanding and management of breast cancer-associated central nervous system metastases.

Metastasis to the central nervous system (CNS) is a devastating neurological complication of systemic cancer. Brain metastases from breast cancer have been documented to occur in approximately 10%-16% of cases over the natural course of the disease with leptomeningeal metastases occurring in approximately 2%-5% of cases of breast cancer. CNS metastases among women with breast cancer tend to occur among those who are younger, have larger tumors, and have a more aggressive histological subtype such as the triple negative and HER2-positive subtypes. Treatment of CNS metastases involves various combinations of whole brain radiation therapy, surgery, stereotactic radiosurgery, and chemotherapy. We will discuss the progress made in the treatment and prevention of breast cancer-associated CNS metastases and will delve into the biological underpinnings of CNS metastases including evaluating the role of breast tumor subtype on the incidence, natural history, prognostic outcome, and impact of therapeutic efficacy.

Entrectinib for NTRK Fusion-Positive Metastatic Melanoma Progressing on Combined PD-1 and CTLA-4 Inhibition: A Case Report.

Introduction: The burden of melanoma is increasing globally. Despite the use of immunotherapy and targeted therapy, the prognosis of metastatic melanoma remains relatively poor. The integration of comprehensive molecular profiling can lead to the detection of actionable biomarkers and the expansion of treatment options, thereby prolonging cancer patient survival. Case Presentation: We herein present the case of a female 54-year-old patient diagnosed with melanoma of the right knee, for which she underwent surgery. Patient showed progression of disease after 10 cycles of adjuvant nivolumab. Ipilimumab (1 mg/kg every 3 weeks) was added to the treatment regimen but no clinical improvement was observed. Molecular profiling was conducted based on patient tissue, and an ANXA2-NTRK3 fusion was detected in the tumor. This specific fusion has not been previously reported; however, it is in-frame and similar to other known oncogenic NTRK fusions. At the time of entrectinib initiation, the patient had clear disease progression on the right leg on standard of care immunotherapy. She was commenced on entrectinib 200 mg once daily for 2 weeks. Dose escalation was attempted, and treatment intensity was managed based on drug tolerability. Good treatment response was observed on laboratory and radiologic parameters. As of September 2023, i.e., 2.5 years after treatment initiation, patient disease continues to be controlled with entrectinib. Conclusion: Profiling of advanced tumors is important to determine the presence of agnostic markers that can be targeted and ultimately improve the prognostic outcome of patients after the failure of standard of care.

Indirect Treatment Comparison of First-Line CDK4/6-Inhibitors in Post-Menopausal Patients with HR+/HER2- Metastatic Breast Cancer.

Background: CDK4/6-inhibitors have demonstrated similar efficacy and are considered an effective first-line endocrine treatment of patients with hormone-receptor positive (HR+)/human-epidermal-growth-factor-receptor-2 negative (HER2-) metastatic breast cancer (MBC) in the endpoint of progression-free survival (PFS). Amongst these, palbociclib was first to achieve regulatory approval, followed subsequently by ribociclib and abemaciclib. However, recent updates of overall survival (OS) showed inconsistencies in the OS benefit for palbociclib compared with the other two CDK4/6-inhibitors. With the lack of head-to-head comparison studies, our study sought to compare indirect survival outcomes between CDK4/6-inhibitors in this setting using a novel reconstructive algorithm. Methods: Phase III randomized trials comparing first-line aromatase inhibitor with/without a CDK4/6-inhibitor in post-menopausal patients with HR+/HER2- MBC were identified through systemic review and literature search of online archives of published manuscripts and conference proceedings. A graphical reconstructive algorithm was utilized to retrieve time-to-event data from reported Kaplan-Meier OS and PFS plots to allow for comparison of survival outcomes. Survival analyses were conducted with Cox proportional-hazards model with a shared-frailty term. Results: Three randomized phase III trials-PALOMA-2, MONALEESA-2 and MONARCH-3-comprising 1827 patients were included. Indirect pairwise comparisons of all CDK4/6-inhibitors showed no significant PFS differences (all p > 0.05). Likewise, indirect treatment comparison between ribociclib vs. palbociclib (one-stage: HR = 0.903, 95%-CI: 0.746-1.094, p = 0.297), abemaciclib vs. palbociclib (one-stage: HR = 0.843, 95%-CI: 0.690-1.030, p = 0.094) and abemaciclib vs. ribociclib (one-stage: HR = 0.933, 95%-CI: 0.753-1.157, p = 0.528) failed to demonstrate a significant OS difference. Conclusions: Findings from this indirect treatment comparison suggest no significant PFS or OS differences between CDK4/6-inhibitors in post-menopausal patients with HR+/HER2- MBC.

Incidence of brain metastases as a first site of recurrence among women with triple receptor-negative breast cancer.

BACKGROUND: This retrospective study sought to define the incidence of brain metastases as a first site of recurrence among women with triple receptor-negative breast cancer (TNBC). METHODS: A total of 2448 patients with stage I through III TNBC who were diagnosed between 1990 and 2010 were identified. We computed the cumulative incidence of developing brain metastases as a first site of recurrence at 2 and 5 years. Cox proportional hazards models were fitted to determine factors that could predict for the development of brain metastases as a first site of recurrence. The Kaplan-Meier product limit method was used to compute survival following a diagnosis of brain metastases. RESULTS: At a median follow-up of 39 months, 115 (4.7%) patients had developed brain metastases as a first site of recurrence. The cumulative incidence at 2 and 5 years was 3.7% (95% confidence interval [CI] = 2.9%-4.5%) and 5.4% (95% CI = 4.4%-6.5%), respectively. Among patients with stage I, II, and III disease, the 2-year cumulative incidence of brain metastases was 0.8%, 3.1%, and 8%, respectively (P < .0001). The 5-year cumulative incidence was 2.8%, 4.6%, and 9.6% among patients with stage I, II, and III disease, respectively (P < .0001). In the multivariable model, patients with stage III disease had a significant increase in the risk of developing brain metastases as a first site of recurrence (hazards ratio = 3.51; 95% CI = 1.85-6.67; P = .0001) compared to patients with stage I disease. Those with stage II disease had a nonsignificant increased risk of developing brain metastases as a first site of recurrence (hazards ratio = 1.61; 95% CI = 0.92-2.81; P = .10) compared with patients with stage I disease. Median survival following a diagnosis of brain metastases was 7.2 months (range, 5.7-9.4 months). CONCLUSIONS: Patients with nonmetastatic TNBC have a high early incidence of developing brain metastases as a first site of recurrence, which is associated with subsequent poor survival. Patients with stage III TNBC in particular would be an ideal cohort in which to research preventive strategies.

The use of bevacizumab among women with metastatic breast cancer: a survey on clinical practice and the ongoing controversy.

BACKGROUND: The US Food and Drug Administration's (FDA's) recent decision to remove the indication of bevacizumab for metastatic breast cancer (MBC) has fueled a debate in the breast cancer community. We conducted a survey to assess the perception of health care workers involved in the management of women with MBC on the FDA's decision to ascertain how it will affect practice and to determine how bevacizumab is commonly used in the community for MBC. METHODS: E-mails were sent out between September and November 2010 using a database of 3000 addresses maintained by the United Arab Emirates Cancer Congress. Individuals working for Roche or Genentech were excluded. The survey consisted of 22 questions that were divided into 3 parts addressing each participant's demographic profile, their opinion of the FDA's decision, and the typical use of bevacizumab in the community in the setting of MBC. RESULTS: A total of 564 participants were included in the final analysis, contributing to an 18.8% response rate. Of these participants, 14.6% were from the United States, 7.8% were from Canada, 31.1% were from Europe, 2.0% were from the United Arab Emirates, 11.1% were from Asia, and 33.3% were from other countries. The majority of participants believed progression-free survival to be a surrogate for overall survival, that cost played a role in the FDA's decision, and that the decision would adversely affect the future of newer drugs currently being investigated for MBC. The majority of participants indicated that they would use bevacizumab for triple receptor-negative MBC (46.5%), would use it in a first-line setting (44.7%), and would use it in combination with paclitaxel (51.9%). CONCLUSION: Our survey results highlight the discord between the opinion of community oncologists and the FDA's recent decision to withdraw the indication of bevacizumab for MBC.

Hormone receptor status influences the locoregional benefit of trastuzumab in patients with nonmetastatic breast cancer.

BACKGROUND: Previous studies have shown that hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status influence the outcome of locoregional treatments. However, the interrelationship of these factors with trastuzumab is unclear. In this study, the role of HR and HER2 status on the locoregional benefit of trastuzumab treatment was investigated in patients with nonmetastatic breast cancer. METHODS: Locoregional outcomes of 5683 women treated at The University of Texas MD Anderson Cancer Center from 2000 to 2008 for invasive breast cancer were analyzed using Kaplan-Meier and Cox regression methods to compare 6 subgroups: HR-positive (HR+)/HER2-negative (HER2-), HR-/HER2- (triple-negative), HR+/HER2+ with or without trastuzumab, and HR-/HER2+ with or without trastuzumab. RESULTS: Overall, locoregional recurrence (LRR) was 5% at 5 years among patients with HER2+ disease. Patients with HR+/HER2+ disease treated with trastuzumab had half the rate of LRR as patients who did not receive trastuzumab, whereas patients with HR-/HER2+ disease had similar rates of LRR regardless of trastuzumab treatment. On Cox regression analysis comparing LRR risk to the cohort with HR+/HER2- disease, only the HR+/HER2+ cohort treated with trastuzumab had similar LRR risk (hazard ratio = 1.24, 95% confidence interval = 0.56-2.73, P = .591). All other subgroups, including the HR+/HER2+ cohort who did not receive trastuzumab, had significantly worse outcomes. LRR risk was highest among patients with triple-negative disease (hazard ratio = 4.73, 95% confidence interval = 3.42-6.54, P < .001). CONCLUSIONS: Among patients with HR+/HER2+ disease, treatment with trastuzumab reduces LRR risk to the more favorable outcome of patients with HR+/HER2- disease. In contrast, the increased LRR risk among patients with HR-/HER2+ disease remains despite treatment with trastuzumab. Additional locoregional strategies are needed in this subgroup of patients.

Defining breast cancer prognosis based on molecular phenotypes: results from a large cohort study.

The objective of this study is to define the survival outcomes associated with distinct molecular phenotypes defined by immunohistochemical staining of paraffin-embedded tissues among invasive breast cancer cases identified from the Nurses' Health Study (NHS). Tissue microarrays were constructed from archived tissue blocks of women diagnosed with breast cancer in the NHS (1976-1997). Invasive non-metastatic breast cancer tumors (n = 1,945) were classified into 1 of 5 molecular phenotypes based on immunohistochemistry assays for estrogen receptor (ER), progesterone receptor (PR), HER2, cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR) and grade. Survival outcomes were estimated using the Kaplan-Meier product limit method. Cox-proportional hazards models were fitted to determine the association of molecular phenotype with survival outcomes after adjusting for covariates. 1,279 (65.8%) tumors were classified as luminal A, 279 (14.3%) as luminal B, 95 (4.9%) as HER2 type, 203 (10.4%) as basal-like and 89 (4.6%) tumors were unclassified. The 5-year breast cancer-specific survival estimates for women with luminal A, luminal B, HER2-type, basal-like and unclassified tumors were 96, 88, 81, 89 and 85%, respectively. In the multivariable model, compared to cases with luminal A tumors, cases with luminal B (HR 1.90, 95% CI 1.33-2.71), HER2-type (HR 1.36, 95% CI 0.87-2.12), basal-like (HR 1.58, 95% CI 1.05-2.39) and unclassified (HR 1.38, 95% CI 0.87-2.20) tumors had higher hazard of breast cancer death. Similar trends were observed for both overall and recurrence-free survival. In conclusion, compared to women who have luminal A tumors those with luminal B, HER2-type, basal-like and unclassified tumors had a worse prognosis, when tumor subtype was defined by immunohistochemistry. This method may provide a cost-effective means of determining prognosis in the clinical setting.