Systemic Treatment of Patients With Metastatic Breast Cancer: ASCO Resource-Stratified Guideline.

PURPOSE: To guide clinicians and policymakers in three global resource-constrained settings on treating patients with metastatic breast cancer (MBC) when Maximal setting-guideline recommended treatment is unavailable. METHODS: A multidisciplinary, multinational panel reviewed existing ASCO guidelines and conducted modified ADAPTE and formal consensus processes. RESULTS: Four published resource-agnostic guidelines were adapted for resource-constrained settings; informing two rounds of formal consensus; recommendations received ≥75% agreement. RECOMMENDATIONS: Clinicians should recommend treatment according to menopausal status, pathological and biomarker features when quality results are available. In first-line, for hormone receptor (HR)-positive MBC, when a non-steroidal aromatase inhibitor and CDK 4/6 inhibitor combination is unavailable, use hormonal therapy alone. For life-threatening disease, use single-agent chemotherapy or surgery for local control. For premenopausal patients, use ovarian suppression or ablation plus hormone therapy in Basic settings. For human epidermal growth factor receptor 2 (HER2)-positive MBC, if trastuzumab, pertuzumab, and chemotherapy are unavailable, use trastuzumab and chemotherapy; if unavailable, use chemotherapy. For HER2-positive, HR-positive MBC, use standard first-line therapy, or endocrine therapy if contraindications. For triple-negative MBC with unknown PD-L1 status, or if PD-L1-positive and immunotherapy unavailable, use single-agent chemotherapy. For germline BRCA1/2 mutation-positive MBC, if poly(ADP-ribose) polymerase inhibitor is unavailable, use hormonal therapy (HR-positive MBC) and chemotherapy (HR-negative MBC). In second-line, for HR-positive MBC, Enhanced setting recommendations depend on prior treatment; for Limited, use tamoxifen or chemotherapy. For HER2-positive MBC, if trastuzumab deruxtecan is unavailable, use trastuzumab emtansine; if unavailable, capecitabine and lapatinib; if unavailable, trastuzumab and/or chemotherapy (hormonal therapy alone for HR-positive MBC).Additional information is available at www.asco.org/resource-stratified-guidelines. It is ASCO's view that healthcare providers and system decision-makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines.

Pyrimidine-chloroquinoline hybrids: Synthesis and antiplasmodial activity.

Triazole tethered 7-chloroquinoline-pyrimidine-5-carboxylate hybrids were synthesized and evaluated for antiplasmodial activity against chloroquine sensitive (CQS) NF54 strain of Plasmodium falciparum. The most active hybrids of the series were further screened against the chloroquine resistant (CQR) Dd2 strain of the parasite and for in vitro cytotoxicity against mammalian Vero cell lines. Further, their physico-chemical properties, binding studies with hemin (monomeric &µ-oxo dimeric) and DNA [pUC-18, calf thymus (CT)] led us to plausible proposed binding mode of the most active member of the present series.

Improving Access to Cancer Treatments: The Role of Biosimilars.

Biologics play a key role in cancer treatment and are principal components of many therapeutic regimens. However, they require complex manufacturing processes, resulting in high cost and occasional shortages in supply. The cost of biologics limits accessibility of cancer treatment for many patients. Effective and affordable cancer therapies are needed globally, more so in developing countries, where health care resources can be limited. Biosimilars, which have biologic activity comparable to their corresponding reference drugs and are often more cost effective, have the potential to enhance treatment accessibility for patients and provide alternatives for decision makers (ie, prescribers, regulators, payers, policymakers, and drug developers). Impending patent expirations of several oncology biologics have opened up a vista for the development of corresponding biosimilars. Several countries have implemented abbreviated pathways for approval of biosimilars; however, challenges to their effective use persist. Some of these include designing appropriate clinical trials for assessing biosimilarity, extrapolation of indications, immunogenicity, interchangeability with the reference drug, lack of awareness and possibly acceptance among health care providers, and potential political barriers. In this review, we discuss the potential role and impact of biosimilars in oncology and the challenges related to their adoption and use. We also review the safety and efficacy of some of the widely used biosimilars in oncology and other therapeutic areas (eg, bevacizumab, darbepoetin, filgrastim, rituximab, and trastuzumab).

A Randomized Noninferiority Trial of Intravenous Iron Isomaltoside versus Oral Iron Sulfate in Patients with Nonmyeloid Malignancies and Anemia Receiving Chemotherapy: The PROFOUND Trial.

STUDY OBJECTIVE: A safe alternative to erythropoiesis-stimulating agents to treat anemia is warranted in patients with cancer and anemia; thus the objective of this trial was to compare the efficacy and safety of intravenous (IV) iron isomaltoside with oral iron in patients with cancer and anemia by testing the noninferiority of IV versus oral iron. DESIGN: Phase III, prospective, open-label, comparative, randomized, noninferiority, multicenter trial. SETTING: Forty-seven hospitals or private cancer clinics in Asia, the United States, and Europe. PATIENTS: A total of 350 patients with cancer and anemia. INTERVENTION: Patients were randomized in a 2:1 ratio to either intravenous iron isomaltoside or oral iron sulfate. Patients in the iron isomaltoside group were then randomized into an infusion subgroup (single intravenous infusions of a maximum dose of 1000 mg over 15 min) or a bolus injection subgroup (bolus injections of 500 mg over 2 min). MEASUREMENTS AND MAIN RESULTS: The primary efficacy outcome was change in hemoglobin concentration from baseline to week 4. Changes in other relevant hematology variables, effect on quality of life, and safety outcomes were also assessed. The primary efficacy outcome was tested for noninferiority, whereas the remaining outcomes were tested for superiority. Iron isomaltoside was noninferior to oral iron in change in hemoglobin concentration from baseline to week 4 (difference estimate 0.016, 95% confidence interval -0.26 to 0.29, p<0.001). A faster onset of the hemoglobin response was observed with infusion of iron isomaltoside (superiority test: p=0.03 at week 1), and a sustained effect on hemoglobin level was shown in both the iron isomaltoside and oral iron treatment groups until week 24. A significant mean decrease in fatigue score was observed from baseline to week 12 in the iron isomaltoside group (p<0.001) but not in the oral iron group (p=0.057). A higher proportion of patients treated with oral iron experienced adverse drug reactions (18.8% vs 6.6%, p<0.001) and discontinued the trial due to intolerance (8.0% vs 0.9%, p=0.001). Transient hypophosphatemia (phosphate level less than 2 mg/dl) was reported at similar low frequencies among the groups: 7.1% in the iron isomaltoside infusion subgroup versus 8.5% in the iron isomaltoside bolus injection subgroup versus 5.4% in the oral iron group. CONCLUSION: This trial demonstrated comparable sustained increases in hemoglobin concentration over time with both iron isomaltoside and oral iron. Iron isomaltoside was better tolerated than oral iron, and fatigue was significantly decreased with iron isomaltoside. Low rates of clinically insignificant hypophosphatemia were reported in patients receiving both treatments.

A probe with aggregation induced emission characteristics for screening of iodide.

The dilution controlled aggregation enhanced emission of spherically aggregated form of a triazole based probe dies down upon detecting iodide over other inorganic anions. The sensing is realised as a dynamic quenching mechanism dominated event. Being highly selective for iodide, the probe finds application in the detection of iodide in human urine.

Ferrocene-pyrimidine conjugates: Synthesis, electrochemistry, physicochemical properties and antiplasmodial activities.

The promise of hybrid antimalarial agents and the precedence set by the antimalarial drug ferroquine prompted us to design ferrocene-pyrimidine conjugates. Herein, we report the synthesis, electrochemistry and anti-plasmodial evaluation of ferrocenyl-pyrimidine conjugates against chloroquine susceptible NF54 strain of the malaria parasite Plasmodium falciparum. Also their physicochemical properties have been studied.

Pyrene-based chemosens or detects picric acid upto attogram level through aggregation enhanced excimer emission.

A pyrene-based small molecular weight probe, exhibiting aggregation enhanced excimer emission has been synthesized. The crystalline emissive form detects 2,4,6-trinitrophenol (picric acid) at parts-per-billion concentration in solution and as low as 0.46 attogram in direct contact mode, operating predominantly in a static quenching mechanism, proposed on the basis of steady state and life-time fluorescence measurements.

Validation of a method to establish practice-based stroke and TIA registers.

This study compares two methods to establish stroke and transient ischaemic attack (TIA) practice-based registers, which are of particular relevance to practices with limited diagnostic coding. Both arms involved a notes review of all patients taking antiplatelets or anticoagulants, and, either a further notes review of all patients with ischaemic heart disease (IHD) or diabetes (extensive arm), or asking about a history of stroke or TIA during IHD or diabetic clinics (pragmatic arm). The extensive arm involved searching 11% of the practice notes, whereas the pragmatic arm only involved 3% and had almost as high a yield. This study suggests that the pragmatic method could be used to help build practice-based stroke and TIA registers.

Treatment of breast cancer in countries with limited resources.

Early and accurate diagnosis of breast cancer is important for optimizing treatment. Local treatment of early stage breast cancer involves either mastectomy or breast-conserving surgery followed by whole-breast irradiation. The pathologic and biologic properties of a woman's breast cancer may be used to estimate her probability for recurrence of and death from breast cancer, as well as the magnitude of benefit she is likely to receive from adjuvant endocrine therapy or cytotoxic chemotherapy. Ovarian ablation or suppression with or without tamoxifen is an effective endocrine therapy in the adjuvant treatment of breast cancer in premenopausal women with estrogen receptor (ER)-positive or ER-unknown breast cancer. In postmenopausal women with ER- and/or progesterone receptor (PR)-positive or PR-unknown breast cancer, the use of tamoxifen or anastrozole is effective adjuvant endocrine therapy. The benefit of tamoxifen is additive to that of chemotherapy. Cytotoxic chemotherapy also improves recurrence rates and survival, with the magnitude of benefit decreasing with increasing age. Substantial support systems are required to optimally and safely use breast-conserving approaches to local therapy or cytotoxic chemotherapy as systemic therapy. Locally advanced breast cancer (LABC) accounts for at least half of all breast cancers in countries with limited resources and has a poor prognosis. Initial treatment of LABC with anthracycline-based chemotherapy is standard and effective. Addition of a sequential, neoadjuvant taxane thereafter increases the rate of pathologic complete responses. Neoadjuvant endocrine therapy may benefit postmenopausal women with hormone receptor-positive LABC. After an initial response to neoadjuvant chemotherapy, the use of local-regional surgery is appropriate. Most women will require a radical or modified radical mastectomy. In those women in whom mastectomy is not possible after neoadjuvant chemotherapy, the use of whole-breast and regional lymph node irradiation alone is appropriate. In those women who cannot receive neoadjuvant chemotherapy because of resource constraints, mastectomy with node dissection, when feasible, may still be considered in an attempt to achieve local-regional control. After local-regional therapy, most women should receive additional systemic chemotherapy. Women with LABC that has a positive or unknown hormone receptor status benefit from endocrine therapy with tamoxifen. The treatment of LABC requires multiple disciplines and is resource intensive. Efforts to reduce the number of breast cancers diagnosed at an advanced stage thus have the potential to improve rates of survival while decreasing the use of limited resources.

Diagnosis of breast cancer in countries with limited resources.

Accurate diagnosis is a necessary step in the management of breast cancer. In women with breast cancer, diagnosis can confirm the presence of the disease, reduce treatment delays, and clarify the predictive and prognostic features of the cancer, which help in planning treatment and counseling women. In women with benign breast conditions, accurate diagnosis avoids erroneous treatment for breast cancer, which can have devastating consequences for the woman and unnecessarily consumes resources. The panel distinguishes between a "clinical diagnosis" of breast cancer (one based on signs and symptoms and imaging findings) and a "pathologic diagnosis" of breast cancer (one based on microscopic examination of cellular or tissue samples). The panel agrees that all women should have a pathologic diagnosis of breast cancer before they are given definitive treatment for the disease, no matter how strongly their clinical findings suggest cancer. The tools for clinical diagnosis include history, clinical breast examination, ultrasound, and diagnostic mammography; these tools provide valuable information and play important supplemental roles in ascertaining the presence of breast cancer. Mammography and ultrasound also help determine the extent of disease within the breast, which is essential when breast-conserving therapy can be offered to women. The tools for pathologic diagnosis include fine-needle aspiration biopsy, core needle biopsy, and standard surgical biopsy. The panel noted that each of these tools has potential benefits and limitations in the limited-resource setting, and concluded that the choice among them must be based on the available tools and expertise. The triple test-checking for correlation of pathology findings, imaging findings, and clinical findings-was identified as a critical practice in diagnosing breast cancer. Panelists uniformly agreed that mastectomy should not be used to diagnose breast cancer, noting that accurate diagnosis can be made by less invasive means. Expertise in pathology was identified as a key requirement for ensuring reliable diagnostic findings. Several approaches were proposed for improving breast pathology, including training pathologists, establishing pathology services in centralized facilities, and organizing international pathology services.