BACKGROUND
Among breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these "HER2-low" cancers.


METHODS
We conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor-positive cohort. The key secondary end points were progression-free survival among all patients and overall survival in the hormone receptor-positive cohort and among all patients.


RESULTS
Of 557 patients who underwent randomization, 494 (88.7%) had hormone receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease. In the hormone receptor-positive cohort, the median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician's choice group (hazard ratio for disease progression or death, 0.51; P<0.001), and overall survival was 23.9 months and 17.5 months, respectively (hazard ratio for death, 0.64; P = 0.003). Among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician's choice group (hazard ratio for disease progression or death, 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P = 0.001). Adverse events of grade 3 or higher occurred in 52.6% of the patients who received trastuzumab deruxtecan and 67.4% of those who received the physician's choice of chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events.


CONCLUSIONS
In this trial involving patients with HER2-low metastatic breast cancer, trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician's choice of chemotherapy. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast04 ClinicalTrials.gov number, NCT03734029.).

/pdf/trastuzumab-deruxtecan-in-previously-treated-her2-low-bgcyevnl.pdf

Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer.

The long-sought discovery of HER2 as an actionable and highly sensitive therapeutic target was a major breakthrough for the treatment of highly aggressive HER2-positive breast cancer, leading to approval of the first HER2-targeted drug - the monoclonal antibody trastuzumab - almost 25 years ago. Since then, progress has been swift and the impressive clinical activity across multiple trials with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates that target HER2 has spawned extensive efforts to develop newer platforms and more targeted therapies. This Review discusses the current standards of care for HER2-positive breast cancer, mechanisms of resistance to HER2-targeted therapy and new therapeutic approaches and agents, including strategies to harness the immune system. 

/pdf/targeting-her2-positive-breast-cancer-advances-and-future-3uipodp4.pdf

Targeting HER2-positive breast cancer: advances and future directions

/pdf/trastuzumab-deruxtecan-versus-trastuzumab-emtansine-in-2529rp3w.pdf

Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial

PURPOSE
Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)-directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and HER2-mutant non-small cell lung cancer. Treatments are limited for other HER2-expressing solid tumors.


PATIENTS AND METHODS
This open-label phase II study evaluated T-DXd (5.4 mg/kg Q3W) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic treatment, or without alternative treatments. Primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included safety, duration of response (DOR), progression-free (PFS), and overall survival (OS).


RESULTS
primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. Median follow-up was 12.75 months. In all patients: ORR, 37.1% (n=99; 95% CI, 31.3-43.2) with responses in all cohorts; median DOR, 11.3 months (95% CI, 9.6-17.8); median PFS, 6.9 months (95% CI, 5.6-8.0); median OS, 13.4 months (95% CI, 11.9-15.5). In patients with central HER2 IHC 3+ expression (n=75): ORR, 61.3% (95% CI, 49.4-72.4); median DOR, 22.1 months (95% CI, 9.6-not reached); median PFS, 11.9 months (95% CI, 8.2-13.0); median OS, 21.1 months (95% CI, 15.3-29.6). Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths.


CONCLUSION
Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pre-treated patients with HER2-expressing tumors receiving T-DXd. Greatest benefit was observed for the IHC 3+ population. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with HER2-expressing solid tumors.

Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial.

BACKGROUND
An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine.


METHODS
This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0-1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5·4 mg/kg or trastuzumab emtansine 3·6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03529110.


FINDINGS
Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab deruxtecan (n=261) or trastuzumab emtansine (n=263). Median duration of study follow-up was 28·4 months (IQR 22·1-32·9) with trastuzumab deruxtecan and 26·5 months (14·5-31·3) with trastuzumab emtansine. Median progression-free survival by blinded independent central review was 28·8 months (95% CI 22·4-37·9) with trastuzumab deruxtecan and 6·8 months (5·6-8·2) with trastuzumab emtansine (hazard ratio [HR] 0·33 [95% CI 0·26-0·43]; nominal p<0·0001). Median overall survival was not reached (95% CI 40·5 months-not estimable), with 72 (28%) overall survival events, in the trastuzumab deruxtecan group and was not reached (34·0 months-not estimable), with 97 (37%) overall survival events, in the trastuzumab emtansine group (HR 0·64; 95% CI 0·47-0·87]; p=0·0037). The number of grade 3 or worse treatment-emergent adverse events was similar in patients who received trastuzumab deruxtecan versus trastuzumab emtansine (145 [56%] patients versus 135 [52%] patients). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 39 (15%) patients treated with trastuzumab deruxtecan and eight (3%) patients treated with trastuzumab emtansine, with no grade 4 or 5 events in either group.


INTERPRETATION
Trastuzumab deruxtecan showed a significant improvement in overall survival versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming trastuzumab deruxtecan as the standard of care in the second-line setting. A manageable safety profile of trastuzumab deruxtecan was confirmed with longer treatment duration.


FUNDING
Daiichi Sankyo and AstraZeneca.

<h3>Introduction</h3> This pooled analysis of nine phase I and II trastuzumab deruxtecan (T-DXd) monotherapy studies described drug-related interstitial lung disease (ILD)/pneumonitis in patients treated with T-DXd. <h3>Methods</h3> Patients who received T-DXd across nine studies were included. Investigator-assessed ILD/pneumonitis events were retrospectively reviewed by an independent adjudication committee; events adjudicated as drug-related ILD/pneumonitis are summarized. <h3>Results</h3> The analysis included 1150 patients (breast cancer, 44.3%; gastric cancer, 25.6%; lung cancer, 17.7%; colorectal cancer, 9.3%; other cancer, 3.0%). Median treatment duration was 5.8 (range, 0.7-56.3) months, with a median of 4 (range, 1-27) prior lines of therapy. The overall incidence of adjudicated drug-related ILD/pneumonitis was 15.4% (grade 5, 2.2%). Most patients with ILD/pneumonitis experienced low-grade events (grade 1 or 2, 77.4%); 87.0% had their first event within 12 months [median, 5.4 (range, <0.1-46.8) months] of their first dose of T-DXd. Based on data review, adjudicated ILD/pneumonitis onset occurred earlier than identified by investigators for 53.2% of events [median difference in onset date, 43 (range, 1-499) days]. Stepwise Cox regression identified several baseline factors potentially associated with increased risk of adjudicated drug-related ILD/pneumonitis: age <65 years, enrollment in Japan, T-DXd dose >6.4 mg/kg, oxygen saturation <95%, moderate/severe renal impairment, presence of lung comorbidities, and time since initial diagnosis >4 years. <h3>Conclusions</h3> In this pooled analysis of heavily treated patients, the incidence of ILD/pneumonitis was 15.4%, with most being low grade and occurring in the first 12 months of treatment. The benefit–risk of T-DXd treatment is positive; however, some patients may be at increased risk of developing ILD/pneumonitis, and further investigation is needed to confirm ILD/pneumonitis risk factors. Close monitoring and proactive management of ILD/pneumonitis are warranted for all. 

Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies

is an important task in data mining and machine learning, in which a model is generated based on training dataset and that model is used to predict class label of unknown dataset. Various algorithms have been proposed to build accurate and scalable classifiers in data mining. These algorithms are only applied to single table. Today most real- world data are stored in relational format which is popular format for structured data which consist of tables connected via relations (primary key/ foreign key). So single table data mining algorithms cannot deal with relational data. To classify data from relational format need of multirelational classification arise which is used to analyze relational data and used to predict behaviour and unknown pattern automatically. For multirelational classification, various techniques are available which include upgrading existing algorithm, flatten relational data and multiple view approach. Multiple view approach learns from multiple views of a relational data and then combines the result of each view to classify unknown data. This paper presents proposed algorithm and experimental results for multiple view approach with voting as a view combination technique.

/pdf/relational-classification-using-multiple-view-approach-with-38m7zf88lm.pdf

Relational Classification using Multiple View Approach with Voting

Introduction: The first ever description of Diabetic Foot Ulcers (DFUs), made in the literature was in the mid-19th century. The management principles for it were laid by late 19th century and are still being followed. For a chronic DFU to heal, offloading of pressure, surgical debridement, correction of hyperglycaemia, the use of antibiotics are the corner stone of management. Offloading is an essential modality of prevention and treatment of recurrent plantar DFU. Aim: To compare offloading dressing to conventional dressing in promoting healing of diabetic plantar ulcers. Materials and Methods: This randomised clinical trial was conducted at Mahatma Gandhi Medical College and Research Institute, Pondicherry between January 2019 to June 2020 among the patients with DFU coming to the Department of General Surgery. A total of 44 patients were included in the study, 22 of these patients underwent offloading dressing and 22 underwent conventional dressing and these patients were followed-up for a duration of 6 weeks and compared on 2nd, 4th and 6th weeks. The patients were compared according to age, gender, duration of diabetes, glycaemic control, risk factors, previous surgery such as wound debridement or previous toe amputation, vascular assessment and site of ulcer, reduction in size of ulcer. The ulcers in both the groups were classified according to the Wagener’s grading of ulcer classification. All data collected was entered into Microsoft Excel 2016 and analysed using Statistical Package for the Social Sciences (SPSS) version 16.0 (IBM SPSS, US) software. A p-value less than 0.05 was considered as statistically significant. Results: Among 44 patients, there was equal number of males and females in both the groups, with the total mean age 53.97±10.10 years. The majority of the study population belonged to the 5th decade (51-60 years), where the youngest patient was of 29 years and oldest was of 72 years. There were 22 patients in offloading group and 24 patients in conventional dressing group as one patient had bilateral plantar ulcers and one patient had two separate ulcers on the plantar aspect of the foot. Total of 45.45% in conventional group and 31.82% of the study population in offloading group had diabetes for 5-10 years of duration. Bad glycaemic control was seen in 40.90% of offloading population and 50% in conventional population. The size reduction percentage of ulcers on comparing both the groups was found to be significant for 2nd week review (p-value=0.03) and was nearly significant for the 6th week review (p-value=0.05). Conclusion: Summarising the above conducted study, offloading dressing was found to be a more efficacious alternative to the conventional dressing as there was greater difference observed in the reduction of the size of ulcer and the patients in the conventional group needed more number of dressings and the duration of healing in the two groups.

Comparison of Offloading Dressing with Conventional Dressing in Healing of Plantar Diabetic Foot Ulcers: A Randomised Clinical Trial

Cysticercosis is a parasitic disease caused by Taenia solium. Central nervous system is the most common site of infestation. Other organs infested are subcutaneous tissue, eye, muscle, liver, and lung. Cysticercosis in muscle can occur in three forms: myalgic type, mass-like pseudotumor, and rarely pseudohypertrophic type. Solitary cysticercosis of muscle without involvement of the central nervous system is rare. In this case report, percutaneous-aspiration-injection-reaspiration (PAIR) has been used as a treatment option for isolated intramuscular cysticercosis of the anterior abdominal wall. Interventional radiological management along with medical management was done to observe complete resolution of the cyst.

PAIR as A Treatment Option for Isolated Intramuscular Cysticercosis: A Case Report

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Papers

Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies

Relational Classification using Multiple View Approach with Voting

Comparison of Offloading Dressing with Conventional Dressing in Healing of Plantar Diabetic Foot Ulcers: A Randomised Clinical Trial

PAIR as A Treatment Option for Isolated Intramuscular Cysticercosis: A Case Report