Natasha Woodward

Use of myocardial deformation imaging to detect preclinical myocardial dysfunction before conventional measures in patients undergoing breast cancer treatment with trastuzumab

BACKGROUND Trastuzumab prolongs survival in patients with human epidermal growth factor receptor type 2-positive breast cancer. Sequential left ventricular (LV) ejection fraction (EF) assessment has been mandated to detect myocardial dysfunction because of the risk of heart failure with this treatment. Myocardial deformation imaging is a sensitive means of detecting LV dysfunction, but this technique has not been evaluated in patients treated with trastuzumab. The aim of this study was to investigate whether changes in tissue deformation, assessed by myocardial strain and strain rate (SR), are able to identify LV dysfunction earlier than conventional echocardiographic measures in patients treated with trastuzumab. METHODS Sequential echocardiograms (n = 152) were performed in 35 female patients (51 +/- 8 years) undergoing trastuzumab therapy for human epidermal growth factor receptor type 2-positive breast cancer. Left ventricular EF was measured by 2- and 3-dimensional (2D and 3D) echocardiography, and myocardial deformation was assessed using tissue Doppler imaging and 2D-based (speckle-tracking) strain and SR. Change over time was compared every 3 months between baseline and 12 months. RESULTS There was no overall change in 3D-EF, 2D-EF, myocardial E-velocity, or strain. However, there were significant reductions seen in tissue Doppler imaging SR (P < .05), 2D-SR (P < .001), and 2D radial SR (P < .001). A drop > or =1 SD in 2D longitudinal SR was seen in 18 (51%) patients; 13 (37%) had a similar drop in radial SR. Of the 18 patients with reduced longitudinal SR, 3 had a concurrent reduction in EF > or =10%, and another 2 showed a reduction over 20 months follow-up. CONCLUSIONS Myocardial deformation identifies preclinical myocardial dysfunction earlier than conventional measures in women undergoing treatment with trastuzumab for breast cancer.

Cisplatin versus carboplatin: comparative review of therapeutic management in solid malignancies

The platinum analogues, cisplatin and carboplatin, are among the most widely used chemotherapeutic agents in oncology. Both agents have a broad spectrum of clinical activity in numerous malignancies including gynaecological cancers, germ cell tumours, head and neck cancer, thoracic cancers and bladder cancer. Although the final mechanism of inducing tumour cell apoptosis is similar for both compounds, cisplatin has been shown to be more effective in treating specific tumour types. Whilst more favourable toxicity profiles are often associated with carboplatin, this can frequently translate to inferior response in certain malignancies. This review succinctly collates the evidence for the preferential use of these platinum analogues in particular settings in addition to the long-standing dilemma surrounding the paucity of biomarkers predicting response to these agents.

Management of aromatase inhibitor induced musculoskeletal symptoms in postmenopausal early Breast cancer: A systematic review and meta-analysis

Aromatase Inhibitors (AI) are widely used for the adjuvant treatment of hormone receptor positive breast cancers in the post-menopausal population. AI are often associated with significant joint and muscular symptoms; symptoms that are commonly referred to as aromatase inhibitor-associated musculoskeletal syndrome (AIMSS). AIMSS adversely impacts health-related quality of life of many patients, and reduces AI compliance. Although there are informal practice recommendations, the limited current level of evidence for management of AIMSS for breast cancer patients on aromatase inhibitors has made development of formal guidelines challenging, and remains an unmet need. This is the first systematic review to consider the evidence for all pharmacological and non-pharmacological interventions in the treatment of AIMSS, including physical therapy, acupuncture and complementary therapies.

Hormone receptor positive, HER2 negative metastatic breast cancer: A systematic review of the current treatment landscape.

Endocrine therapy for the treatment of hormone receptor positive, HER2 negative, metastatic breast cancer is continually evolving. We systematically reviewed phase 2 and 3 randomized controlled trials (RCTs) of agents used in this setting to assess the effectiveness and safety of these agents for postmenopausal women. Across the 32 studies in more than 10 000 patients, the greatest improvement in progression‐free survival (PFS) was seen with the addition of a cyclin‐dependent kinase (CDK)4/6 inhibitor to standard endocrine therapy. Treatment with a mammalian target of rapamycin (mTOR) inhibitor, phosphoinositol‐3‐kinase (Pi3K) inhibitor, vascular endothelial growth factor (VEGF) inhibitor and with a selective estrogen receptor degrader (SERD) also showed benefit in PFS for selected trials. Overall survival (OS) improved with the use of mTOR inhibitors and a SERD; however, studies were not powered for an OS endpoint. Encouraging results from early studies of histone deacetylase (HDAC) and B‐cell lymphoma (BCL2) inhibitors are yet to be confirmed in phase III clinical trials. Study discontinuation rates and toxicity‐related deaths were highest with VEGF inhibitors in combination with endocrine therapy, limiting their use in hormone receptor positive breast cancer. CDK4/6 inhibitors and mTOR inhibitors appeared to have activity in both first and second line settings, but required additional monitoring for common toxicities. The activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors was limited to the first‐line setting and treatment discontinuation rates were higher than with mTOR inhibitors and SERDs. Overall, PFS benefit appears to be greatest when agents acting on CDK4/6, mTOR and Pi3K pathways, and SERDs are added to standard endocrine therapy. If these early results persist in further studies, these data are likely to change the way we treat hormone receptor positive, HER2 negative metastatic breast cancer. In the follow‐up article to this review, we will consider the potential future treatment options for these patients.

Maintaining Dose Intensity of Adjuvant Chemotherapy in Older Patients With Breast Cancer

Introduction Maintaining the relative dose intensity (RDI) of adjuvant chemotherapy at ≥ 85% has been associated with improved treatment outcomes in early‐stage breast cancer (ESBC). Increasing evidence has suggested that patients aged ≥ 65 years can maintain the optimal RDI for standard chemotherapy regimens. The present study investigated the RDI of newer adjuvant chemotherapy regimens in this demographic. Patients and Methods We retrospectively analyzed the data from 281 patients aged ≥ 65 years with a diagnosis of ESBC who had received adjuvant chemotherapy across 3 sites in Queensland, Australia from 2010 to 2015. The primary endpoint was the proportion of patients who had received an RDI of ≥ 85%. Results The median age at diagnosis was 68 years (range, 65‐85 years), with 36.3% aged > 70 years. The patient characteristics included tumor stage T3 or T4 in 17% and node‐positive disease in 60%. The common chemotherapy regimens included docetaxel/cyclophosphamide (23%), 5‐fluorouracil/epirubicin/cyclophosphamide plus docetaxel or paclitaxel (17%); Adriamycin/cyclophosphamide/weekly paclitaxel (38%); and docetaxel/carboplatin/trastuzumab (11%). Primary (15%) and secondary (54%) granulocyte colony‐stimulating factor (G‐CSF) was used. An RDI of ≥ 85% was achieved in 63% of the patients. Significant associations were noted between a reduced RDI and age ≥ 70 years (P < .001), Charlson comorbidity index ≥ 1 (P = .043), initial dose reductions (P = .01), secondary G‐CSF use (P = .45), hospital admission (P < .001), and febrile neutropenia (P = .007). Treatment‐related toxicities were the most common reason for noncompletion, with high rates of hospital admissions (46%) and febrile neutropenia (22%). Conclusion Our findings suggest that patients aged ≥ 65 years with ESBC can maintain an optimal RDI with modern chemotherapy regimens. Appropriate geriatric assessment and the use of supportive measures such as G‐CSF could better assist select groups to maintain an optimal dose intensity. Micro‐Abstract A suboptimal dose intensity of adjuvant chemotherapy has been associated with a poor prognosis in patients with early‐stage breast cancer. We investigated the relative dose intensity (RDI) of modern adjuvant chemotherapy regimens in patients aged ≥ 65 years. An RDI of ≥ 85% was achieved in 177 of 281 included patients (63%). Better supportive care of risk groups might further optimize the RDI.

Hormone receptor positive, HER2 negative metastatic breast cancer: Impact of CDK4/6 inhibitors on the current treatment paradigm

Resistance to endocrine therapy is a significant therapeutic challenge in the treatment of women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–) advanced breast cancer. Cyclin‐dependent kinase (CDK)4/6 inhibitors in combination with endocrine therapy have been shown to improve progression free survival, overall response rate and clinical benefit rate in women with HR+ HER2– metastatic breast cancer compared with endocrine therapy alone. This review examines the clinical evidence to support the use of CDK4/6 inhibitors in first and second line settings. Practical guidance is provided for the use of CDK4/6 inhibitors, including tolerability data, monitoring requirements and management of key toxicities for each of the available agents.

Emerging data and future directions for CDK4/6 inhibitor treatment of patients with hormone receptor positive HER2-non-amplified metastatic breast cancer

Cyclin‐dependent kinase (CDK4/6) inhibitors in combination with endocrine therapy are currently the optimal first line treatment for hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) non‐amplified metastatic breast cancer (MBC). However, not all patients benefit from this treatment and all patients will inevitably progress. Identifying therapeutic strategies in this setting is therefore of immediate clinical importance. We present an overview of the mechanisms of resistance to CDK4/6 inhibitors and review potential biomarkers that may guide therapy selection. We also discuss the use of CDK4/6 inhibitors in the context of non‐HR‐positive/HER2‐non‐amplified breast cancer and in combination with therapies other than endocrine therapy.

Absent progesterone receptor expression in the lymph node metastases of ER-positive, HER2-negative breast cancer is associated with relapse on tamoxifen

Aims Progesterone receptor (PR) expression is prognostic in early stage breast cancer. There are several reports of discordant expression between primary tumour and axillary lymph node (ALN) metastasis expression of oestrogen receptor (ER) and PR. We sought to determine whether expression of these biomarkers in the synchronous ALN metastases of ER positive (+), HER2 negative (−) breast cancer could provide more accurate prognostic information. Methods The retrospective cohort included 229 patients from a single institution with ER+, HER2− breast cancer who had synchronous ALN metastatic disease (2005–2014). PR expression was correlated with relapse-free survival, and subset analysis was performed for patients who received adjuvant tamoxifen or an aromatase inhibitor. Results One patient had an ER+ primary tumour, which was ER− in the ALN metastasis. 27 (11.3%) were PR− in the primary tumour and 56 (23.6%) in the ALN metastasis. The predominant change was from PR+ in the primary tumour to PR− in the lymph node. Absence of PR expression in the ALN was significantly associated with relapse; however, this was not the case in the primary tumour. In a subset analysis of patients taking adjuvant endocrine therapy, poorer prognosis was limited to those with PR− metastases on tamoxifen (HR=5.203, 95% CI 1.649 to 16.416, p=0.005). No significant prognostic effect of PR− metastases in patients taking aromatase inhibitors was seen (HR=1.519, 95% CI 0.675 to 3.418, p=0.312). Conclusions Evaluation of PR expression in ALN metastasis may enable prediction of patients who are less likely to benefit from adjuvant tamoxifen. This study should be replicated in other cohorts.

Abstract P4-21-31: Updated safety results from the first multicenter, open-label, phase IIIb study investigating the combination of pertuzumab with subcutaneous trastuzumab and a taxane in patients with HER2-positive metastatic breast cancer (SAPPHIRE)

Background: Pertuzumab targets the human epidermal growth factor receptor 2 (HER2) through an independent epitope to that of trastuzumab. Improved efficacy with acceptable toxicity has been shown, in metastatic breast cancer (mBC) for pertuzumab in combination with intravenous (IV) trastuzumab and docetaxel.1 This study aimed to assess the safety, tolerability and efficacy of combining IV pertuzumab with subcutaneous (SC) trastuzumab and a taxane, as 1st-line therapy in patients (pts) with HER2+ mBC. We present safety data with 19 months (mo) of median follow-up. Methods: SAPPHIRE (NCT02019277) is a multicentre, open-label, phase IIIb study. Primary objective: safety and tolerability of IV pertuzumab + SC trastuzumab and investigator9s choice of taxane. Pts ≥18 years with confirmed HER2+ mBC and ECOG PS 0-2 were included. The incidence and severity of adverse events (AEs), serious (S) AEs and AEs leading to premature discontinuation of study treatment were analyzed by taxane group. Results: 50 pts enrolled in the study. Taxanes of choice: nab-paclitaxel (NP; n=36), docetaxel (D; n=13) and paclitaxel (P; n=1). As of March 4th 2016, 34 pts had withdrawn from study; median follow-up= 19mo (range: 6-27). 28(56%) pts received >18 cycles of study medication. All patients experienced AEs with 326 AEs in the D group and 675 in the NP group; the majority being grade 1-2. The most common AEs were diarrhea, fatigue, peripheral neuropathy, alopecia, and rash. Grade 3+ AEs (n=77) were reported in 30 (60%) pts, 20 in the D group (8 pts; 62%) and 57 in the NP group (22 pts, 61%). The most common grade 3+ AEs in the D group were febrile neutropenia (4 pts, 31%) and neutropenia (3 pts; 23%); and in the NP group neutropenia (3 pts; 8%), anemia, diarrhea, cellulitis, peripheral neuropathy, LVEF decreased and pulmonary embolism each reported in 2(6%) pts . SAEs (n=44) were reported in 25(50%) pts, 11 (8 pts; 62%) in the D group and 33 (17 pts; 47%) in the NP group. The most common SAEs in the D group were febrile neutropenia (4 pts, 31%) and pyrexia (2 pts, 15%); and in the NP group: pyrexia (5 pts, 14%), cellulitis (2 pts, 6%) and pulmonary embolism (2 pts, 6%). AEs of suspected cardiac disorders (n=12) were reported in 7(14%) pts; atrial fibrillation, cardiomyopathy, myocardial ischemia, and dyspnea each reported in 1(2%) pt; and LVEF decreased, palpitation, hypertension each reported in 2(4%) pts. AEs leading to study drug discontinuation (n=6) were reported in 6(12%) pts [LVEF decreased (3), drug hypersensitivity, syncope and blister]. AEs leading to chemotherapy discontinuation (n=24) were reported in 10(20%) pts. 4(8%) pts died on study (disease progression). Conclusion: No new safety signals have been reported in this study. Of further clinical interest is the finding that no cases of febrile neutropenia were reported in the NP taxane group compared to 4 in the D group. The safety profile remains consistent with the CLEOPATRA,1 PERUSE2 and HannaH3 studies, indicating the combination is safe and tolerable. 1.Baselga, et al. NEJM 2012;366:109 2.Bachelot, et al. JCO 2014;32:5s(abstr#548) 3.Ismael, et al. Lancet Onc 2012;13:869. Citation Format: Woodward N, De Boer RH, Redfern A, White M, Roberts W, Truman M, Beith J. Updated safety results from the first multicenter, open-label, phase IIIb study investigating the combination of pertuzumab with subcutaneous trastuzumab and a taxane in patients with HER2-positive metastatic breast cancer (SAPPHIRE) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-31.

A phase 3, open-label, randomized, 2-arm international study of the oral dual PARP inhibitor talazoparib in germline BRCA mutation subjects with locally advanced and/or metastatic breast cancer (EMBRACA)

Background: Cancer cells with deleterious mutations in breast cancer susceptibility genes 1 and 2 (BRCA1/2) are deficient in the DNA double-strand break repair mechanism, rendering them highly dependent on the single-strand break repair pathway, regulated by poly(ADP-ribose) polymerase (PARP). Inhibition of PARP results in synthetic lethality in cells with a BRCA1/2 mutation because of accumulation of irreparable DNA damage; PARP inhibitors have the potential to be selectively toxic for BRCA-mutated cells. In addition to catalytic inhibition, it has been shown that some PARP inhibitors induce PARP trapping at sites of DNA damage. The capacity to trap PARP-DNA complexes varies widely across different PARP inhibitors and is not correlated with PARP catalytic inhibition. Preclinical models have shown trapping PARP on DNA is more potent at inducing cancer cell death than enzymatic inhibition of PARP alone. Talazoparib is a dual-mechanism PARP inhibitor that both inhibits the PARP enzyme and effectively traps PARP on DNA, preventing DNA damage repair and resulting in cell death in BRCA1/2-mutated cells. In preclinical studies, talazoparib at nanomolar concentrations showed the highest efficiency at trapping PARP-DNA complexes relative to other PARP inhibitors. In a previous phase 1/2 clinical study, talazoparib as monotherapy (1 mg once daily) resulted in a 50% response rate and an 86% clinical benefit rate at 24 weeks in 14 patients with a germline BRCA1/2 mutation and advanced breast cancer (aBC). Methods: This open-label, randomized, 2-arm, international phase 3 trial (EMBRACA) compares the efficacy and safety of talazoparib with protocol-specific physician9s choice (capecitabine, eribulin, gemcitabine or vinorelbine) in patients with aBC. The primary objective is progression-free survival by central imaging. Secondary objectives are objective response rate, overall survival, safety and pharmacokinetics of talazoparib. Exploratory objectives include health-related quality of life measurements and biomarker research in blood and tumor samples that may permit characterization of mechanisms involved in tumor sensitivity and resistance to talazoparib. Key patient eligibility criteria include aged ≥18 years with histologically/cytologically confirmed breast cancer; locally advanced and/or metastatic disease appropriate for systemic single-agent cytotoxic chemotherapy; deleterious or pathogenic germline BRCA1/2 mutations by central laboratory; ≤3 prior cytotoxic chemotherapy regimens for advanced disease (prior platinum is allowed provided patients did not relapse within 6 months in the adjuvant setting or did not progress on platinum therapy); prior treatment with a taxane and/or anthracycline unless medically contraindicated; and ECOG performance status ≤2. Patients (N=429) will be randomized 2:1 to receive either talazoparib capsules (1 mg/day, 21-day cycles) or physician9s choice treatment. This trial is currently enrolling patients from the USA, Europe, Israel, Ukraine, Russia, Korea, Australia, Taiwan and Brazil (NCT01945775). This study is funded by Medivation, Inc. Citation Format: Litton J, Ettl J, Hurvitz SA, Mina LA, Rugo HS, Lee K-H, Yerushalmi R, Woodward N, Goncalves A, Moreno F, Roche H, Im Y-H, Martin M, Bhattacharya S, Peterson A, Hannah A, Eiermann W, Blum J. A phase 3, open-label, randomized, 2-arm international study of the oral dual PARP inhibitor talazoparib in germline BRCA mutation subjects with locally advanced and/or metastatic breast cancer (EMBRACA) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-13.