Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial.

BACKGROUND: HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T. PATIENTS AND METHODS: Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing. RESULTS: ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response. CONCLUSIONS: The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.

A randomized controlled trial of hand/foot-cooling by hilotherapy to prevent oxaliplatin-related peripheral neuropathy in patients with malignancies of the digestive system.

BACKGROUND: Both acute and chronic symptoms of oxaliplatin-induced peripheral neuropathy (OIPN) affect patients' treatment dose and duration as well as quality-of-life. Hand/foot-cooling has been shown to reduce taxane-induced peripheral neuropathy but there is unclear evidence in the setting of oxaliplatin. PATIENTS AND METHODS: In a monocentric, open-label phase II trial, patients with malignancies of the digestive system receiving oxaliplatin-based chemotherapy were randomly assigned to receive either continuous cooling of hands and feet using hilotherapy at 11°C during oxaliplatin infusion compared with usual care (no cooling). The primary endpoint was grade ≥2 neuropathy-free rate in 12 weeks after initiation of chemotherapy. Secondary endpoints included OIPN-related treatment alterations, acute OIPN symptoms and perceived comfort of the intervention. RESULTS: The intention-to-treat population included 39 patients in the hilotherapy group and 38 in the control group. The grade ≥2 neuropathy-free rate at 12 weeks was 100% in the experimental group versus 80.5% in the control group (P = 0.006). This effect was persistent at 24 weeks (66.0% versus 49.2%, respectively) (P = 0.039). Next, treatment alterations-free rate at week 12 was 93.5% in the hilotherapy group compared with 83.3% in the control group (P = 0.131). Patients in the hilotherapy group experienced significantly less acute OIPN symptoms of numbness or tingling [odds ratio (OR) 0.05, 95% confidence interval (CI) 0.02-0.11, P < 0.0001], pain (OR 0.06, 95% CI 0.02-0.15, P < 0.0001) and/or cold sensitivity (OR 0.02, 95% CI 0.01-0.05, P < 0.0001) in fingers or toes as well as less pharyngeal cold sensitivity (OR 0.14, 95% CI 0.05-0.42, P = 0.0005). The majority of patients in the hilotherapy group rated the intervention as neutral, rather comfortable or very comfortable. CONCLUSIONS: In this first study on hand/foot-cooling in oxaliplatin alone, hilotherapy significantly reduced the incidence of grade ≥2 OIPN at 12 and 24 weeks. Hilotherapy also reduced acute OIPN symptoms and was generally well tolerated.

Current and future diagnostic and treatment strategies for patients with invasive lobular breast cancer.

BACKGROUND: Invasive lobular breast cancer (ILC) is the second most common type of breast cancer after invasive breast cancer of no special type (NST), representing up to 15% of all breast cancers. DESIGN: Latest data on ILC are presented, focusing on diagnosis, molecular make-up according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) guidelines, treatment in the early and metastatic setting and ILC-focused clinical trials. RESULTS: At the imaging level, magnetic resonance imaging-based and novel positron emission tomography/computed tomography-based techniques can overcome the limitations of currently used imaging techniques for diagnosing ILC. At the pathology level, E-cadherin immunohistochemistry could help improving inter-pathologist agreement. The majority of patients with ILC do not seem to benefit as much from (neo-)adjuvant chemotherapy as patients with NST, although chemotherapy might be required in a subset of high-risk patients. No differences in treatment efficacy are seen for anti-human epidermal growth factor receptor 2 (HER2) therapies in the adjuvant setting and cyclin-dependent kinases 4 and 6 inhibitors in the metastatic setting. The clinical utility of the commercially available prognostic gene expression-based tests is unclear for patients with ILC. Several ESCAT alterations differ in frequency between ILC and NST. Germline BRCA1 and PALB2 alterations are less frequent in patients with ILC, while germline CDH1 (gene coding for E-cadherin) alterations are more frequent in patients with ILC. Somatic HER2 mutations are more frequent in ILC, especially in metastases (15% ILC versus 5% NST). A high tumour mutational burden, relevant for immune checkpoint inhibition, is more frequent in ILC metastases (16%) than in NST metastases (5%). Tumours with somatic inactivating CDH1 mutations may be vulnerable for treatment with ROS1 inhibitors, a concept currently investigated in early and metastatic ILC. CONCLUSION: ILC is a unique malignancy based on its pathological and biological features leading to differences in diagnosis as well as in treatment response, resistance and targets as compared to NST.

Preventing taxane-related peripheral neuropathy, pain and nail toxicity: a prospective self-controlled trial comparing hilotherapy with frozen gloves in early breast cancer.

PURPOSE: The prevention of taxane-related toxicities at the extremities is highly important for patients' treatment and quality-of-life. Several studies endorse hand/foot-cooling using frozen gloves as a prophylactic intervention. Unlike frozen gloves, hilotherapy produces cooling at a constant temperature. Comparative data with frozen gloves are unavailable. METHODS: This prospective self-controlled study explores the efficacy of hilotherapy at the right hand and foot compared to frozen gloves at the left in patients with early breast cancer treated with weekly paclitaxel 80 mg/m2 or three-weekly docetaxel 75 mg/m2. Patient-reported outcomes were collected at baseline, 6, 12, 18 and 24 weeks after the start of treatment. Primary and secondary endpoints were the incidence of any-grade and ≥ grade 2 side-effects (peripheral neuropathy, pain and nail toxicities), and perceived comfort of both interventions. RESULTS: Sixty-two patients participated. The incidence of any-grade side-effects was similar on both sides, 85.5% with hilotherapy and 90.3% with frozen gloves (p = 1.000). The incidence of ≥ grade 2 side-effects at the extremities was significantly lower with hilotherapy: 43.6% compared to 61.3% with frozen gloves (p = 0.013). Perceived comfort was significantly better for hilotherapy than for frozen gloves (p < 0.0001). CONCLUSIONS: Compared to frozen gloves, continuous cooling of hands and feet using hilotherapy produces better prevention of ≥ grade 2 patient-reported side-effects at the extremities (peripheral neuropathy, pain and nail toxicities). Perceived comfort was significantly better for hilotherapy. From a clinical and patient perspective, hilotherapy is a better alternative for preventing clinically significant taxane-related side-effects.

Veliparib monotherapy following carboplatin/paclitaxel plus veliparib combination therapy in patients with germline BRCA-associated advanced breast cancer: results of exploratory analyses from the phase III BROCADE3 trial.

BACKGROUND: In the BROCADE3 trial, addition of the poly(ADP-ribose) polymerase inhibitor, veliparib, to carboplatin/paclitaxel improved progression-free survival (PFS) (hazard ratio 0.71, 95% confidence interval 0.57-0.88; P = 0.002) in patients with advanced human epidermal growth factor receptor 2-negative, germline BRCA1/2-mutated breast cancer. A subset of patients discontinued both carboplatin and paclitaxel before progression and continued on veliparib/placebo maintenance monotherapy until progression. Analyses in this patient subgroup are reported. PATIENTS AND METHODS: Patients were randomized 2 : 1 to veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Veliparib (120 mg twice daily) or placebo was given on days -2 to 5, carboplatin (area under the curve 6 mg/ml) on day 1, and paclitaxel (80 mg/m2) on days 1, 8, and 15 of 21-day cycles. Patients who discontinued both carboplatin and paclitaxel before progression received blinded study drug monotherapy at an increased dose of 300-400 mg twice daily continuously. PFS was the primary endpoint. Exploratory analyses were carried out in the subgroup of patients who received blinded study drug as monotherapy. A time-varying Cox model including data from all patients was also used to evaluate treatment effect in the combination and monotherapy phases. RESULTS: A total of 136 of 337 patients randomized to veliparib plus carboplatin/paclitaxel and 58/172 patients randomized to placebo plus carboplatin/paclitaxel discontinued both carboplatin and paclitaxel before progression and continued on blinded veliparib or placebo monotherapy. In this blinded monotherapy subgroup, investigator-assessed median PFS from randomization was 25.7 months with veliparib versus 14.6 months with placebo. Hazard ratios from a time-varying Cox model favored veliparib during both combination therapy and monotherapy. Any-grade adverse events occurring in the monotherapy phase were primarily gastrointestinal. The most common grade ≥3 adverse events were neutropenia and anemia (4% each with veliparib; 5% and 2%, respectively, with placebo). CONCLUSIONS: Veliparib maintenance monotherapy had a tolerable safety profile and may extend PFS following combination chemotherapy.

Current landscape of ESMO/ASCO Global Curriculum adoption and medical oncology recognition: a global survey.

BACKGROUND: With the implementation of multidisciplinary treatment and development of multiple novel anticancer drugs in parallel with expanding knowledge of supportive and palliative care, a need for separate training and specialisation in medical oncology emerged. A Global Curriculum (GC) in medical oncology, developed and updated by a joint European Society for Medical Oncology/American Society of Clinical Oncology (ESMO/ASCO) GC Task Force/Working Group (GC WG), greatly contributed to the recognition of medical oncology worldwide. MATERIAL AND METHODS: ESMO/ASCO GC WG carried out a global survey on medical oncology recognition and GC adoption in 2019. RESULTS: Based on our survey, medical oncology is recognised as a separate specialty or sub-specialty in 47/62 (75%) countries participating in the survey; with a great majority of them (39/47, 83%) recognising medical oncology as a standalone specialty. Additionally, in 9 of 62 (15%) countries, medical oncology is trained together with haematology as a specialty in haemato-oncology or together with radiotherapy as a specialty in clinical oncology. As many as two-thirds of the responding countries reported that the ESMO/ASCO GC has been either fully or partially adopted or adapted in their curriculum. It has been adopted in a vast majority of countries with established training in medical oncology (28/41; 68%) and adapted in 12 countries with mixed training in haemato-oncology, clinical oncology or other specialty responsible for training on systemic anticancer treatment. CONCLUSIONS: With 75% of participating countries reporting medical oncology as a separate specialty or sub-specialty and as high as 68% of them reporting on GC adoption, the results of our survey on global landscape are reassuring. Despite a lack of data for some regions, this survey represents the most comprehensive and up-to-date information about recognition of medical oncology and GC adoption worldwide and will allow both societies to further improve the dissemination of the GC and global recognition of medical oncology, thus contributing to better cancer care worldwide.

Intra-Arterial Therapies for Liver Metastatic Breast Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: Performing a systematic review and meta-analysis to assess the evidence of intra-arterial therapies in liver metastatic breast cancer (LMBC) patients. METHODS: A systemic literature search was performed in PubMed, EMBASE, SCOPUS for studies regarding intra-arterial therapies in LMBC patients. Full text studies of LMBC patients (n ≥ 10) published between January 2010 and December 2020 were included when at least one outcome among response rate, adverse events or survival was available. Response rates were pooled using generalized linear mixed models. A weighted estimate of the population median overall survival (OS) was obtained under the assumption of exponentially distributed survival times. RESULTS: A total of 26 studies (1266 patients) were included. Eleven articles reported on transarterial radioembolization (TARE), ten on transarterial chemoembolization (TACE) and four on chemo-infusion. One retrospective study compared TARE and TACE. Pooled response rates were 49% for TARE (95%CI 32-67%), 34% for TACE (95%CI 22-50%) and 19% for chemo-infusion (95%CI 14-25%). Pooled median survival was 9.2 months (range 6.1-35.4 months) for TARE, 17.8 months (range 4.6-47.0) for TACE and 7.9 months (range 7.0-14.2) for chemo-infusion. No comparison for OS was possible due to missing survival rates at specific time points (1 and 2 year OS) and the large heterogeneity. CONCLUSION: Although results have to be interpreted with caution due to the large heterogeneity, the superior response rate of TARE and TACE compared to chemo-infusion suggests first choice of TARE or TACE in chemorefractory LMBC patients. Chemo-infusion could be considered in LMBC patients not suitable for TARE or TACE. LEVEL OF EVIDENCE: 3a.

Assessment of potential process quality indicators for systemic treatment of breast cancer in Belgium: a population-based study.

BACKGROUND: Quality indicators (QIs) for the management of breast cancer (BC) have been published in Europe and internationally. In Belgium, a task force was established to select measurable process indicators of systemic treatment for BC, focusing on appropriateness of delivered care. The objective of this study was to evaluate the results of the selected QIs, both nationally and among individual centres. PATIENTS AND METHODS: Female Belgian residents with unilateral primary invasive BC diagnosed between 2010 and 2014 were selected from the Belgian Cancer Registry database. The national number enabled linkage with the national reimbursement database, which contains information on all reimbursed medical procedures. A total of 12 process indicators were measured on the population and hospital level. Intercentre variability was assessed by median results and interquartile ranges. RESULTS: A total of 48 872 patients were included in the study. QIs concerning specific BC subtypes only applied to patients diagnosed in 2014 (n = 9855). Clinical stage (cStage) I patients (n = 17 116) were staged with positron emission tomography/computed tomography. Among patients who were pT1aN0 human epidermal growth factor receptor 2 (HER2) positive (n = 47), 25.5% (n = 12) received adjuvant trastuzumab. Among patients with de novo metastatic luminal A/B-like HER2-negative BC (n = 295), 17.3% (n = 51) received upfront chemotherapy. (Neo)adjuvant chemotherapy was administered in 52.4% (n = 12 592) of operated women with cStage I-III, in 37.0% (n = 1270) of operated women with cStage I-III luminal A/B-like HER2-negative BC, and in 19.1% of operated women with cStage I luminal A/B-like HER2-negative BC. In the population of operated patients with cStage I-III, of those younger than 70 years that started adjuvant endocrine therapy (n = 3591), 81.7% (n = 2932) continued treatment for ≥4.5 years. Among patients in cStage I-III older than 70 years (n = 8544), 19.0% (n = 1622) received (neo)adjuvant chemotherapy, whereas among patients with cStage I-III luminal A/B-like HER2-negative BC (n = 1388), 13.0% (n = 181) received (neo)adjuvant chemotherapy. In patients with cStage I-II luminal A/B-like HER2-negative BC older than 70 years (n = 1477), 11.6% (n = 171) were not operated and received upfront endocrine treatment. CONCLUSION: Well-considered QIs using population-based data can evaluate quality of care and expose disparities among treatment centres. Their use in daily practice should be implemented in all centres treating BC.

Detection of secondary metastatic breast cancer by measurement of plasma CA 15.3.

BACKGROUND: Most current guidelines do not recommend the serial analysis of tumour marker CA 15.3 in the follow-up of asymptomatic patients treated for early breast cancer (EBC). These guidelines are based on small-scale studies carried out in an era with more limited treatment options than today. In our large academic centre, serial measurements of CA 15.3 are used routinely in the follow-up of EBC, whereas imaging for distant metastases is only carried out on indication. PATIENTS AND METHODS: In this retrospective single-centre study, patients were included if they were treated for EBC between 1 January 2000 and 1 January 2018, diagnosed with secondary metastatic disease at least 6 months after initial surgery and had CA 15.3 available at the time of diagnosis of metastases. The primary objective was to evaluate the proportion of patients in whom metastatic disease was discovered by an increasing CA 15.3. Information on the method of metastases detection, CA 15.3 evolution and survival was collected after approval of the ethics committee. RESULTS: At the moment of diagnosis of metastases, 451 of 730 included patients (62%) had CA 15.3 levels above the upper limit of normal (>30 kU/l). In 269 patients (37%), an increasing CA 15.3 was the first sign that led to the diagnosis of metastases. This was most frequent in luminal A-like tumours (48%) and in liver (45%) and bone (41%) localisation of metastases. By contrast, reported symptoms triggered the diagnosis of metastatic disease in 48% of the patients. Median overall survival was significantly longer when the relapse was discovered by CA 15.3 elevation versus those discovered by another trigger (abnormal clinical examination or history, abnormal laboratory tests or an incidental finding) (35 versus 22 months; P = 0.0027). CONCLUSION: When CA 15.3 is systematically used in the follow-up of EBC patients, the diagnosis of metastatic disease is made in 37% by a CA 15.3 increase.

Sacituzumab govitecan and trastuzumab deruxtecan: two new antibody-drug conjugates in the breast cancer treatment landscape.

BACKGROUND: Two new antibody-drug conjugates (ADCs) containing a topoisomerase I inhibitor payload have recently emerged in the breast cancer (BC) treatment landscape. Sacituzumab govitecan-hziy (SG) is a first-in-class anti-trophoblast cell-surface antigen 2 ADC approved for pretreated metastatic triple-negative breast cancer (mTNBC) and trastuzumab deruxtecan (T-DXd) gained approval for human epidermal growth factor receptor-2 (HER2)-positive advanced BC (aBC). We aim to provide a contemporary review and the current clinical trial landscape of SG and T-DXd in BC. MATERIALS AND METHODS: We conducted a literature search from Medline database through PubMed, major conference proceedings [abstracts from European Society for Medical Oncology (Breast) Congress, American Society of Clinical Oncology annual meeting, San Antonio Breast Cancer Symposium] and ClinicalTrials.gov with search terms 'sacituzumab govitecan', 'IMMU-132', 'trastuzumab deruxtecan' and 'DS-8201a' up to 21 March 2021. RESULTS: We assessed 293 records for eligibility, of which 153 were included in this review after screening and exclusion. For SG, efficacy and safety data are available from a phase III trial in pretreated mTNBC and from a phase I/II basket study in mTNBC and hormone receptor-positive/HER2-negative aBC. Thirteen trials with pending primary analysis are ongoing with SG as single agent or in combination, of which 11 are enrolling (2/11 in the early setting). For T-DXd, efficacy/safety data are available as single agent in pretreated HER2-positive (phase Ib and phase II) and in HER2-low aBC (phase Ib), and in combination with nivolumab in HER2-low/positive aBC (phase Ib). Of 23 ongoing trials with T-DXd, 12 are open for enrollment and 3 phase III trials have completed recruitment. The distinct safety profiles of both drugs and their management are discussed. CONCLUSION: Given their robust single-agent activity, SG and T-DXd are expected to substantially impact treatment standards, both in and far beyond the currently approved indications. Several trials are investigating new treatment settings for both drugs, including a transition to earlier lines and combinations with other anticancer treatments such as immune checkpoint inhibitors.

Features of durable response and treatment efficacy for capecitabine monotherapy in advanced breast cancer: real-world evidence from a large single-centre cohort.

PURPOSE: In metastatic breast cancer (MBC) population treated with capecitabine monotherapy, we investigated clinical-pathological features as possible biomarkers for the oncological outcome. METHODS: Retrospective study of consecutive MBC patients treated at University Hospitals Leuven starting capecitabine between 1999 and 2017. The primary endpoint was the durable response (DR), defined as non-progressive disease for > 52 weeks. Other main endpoints were objective response rate (ORR), time to progression (TTP) and overall survival (OS). RESULTS: We included 506 patients; mean age at primary breast cancer diagnosis was 51.2 years; 18.2% had de novo MBC; 98.8% were pre-treated with taxanes and/or anthracycline. DR was reached in 11.6%. Patients with DR, as compared to those without DR, were more likely oestrogen receptor (ER) positive (91.5% vs. 76.8%, p = 0.010) at first diagnosis, had a lower incidence of lymph node (LN) involvement (35.6% vs. 49.9%, p = 0.039) before starting capecitabine, were more likely to present with metastases limited to ≤ 2 involved sites (54.2% vs. 38.5%, p = 0.020) and time from metastasis to start of capecitabine was longer (mean 3.5 vs. 2.7 years, p = 0.020). ORR was 22%. Median TTP and OS were 28 and 58 weeks, respectively. In multivariate analysis (only performed for TTP), ER positivity (hazard ratio (HR) = 0.529, p < 0.0001), HER2 negativity (HR = 0.582, p = 0.024), absence of LN (HR = 0.751, p = 0.008) and liver involvement (HR = 0.746, p = 0.013), older age at capecitabine start (HR = 0.925, p < 0.0001) and younger age at diagnosis of MBC (HR = 0.935, p = 0.001) were significant features of longer TTP. CONCLUSION: Our data display relevant clinical-pathological features associated with DR and TTP in patients receiving capecitabine monotherapy for MBC.

Scalp cooling in breast cancer patients treated with docetaxel-cyclophosphamide: patient- and nurse-reported results.

PURPOSE: Recent evidence supports the efficacy of scalp cooling in preventing chemotherapy-induced alopecia in breast cancer treatments. However, efficacy largely varies between treatment regimens. The aim of this study was to explore the patient- and nurse-reported results of scalp cooling in terms of hair loss and need for a wig/head cover in patients with breast cancer treated with 3-weekly docetaxel 75 mg/m2- cyclophosphamide 600 mg/m2. METHODS: We studied nurse-reported efficacy as noted in the electronic patient files of 85 patients treated with docetaxel 75 mg/m2- cyclophosphamide 600 mg/m2 between 1/1/2017 and 1/1/2020. Sixty-nine of them also self-reported on their scalp cooling results up to one year after adjuvant chemotherapy in a retrospective way. RESULTS: Nurse- and patient-reported data showed that scalp cooling was successful (i.e., hair loss < 50%) in 47.1 and 44.9% of patients, respectively, and 55% of patients were (very) satisfied with the result of scalp cooling. Scalp cooling was perceived as (very) uncomfortable in 36.2% of patients. Regarding hair status one year after treatment, 47 patients (55.3%) reported no changes compared to their hair status before treatment. CONCLUSIONS: Scalp cooling is successful in preventing severe chemotherapy-induced alopecia in almost half of the patients with breast cancer treated with docetaxel 75 mg/m2- cyclophosphamide 600 mg/m2. Better understanding of the success rate of scalp cooling enables correct patient information and decision-making support.

Efficacy of anti-HER2 therapy in metastatic breast cancer by discordance of HER2 expression between primary and metastatic breast cancer.

PURPOSE: In stage IV breast cancer, the efficacy of human epidermal growth factor receptor 2 (HER2) targeted therapies in cases with discordance in HER2 expression between primary and metastatic site is not well known. We studied progression free (PFS) and overall survival (OS) by HER2 concordance when treating women with taxane-trastuzumab (± pertuzumab) in first or second line and trastuzumab-emtansine (T-DM1) or capecitabine-lapatinib in later lines. PATIENTS AND METHODS: Retrospective monocentric study including all breast cancer patients receiving trastuzumab between January 2002 and September 2017 at the University Hospital in Leuven; we selected metastatic patients with an available HER2 status in primary and metastatic site. The Kaplan-Meier method was used for estimating PFS/OS and log-rank test for analyzing between group differences. A Cox model is used for testing difference between groups while correcting for Pertuzumab. Multivariable Cox regression is used to model overall survival as a function group, correcting for possible confounders. RESULTS: We included 74 patients; 46 had an unchanged HER2 status (positive/positive), 9 lost HER2 (positive/negative), while 19 acquired HER2 amplification (negative/positive). 25 out of 28 cases with a discordant HER2 status were positive for ER and/or PgR in the primary site. HER2 positive/negative cases had a significantly lower PFS for taxane-trastuzumab-(pertuzumab) (PFS = 5.5 months), compared to HER2 positive/positive (PFS 9 months, p = 0.01) and HER2 negative/positive (PFS 14 months, p = 0.01) patients. PFS for later line T-DM1 (n = 30) was significantly higher for the HER2 positive/positive group (PFS 6.0 months) than for the discordant groups HER2 negative/positive (PFS 1.0 month, p = 0.04) and HER2 positive/negative (PFS 1.5 month, p = 0.01). After correcting for possible confounders, the HER2 positive/negative group had a significantly worse OS compared to HER2 positive/positive (HR 0.19, 95% CI 0.08-0.44) and negative/positive (HR 0.15, 95% 0.06-0.38). CONCLUSION: Conversion of HER2 status was seen in 28 out of 74 cases and was mostly observed in hormone receptor-positive tumors. In contrast to patients with HER2 loss, patients with a positive conversion of HER2 status derived substantial benefit from first line treatment with taxane-trastuzumab-(pertuzumab). This study highlights the importance of re-biopsying the metastatic lesion and changing treatment according to the last HER2 result.

Intra-arterial Mitomycin C infusion in a large cohort of advanced liver metastatic breast cancer patients: safety, efficacy and factors influencing survival.

PURPOSE: The aim of this study was to determine the safety and efficacy of Mitomycin C (MMC) infusion in a large cohort of advanced liver metastatic breast cancer patients (LMBC) and to determine factors influencing overall survival (OS). METHODS: We retrospectively analysed LMBC patients, treated with MMC infusion between 2000 and 2017. Hepatic response was measured with baseline CT scans and first available CT scan after MMC infusion by RECIST 1.1 criteria. Adverse events were registered by the CTCAE version 5.0. OS and hepatic progression free survival (hPFS) were evaluated using Kaplan-Meier estimates. After univariable analysis, a stepwise forward multivariable (MV) prediction analysis was developed to select independent pre-treatment factors associated with OS. RESULTS: We included 176 patients with a total of 599 MMC infusions, mostly heavily pre-treated patients with a median time from diagnosis of MBC to MMC infusion of 36.9 months. RECIST evaluation of liver lesions (n = 132) showed a partial response rate of 15%, stable disease of 43% and progressive disease in 17%. Adverse events grade 3 and 4 were reported in 17.5%. Median PFS was 5.5 months and median OS was 7.8 months. Significant independent baseline predictors of worse OS included number of prior systemic chemotherapy lines, prior liver ablation, higher liver tumour burden and elevated levels of bilirubin and ALT. CONCLUSION: MMC infusion is safe and effective in advanced LMBC patients. An increased number of prior therapies, a higher liver tumour burden and elevated levels of bilirubin and ALT were associated with a worse OS.

Determining clinically important differences in health-related quality of life in older patients with cancer undergoing chemotherapy or surgery.

PURPOSE: Using the EORTC Global Health Status (GHS) scale, we aimed to determine minimal clinically important differences (MCID) in health-related quality of life (HRQOL) changes for older cancer patients with a geriatric risk profile, as defined by the geriatric 8 (G8) health screening tool, undergoing treatment. Simultaneously, we assessed baseline patient characteristics prognostic for HRQOL changes. METHODS: Our analysis included 1424 (G8 ≤ 14) older patients with cancer scheduled to receive chemotherapy (n = 683) or surgery (n = 741). Anchor-based methods, linking the GHS score to clinical indicators, were used to determine MCID between baseline and follow-up at 3 months. A threshold of 0.2 standard deviation (SD) was used to exclude MCID estimates too small for interpretation. Logistic regressions analysed baseline patient characteristics prognostic for HRQOL changes. RESULTS: The 15-item Geriatric Depression Scale (GDS15), Visual Analogue Scale (VAS) for Fatigue and ECOG Performance Status (PS) were selected as clinical anchors. In the surgery group, MCID estimates for improvement and deterioration were ECOG PS (5*, 11*), GDS15 (5*, 2) and VAS Fatigue (3, 9*). In the chemotherapy group, MCID estimates for improvement and deterioration were ECOG PS (8*, 7*), GDS15 (5, 4) and VAS Fatigue (5, 5*). Estimates with * were > 0.2 SD threshold. Patients experiencing pain or malnutrition (surgery group) or fatigue (chemotherapy group) at baseline showed a significantly stable or improved HRQOL (p < 0.05) after their treatment. CONCLUSION: The reported MCID for improvement and deterioration depended on the anchor used and treatment received. The estimates can be used to evaluate significant changes in HRQOL and to determine sample sizes in clinical trials.

Adherence to geriatric assessment-based recommendations in older patients with cancer: a multicenter prospective cohort study in Belgium.

Background: In the general older population, geriatric assessment (GA)-guided treatment plans can improve overall survival, quality of life and functional status (FS). In GA-related research in geriatric oncology, studies mainly focused on geriatric screening and GA but not on geriatric recommendations, interventions and follow-up. The aim of this study was to investigate the adherence to geriatric recommendations and subsequent actions undertaken in older patients with cancer. Patient and methods: A prospective Belgian multicenter (N = 22) cohort study included patients ≥70 years with a malignant tumor upon oncologic treatment decision. Patients with an abnormal result on the geriatric screening (G8 ≤14/17) underwent GA. Geriatric recommendations were formulated based on GA results. At follow-up the adherence to geriatric recommendations was documented including a description of actions undertaken. Results: From November 2012 till February 2015, G8 screening was carried out in 8451 patients, of which 5838 patients had an abnormal result. Geriatric recommendations data were available for 5631 patients. Geriatric recommendations were made for 4459 patients. Geriatric interventions data were available for 4167 patients. A total of 12 384 geriatric recommendations were made. At least one different geriatric recommendation was implemented in 2874 patients. A dietician, social worker and geriatrician intervened most frequently for problems detected on the nutritional, social and functional domain. A total of 7569 actions were undertaken for a total of 5725 geriatric interventions, most frequently nutritional support and supplements, extended home care and psychological support. Conclusions: This large-scale Belgian study focuses on the adherence to geriatric recommendations and subsequent actions undertaken and contributes to the optimal management of older patients with cancer. We identified the domains for which geriatric recommendations are most frequently made and adhered to, and which referrals to other health care workers and facilities are frequently applied in the multidisciplinary approach of older patients with cancer.

Palbociclib in highly pretreated metastatic ER-positive HER2-negative breast cancer.

PURPOSE: We aimed to investigate the role of palbociclib, a first-in-class cyclin-dependent kinase 4 and 6 inhibitor, in postmenopausal women with highly pretreated endocrine therapy-resistant metastatic breast cancer (MBC). METHODS: Between 28 September 2015 and 14 March 2017, a compassionate use program was established in the University Hospitals Leuven in which 82 postmenopausal women with estrogen receptor-positive, HER2-negative MBC were included after at least four lines of systemic treatment. The efficacy and safety analysis was performed in 82 patients who had received at least one dose of palbociclib and who had at least 6-month follow-up at the data cut-off point. The primary objective was the evaluation of efficacy of the combination of palbociclib and endocrine therapy with clinical benefit as primary endpoint, defined as the absence of progressive disease and being on treatment for at least 6 months. Secondary objectives were the evaluation of toxicity and the identification of potential predictors for clinical benefit. RESULTS: The median age of the patients was 67.1 years (range 34.8-85.9) at the time of inclusion. The average duration of treatment was 5.6 months (range 1-19), with a median progression-free survival of 3.17 (95% CI 2.76-4.70) months. At the data cut-off point, 10 patients were still on treatment with palbociclib. In this highly pretreated setting, 34 patients experienced no progressive disease within 6 months, resulting in an overall clinical benefit rate (CBR) of 41.5%. 20.7% (17/82) showed stable disease for ≥ 9 months and 13.4% for ≥ 12 months. None of the investigated predicting factors were significantly associated with clinical benefit at 6 months. For 43.9% of the patients, treatment delay or dose reduction was indicated. CONCLUSIONS: Palbociclib in combination with endocrine therapy shows an unexpectedly high CBR and favorable safety profile in heavily pretreated endocrine-resistant estrogen receptor-positive, HER2-negative MBC patients.

Breast cancer subtype and survival by parity and time since last birth.

BACKGROUND: Pregnancy affects breast cancer risk but how it affects the subtype and prognosis remain controversial. We studied the effect of parity and time since last birth on breast cancer subtype and outcome. PATIENTS AND METHODS: We conducted a retrospective multivariate cohort study including all premenopausal women with early breast cancer aged ≤ 50 years (N = 1306) at diagnosis at the University Hospitals Leuven (Jan. 2000-Dec. 2009). Primary study endpoints were the breast cancer subtype, disease-free survival, and distant disease-free survival by parity and time since last birth. Statistical methods used were baseline-category logits models and Cox proportional hazard models. Multivariable models were used to correct for possible confounders. RESULTS: Breast cancer subtypes did not differ between nulliparous (N = 266) and parous women (N = 1040) but subtypes differed significantly in parous women by time since last birth (p < 0.001). Tumors within 5 years of last birth were proportionally more likely triple negative and HER-2 like, even when corrected for age at diagnosis. After a mean follow-up period of 10 years, parous women had a better disease-free survival compared to nulliparous women (HR 0.733; CI 0.560-0.961; p = 0.025, HR 0.738; CI 0.559-0.974; p = 0.032 before and after correction for known prognostic factors, respectively). In parous women, a longer time since last birth was correlated with a longer disease-free survival compared to patients with a recent pregnancy (HR 0.976; CI 0.957-0.996; p = 0.018). However, after correction, this association completely disappeared (HR 1.010; CI 0.982-1.040; p = 0.480). CONCLUSION: We observed a better disease-free survival for parous than nulliparous women. The influence of recent birth on disease-free survival is probably due to tumor and patient characteristics, as recent birth is associated with more aggressive subtypes.