Preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer (PHranceSCa): A randomised, open-label phase II study.

AIM: The aim of the study was to assess patient preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC) in patients with HER2-positive early breast cancer in PHranceSCa (NCT03674112). MATERIALS AND METHODS: Patients who completed neoadjuvant P + H + chemotherapy + surgery were randomised 1:1 to three intravenous (IV) P + H cycles followed by three cycles of PH FDC SC or vice versa (crossover) and then chose subcutaneous (SC) injection or IV infusion to continue up to 18 cycles (continuation). Assessments were via patient and healthcare professional (HCP) questionnaires. RESULTS: One hundred and sixty patients were randomised (cut-off: 24 February 2020); 136 (85.0%, 95% confidence interval: 78.5-90.2%) preferred SC; 22 (13.8%) preferred IV; 2 (1.3%) had no preference. The main reasons for SC preference were reduced clinic time (n = 119) and comfort during administration (n = 73). One hundred and forty-one patients (88.1%) were very satisfied/satisfied with SC injection versus 108 (67.5%) with IV infusion; 86.9% chose PH FDC SC continuation. HCP perceptions of median patient treatment room time ranged from 33.0-50.0 min with SC and 130.0-300.0 min with IV. Most adverse events (AEs) were grade 1/2 (no 4/5s); serious AE rates were low. AE rates before and after switching were similar (cycles 1-3 IV → cycles 4-6 SC: 77.5% → 72.5%; cycles 1-3 SC → cycles 4-6 IV: 77.5% → 63.8%). CONCLUSION: Most patients strongly preferred PH FDC SC over P + H IV. PH FDC SC was generally well tolerated, with no new safety signals (even when switching), and offers a quicker alternative to IV infusion.

Patient-reported outcomes from KATHERINE: A phase 3 study of adjuvant trastuzumab emtansine versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for human epidermal growth factor receptor 2-positive breast cancer.

BACKGROUND: The phase 3 KATHERINE trial demonstrated significantly improved invasive disease-free survival with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab in patients with HER2-positive early breast cancer and residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy. METHODS: Patients who received taxane- and trastuzumab-containing neoadjuvant therapy (with/without anthracyclines) and had residual invasive disease (breast and/or axillary nodes) at surgery were randomly assigned to 14 cycles of adjuvant T-DM1 (3.6 mg/kg intravenously every 3 weeks) or trastuzumab (6 mg/kg intravenously every 3 weeks). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and breast cancer module (QLQ-BR23) were completed at screening, at day 1 of cycles 5 and 11, within 30 days after study drug completion, and at 6- and 12-month follow-up visits. RESULTS: Of patients who were randomly assigned to T-DM1 (n = 743) and trastuzumab (n = 743), 612 (82%) and 640 (86%), respectively, had valid baseline and ≥1 postbaseline assessments. No clinically meaningful changes (≥10 points) from baseline in mean QLQ-C30 and QLQ-BR23 scores occurred in either arm. More patients receiving T-DM1 reported clinically meaningful deterioration at any assessment point in role functioning (49% vs 41%), appetite loss (38% vs 28%), constipation (47% vs 38%), fatigue (66% vs 60%), nausea/vomiting (39% vs 30%), and systemic therapy side effects (49% vs 36%). These differences were no longer apparent at the 6-month follow-up assessment, except for role functioning (23% vs 16%). CONCLUSION: These data suggest that health-related quality of life was generally maintained in both study arms over the course of treatment.

The influence of breast cancer subtypes on the response to anthracycline neoadjuvant chemotherapy in locally advanced breast cancer patients.

PURPOSE: The objective of neoadjuvant chemotherapy (NACT) for locally advanced breast cancer (LABC) is downstaging to achieve resectability. According to the protocol for the treatment of LABC more than 10 years ago, the routine NACT for LABC in Serbia consisted of 4 cycles of FAC (fluorouracil, doxorubicin, cyclophosphamide). The aim of this analysis was to assess the influence of biologic subtypes of BC on the response to NACT and on the disease outcome in these patients. METHODS: We analyzed 190 patients with median age of 52 years (range 26-74), diagnosed with LABC between Jun/2002 and Dec/2005 and treated with 4 cycles of FAC. Patients with clinical response to NACT (162/192;85.26%) were subjected to radical mastectomy after which the majority of them received 3 cycles of adjuvant FAC, adjuvant tamoxifen if HR-positive disease, and postoperative radiotherapy. We retrospectively determined by immunohistochemistry estrogen receptor (ER)/ progesterone receptor (PgR)/HER2 status from BC biopsies in all patients who were divided in 4 subgroups. Pathological complete remission (pCR) was defined as ypT0N0. The main end points were disease-free survival (DFS) and overall survival (OS). Statistics included Fisher's exact test, KaplanMeier product-limit method and Log-rank test. RESULTS: After a median follow up of 76 months (range 3-128) 104/190 patients (54.74%) experienced disease relapse, while 78/190 (41.05%) died. Of 157 patients with known receptor status the numbers of 4 subtypes were as follows: 31/190 (16.32%) triple negative (TN) BC, 22/190 (11.58%) HR-/HER2+, 97/190 (51%) HR+/HER2- and 17/190 (8.95%) HR+/HER2+. Ten out of 190 patients (6.17%) achieved pCR and had significantly longer DFS (Log-rank test, p=0.042), and a trend to prolonged OS (Log-rank test, p=0.092). There was a significant difference (Fisher exact test, p=7.7 × 10-6) between pCR rates among 4 BC subtypes: 3/31 (9.68%) in TNBC, 6/22 (27.27%) in HR-/HER2+, 0/97 in HR+/HER2- and 1/17 (5.88%) in HR+/HER2+ patients. This difference was achieved on the account of the difference between TNBC and HR-/HER2+ BC subtypes (Fisher's exact test, p=6.85×10-6, Bonferroni correction: 0.05/6=0.0083). There were no differences in DFS and OS between the 4 BC subtypes. CONCLUSION: Although there was a significantly higher number of patients achieving pCR among HR-/HER2+ subtype compared to other BC subtypes, this did not translate into improvement in long-term disease outcome of these patients.

Serbian consensus of neoadjuvant therapy for breast cancer: NeoPULSE.

Even though surgery is the primary treatment of operable breast cancer, it has been known for decades that the administration of postoperative adjuvant or preoperative neoadjuvant therapy is extremely important. Indications for neodjuvant therapy administration have been expanded over the years, and nowadays this kind of treatment represents an inevitable option in early breast cancer treatment. The NeoPULSE project, which gathered a group of experts in the field of breast cancer from five Serbian university centres, was formed with the aim to define optimal breast cancer diagnosis, indications for neoadjuvant therapy, therapeutic combinations in relation to molecular/biological parameters of breast cancer, as well as the treatment after neoadjuvant therapy. During two separate expert meetings involving surgeons, medical oncologists, radiation oncologists, a pathologist, and a "Blueprint" workshop, the project participants answered questions over the indications for neoadjuvant therapy. The first part covered local practice and referred to the existence and work of a multidisciplinary team, as well as commonly applied therapeutic regimens in the neoadjuvant setting. Experts analysed personal views regarding indications for the administration and benefits of neoadjuvant therapy, their perception on the correlation between achieving a pathological complete response (pCR) and the outcome of treatment, as well as the attitude towards controversies about this type of treatment, primarily regarding a possible change in the receptor status after therapy and therapeutic options after a suboptimal response. The analysis of the answers pointed to problems and deviations from recommendations in everyday clinical practice, based on which appropriate solutions were proposed. The establishment of such a panel and consensus is an attempt to modernize multidisciplinary teams in Serbia, achieve reaching uniform decisions of all subjects dealing with breast cancer, and therefore, at least in one segment, improve breast cancer treatment in Serbia.

Efficacy and Safety of Oral NEPA (Netupitant/Palonosetron), the First Fixed-Combination Antiemetic, in Patients With Gynecological Cancers Receiving Platinum-Based Chemotherapy.

OBJECTIVE: Patients with gynecological cancers are at high risk for chemotherapy-induced nausea and vomiting (CINV) after platinum-based chemotherapy (CT). NEPA (300-mg netupitant, 0.50-mg palonosetron) is the first oral fixed-combination antiemetic. Pivotal trials demonstrated the superiority of oral NEPA over intravenous palonosetron in preventing CINV after highly emetogenic (anthracycline-cyclophosphamide-based [AC] and cisplatin-based [non-AC]) CT. This post hoc subset analysis considered patients with gynecological cancer receiving cisplatin- or carboplatin-based CT from 1 pivotal trial and from 1 multicycle safety trial to evaluate the efficacy of oral NEPA in preventing CINV. METHODS: Single-dose NEPA was given before CT in combination with dexamethasone. The efficacy end points for the acute (0-24 hours), delayed (25-120 hours), and overall (0-120 hours) CINV phases after CT included complete response (CR; no emesis, no rescue medication) and no significant nausea (<25 mm on a 0- to 100-mm visual analog scale). Safety was also assessed. RESULTS: For cisplatin-induced CINV, NEPA achieved high CR rates (acute phase: >90%; delayed, overall phases: ≥85%). For carboplatin-induced CINV, NEPA was also highly effective, with high acute, delayed, and overall CR rates (cycle 1: >75%; cycles 2-4: >95%). No significant nausea rates were more than 90% and more than 80% in the acute and delayed phases, respectively, for patients receiving cisplatin or carboplatin. NEPA was well tolerated. CONCLUSIONS: Results suggest that oral NEPA is effective and safe in preventing CINV in patients with gynecological cancers treated with cisplatin- or carboplatin-based CT. Single fixed-combination NEPA is a convenient option for CINV prevention in high-risk CINV patients.

Novel BRCA1 splice-site mutation in ovarian cancer patients of Slavic origin.

Mutations in breast cancer susceptibility gene 1 (BRCA1) lead to defects in a number of cellular pathways including DNA damage repair and transcriptional regulation, resulting in the elevated genome instability and predisposing to breast and ovarian cancers. We report a novel mutation LRG_292t1:c.4356delA,p.(Ala1453Glnfs*3) in the 12th exon of BRCA1, in the splice site region near the donor site of intron 12. It is a frameshift mutation with the termination codon generated on the third amino acid position from the site of deletion. Human Splice Finder 3.0 and MutationTaster have assessed this variation as disease causing, based on the alteration of splicing, creation of premature stop codon and other potential alterations initiated by nucleotide deletion. Among the most important alterations are frameshift and splice site changes (score of the newly created donor splice site: 0.82). c.4356delA was associated with two ovarian cancer cases in two families of Slavic origin. It was detected by next generation sequencing, and confirmed with Sanger sequencing in both cases. Because of the fact that it changes the reading frame of the protein, novel mutation c.4356delA p.(Ala1453Glnfs*3) in BRCA1 gene might be of clinical significance for hereditary ovarian cancer. Further functional as well as segregation analyses within the families are necessary for appropriate clinical classification of this variant. Since it has been detected in two ovarian cancer patients of Slavic origin, it is worth investigating founder effect of this mutation in Slavic populations.

Polymorphic expression of glutathione transferases A1, M1, P1 and T1 in epithelial ovarian cancer: a Serbian case-control study.

PURPOSE: Since several studies have proposed that epithelial ovarian cancer should not be considered as a single disease entity and that it results from an accumulation of genetic changes, we aimed to assess the polymorphic expression of major cytosolic glutathione S-transferases (GSTM1, T1, A1 and P1) with respect to ovarian cancer susceptibility and aggressiveness. METHODS: This case-control study was conducted on 93 newly diagnosed epithelial ovarian cancer patients and 178 healthy matched controls. The multiplex polymerase chain reaction (PCR) was used to detect homozygous deletions of GSTM1 and GSTT1 genes. Analysis of the single nucleotide polymorphism (SNP) GSTA1 C69T was performed using PCR-restriction fragment length polymorphism (RFLP), while for SNP GSTP1 Ile105Val real-time PCR was used. RESULTS: No significant association to ovarian cancer risk was found for individual GSTM1, GSTA1 and GSTP1 genotypes (p>0.05). However, the carriers of GSTT1-active genotype were at 2-fold higher risk of ovarian cancer development (95%CI: 1.00-4.01, p=0.049), which was even more elevated in the subgroup of patients with positive family history of cancer. Moreover, the frequency of all three GST genotypes that might be associated to ovarian cancer risk (GSTT1-active, GSTA1-active and GSTP1-referent) was significantly higher in patients than in the control group (p=0.042). Even more, patients who were carriers of combination of these three genotypes represented over 64% of the total number of patients within any of the International Federation of Gynecology and Obstetrics (FIGO) stages of ovarian cancer. CONCLUSIONS: This study provides supportive evidence that GSTs might affect both susceptibility and progression of ovarian cancer.

Delays in diagnosis and treatment of breast cancer: a multinational analysis.

BACKGROUND: Reducing treatment delay improves outcomes in breast cancer. The aim of this study was to determine factors influencing patient- and system-related delays in commencing breast cancer treatment in different countries. METHODS: A total of 6588 female breast cancer patients from 12 countries were surveyed. Total delay time was determined as the sum of the patient-related delay time (time between onset of the first symptoms and the first medical visit) and system-related delay time (time between the first medical visit and the start of therapy). RESULTS: The average patient-related delay time and total delay time were 4.7 (range: 3.4-6.2) weeks and 14.4 (range: 11.5-29.4) weeks, respectively. Longer patient-related delay times were associated with distrust and disregard, and shorter patient-related delay times were associated with fear of breast cancer, practicing self-examination, higher education level, being employed, having support from friends and family and living in big cities. The average system-related delay time was 11.1 (range: 8.3-24.7) weeks. Cancer diagnosis made by an oncologist versus another physician, higher education level, older age, family history of female cancers and having a breast lump as the first cancer sign were associated with shorter system-related delay times. Longer patient-related delay times and higher levels of distrust and disregard were predictors of longer system-related delay times. CONCLUSIONS: The delay in diagnosis and treatment of breast cancer remains a serious problem. Several psychological and behavioural patient attributes strongly determine both patient-related delay time and system-related delay time, but their strength is different in particular countries.

Platinum - sensitive relapsed epithelial ovarian cancer: not all the patients benefit from reinduction with carboplatin and paclitaxel.

BACKGROUND: It is widely accepted that patients with ovarian cancer relapsing 6 to 12 months after completion of a platinum-based regimen are considered to be partially platinum-sensitive. The aim of this study was to evaluate and correlate the efficacy and toxicity of reinduction with paclitaxel-carboplatin in a platinum-sensitive epithelial ovarian cancer patient cohort with previous platinum-free interval (PFI). MATERIAL/METHODS: We studied retrospectively 39 patients with platinum-sensitive epithelial ovarian cancer, who received primary chemotherapy at the Institute for Oncology and Radiology of Serbia, between January 2002 and May 2008. All patients were treated with paclitaxel and carboplatin for metastatic disease. Subsequent to progression, patients were re-treated with the same chemotherapy in group A (PFI 6-12 months) or group B (PFI ≥12 months). RESULTS: The number of patients in group A was 14, and in group B it was 25. Response rate to reinduction in group A was 36% (partial response, 36%; stable disease, 0%; progressive disease, 64%) and in group B was 68% (complete response, 60%; partial response, 8%; stable disease, 4%; progressive disease, 28%; P=.05). The median response duration of the patients in group A arm was 20 months, whereas it was 17 months for those in group B (P=.721). There were no significant differences in the toxicity profile between the 2 groups. CONCLUSIONS: In terms of objective response rate this study supports the reinduction of carboplatin and paclitaxel in patients with a prior PFI of at least 12 months only. To define the best approach and the optimal treatment of patients with partially platinum-sensitive disease more precisely, future studies should apply treatment-free interval as a stratification criterion.

[Association of estrogen and progesterone receptor levels and the expected response to chemotherapy and hormone therapy in breast carcinoma with increased expression of human epidermal growth factor 2]. / Zdruzeni sadrzaj receptora za estrogen i progesteron u predvidjanju odgovora na hemioterapiju u hormonsku terapiju u karcinomu dojke sa povecanom ekspresijom receptora za humani epidermalni faktor rasta dva.

The predictive value of Human Epidermal growth factor Receptor 2 (HER-2) on the response to chemotherapy and endocrine therapy in breast cancer patients has not yet been determined. The expression of other biomarkers in breast cancer can further influence the response to therapy. The aim of our study was to investigate if status of steroid receptors (SR) influenced the response to anthracycline-containing chemotherapy and tamoxifen in a group of HER-2 positive advanced breast cancer patients. Forty breast cancer patients, who were entered into the various prospective clinical trials conducted at the Institute of Oncology and Radiology of Serbia during their metastatic phase of disease, were involved into this analysis. Steroid receptors content were determined both by biochemical method and immunohistochemical (ICH) method, while HER-2 content were determined only by ICH method. Twelve out of 40 women were sequentially treated by anthracycline-containing chemotherapy and, always upon disease progression, with antiestrogen tamoxifen. The objective response to anthracycline therapy was obtained in 4 out of 12 patients (RR = 0.33, CI 95% = 0.05-0.61). In three of them the response to tamoxifen was noticed, as well. Of 8 anthracycline resistant patients in this group, 7 patients also had disease progression as best response to tamoxifen despite the fact that most of them (5 out of 7 tamoxifen resistant women) had positive SR status. Our results showed a trend (Fisher test, p = 0.06) that clinical response to anthracycline-containing chemotherapy might be of some predictive value for the response to subsequent tamoxifen therapy in HER-2 positive advanced breast cancer patients. However, these results were obtained on a small number of patients, so further investigation is warranted.