TROPION-Breast01: Datopotamab deruxtecan vs chemotherapy in pre-treated inoperable or metastatic HR+/HER2- breast cancer.

Improving the prognosis for patients with metastatic HR+/HER2- breast cancer remains an unmet need. Patients with tumors that have progressed on endocrine therapy and/or are not eligible for endocrine therapy had limited treatment options beyond chemotherapy. Antibody-drug conjugates are a novel and promising treatment class in this setting. Datopotamab deruxtecan (Dato-DXd) consists of a TROP2-directed humanized IgG1 monoclonal antibody attached via a serum-stable cleavable linker to a topoisomerase I inhibitor payload. TROPION-Breast01 is an ongoing phase III study that is evaluating the efficacy and safety of Dato-DXd compared with investigator's choice of standard-of-care chemotherapy in patients with inoperable or metastatic HR+/HER2- breast cancer who have received one or two prior lines of systemic chemotherapy in the inoperable or metastatic setting. Clinical Trial Registration: NCT05104866 (ClinicalTrials.gov).

Antibody-drug conjugates are a type of drug with two parts: an antibody that directs the drug to the cancer cells and a cancer-cell killing toxic payload. By binding to cancer cells before releasing the payload, treatment is directed to the site of action so there are fewer side effects in the rest of the body. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugates made up of datopotamab (antibody) and DXd (payload) which are joined together via a stable linker. Datopotamab binds to a protein found on cancer cells called TROP2; it then goes inside and releases the DXd payload to kill the tumor cells. DXd may leak out to surrounding cancer cells and kill those as well. The TROPION-Breast01 study is comparing Dato-DXd with standard-of-care chemotherapy. Around 700 patients will take part, who have: Tumors that cannot be surgically removed. Tumors that are hormone receptor-positive and do not have HER2 overexpression. Had one or two lines of previous chemotherapy (after the tumor could not be surgically removed, or had spread). Had tumor growth despite hormonal therapy or are ineligible for hormonal therapy. Patients who meet the entry criteria will be randomly assigned to a treatment group in equal numbers to either Dato-DXd or an appropriate chemotherapy, out of four options chosen by the treating doctor. At the end of the study, researchers will look at whether the patients who receive Dato-DXd live longer without their breast cancer getting worse, compared with patients who receive chemotherapy. This study is also looking at how the treatment affects patients' quality of life.

[Fertility preservation in female cancer patients.] / Daganatos nobetegek termékenységének megorzése.

In Hungary, an average of 2066 women under the age of 40 are diagnosed with cancer each year according to data from the National Cancer Registry. Approximately two-thirds of these patients require gonadotoxic treatment for their disease, which could potentially reduce their chances of future conception and childbirth. Currently, there are no professional guidelines on fertility preservation in Hungary, however, it is important to inform patients about their options. In our previous paper, we presented the gonadotoxic effects of oncotherapies and the currently available fertility preservation techniques. This second paper provides current treatment methods and recommends fertility preservation techniques in different cancer types. The success of an oncofertility program relies heavily on the effective communication and collaboration between oncologists and reproductive specialists involved in fertility preservation. This paper may be the first step in elaborating a guideline towards improving access to oncofertility services and ultimately improving the quality of life for young cancer survivors in Hungary. Orv Hetil. 2023; 164(29): 1134-1145.

Corrigendum: Systemic treatment of breast cancer. 1st Central-Eastern European professional Consensus Statement on breast cancer.

[This corrects the article DOI: 10.3389/pore.2022.1610383.].

Avelumab Plus Talazoparib in Patients With Advanced Solid Tumors: The JAVELIN PARP Medley Nonrandomized Controlled Trial.

Importance: Preclinical data suggest that poly(ADP-ribose) polymerase (PARP) inhibitors have synergistic activity when combined with immune checkpoint inhibitors (ICIs); however, it is unknown which tumor types or molecular subtypes may benefit from this combination. Objective: To investigate responses associated with the combination of avelumab and talazoparib in different tumor types and/or molecular subtypes. Design, Setting, and Participants: In this phase 1b and 2 basket nonrandomized controlled trial, patients with advanced solid tumors were enrolled in the following cohorts: non-small cell lung cancer (NSCLC); DNA damage response (DDR)-positive NSCLC; triple-negative breast cancer (TNBC); hormone receptor-positive, human epidermal growth factor receptor 2 (ERBB2)-negative, DDR-positive breast cancer; recurrent, platinum-sensitive ovarian cancer (OC); recurrent, platinum-sensitive, BRCA1/2-altered OC; urothelial cancer; metastatic castration-resistant prostate cancer (mCRPC); DDR-positive mCRPC; and BRCA1/2- or ATM-altered solid tumors. Data were analyzed between June 17, 2021, and August 6, 2021. Interventions: All patients in phases 1b and 2 received avelumab plus talazoparib. Main Outcomes and Measures: The phase 1b primary end point was dose-limiting toxic effects. The phase 2 primary end point was objective response, measured as objective response rate (ORR). Secondary end points included safety, time to response, duration of response (DOR), progression-free survival, time to prostate-specific antigen progression and PSA response of 50% or greater (for mCRPC), cancer antigen 125 response (for OC), pharmacokinetics, immunogenicity, and biomarkers. Results: A total of 223 patients (mean [SD] age, 63.2 [11.0] years; 117 [52.5%] men) were treated, including 12 patients in phase 1b and 211 patients in phase 2. The recommended phase 2 dose was avelumab 800 mg every 2 weeks plus talazoparib 1 mg once daily. In phase 2, the ORR was 18.2% (95% CI, 5.2%-40.3%) in patients with TNBC; 34.8% (95% CI, 16.4%-57.3%) in patients with HR-positive, ERBB2-negative, and DDR-positive BC; and 63.6% (95% CI, 30.8%-89.1%) in patients with platinum-sensitive, BRCA1/2-altered OC. Responses occurred more frequently in patients with BRCA1/2-altered tumors. Durable responses were observed in patients with TNBC (median [range] DOR, 11.1 [3.4-20.4] months); HR-positive, ERBB2-negative, and DDR-positive BC (median [range] DOR, 15.7 [3.9 to ≥20.6] months); and BRCA1/2-altered OC (median DOR not reached; range, 5.6 to ≥18.4 months). The most common grade 3 or greater treatment-related adverse events were anemia (75 patients [33.6%]), thrombocytopenia (48 patients [21.5%]), and neutropenia (31 patients [13.9%]). Conclusions and Relevance: This nonrandomized controlled trial found that ORRs for avelumab plus talazoparib were comparable with those with PARP inhibitor or ICI monotherapy. Prolonged DOR in patients with TNBC; HR-positive, ERBB2-negative, and DDR-positive BC; and BRCA1/2-altered OC warrant further investigation in randomized clinical trials. These data highlight the importance of prospective patient selection in future studies of ICI and PARP-inhibitor combinations. Trial Registration: ClinicalTrials.gov Identifier: NCT03330405.

Systemic Treatment of Breast Cancer. 1st Central-Eastern European Professional Consensus Statement on Breast Cancer.

This text is based on the recommendations accepted by the 4th Hungarian Consensus Conference on Breast Cancer, modified based on the international consultation and conference within the frames of the Central-Eastern European Academy of Oncology. The professional guideline primarily reflects the resolutions and recommendations of the current ESMO, NCCN and ABC5, as well as that of the St. Gallen Consensus Conference statements. The recommendations cover classical prognostic factors and certain multigene tests, which play an important role in therapeutic decision-making. From a didactic point of view, the text first addresses early and then locally advanced breast cancer, followed by locoregionally recurrent and metastatic breast cancer. Within these, we discuss each group according to the available therapeutic options. At the end of the recommendations, we summarize the criteria for treatment in certain rare clinical situations.

Ribociclib plus letrozole in patients with hormone receptor-positive, HER2-negative advanced breast cancer with no prior endocrine therapy: subgroup safety analysis from the phase 3b CompLEEment-1 trial.

BACKGROUND: The CDK4/6 inhibitor, ribociclib in combination with endocrine therapy significantly improved progression-free survival in the first line setting in post-menopausal patients with HR+/HER2- advanced breast cancer (ABC) in a pivotal phase 3, placebo-controlled trial (MONALEESA-2) and demonstrated superior overall survival in premenopausal patients with HR+/HER2- ABC (MONALEESA-7). The multinational, phase 3b, CompLEEment-1 trial, which assessed the safety and efficacy of ribociclib plus letrozole in a broader population of patients who have not received prior endocrine therapy for advanced disease, is the largest phase 3 clinical trial to date to evaluate the safety and efficacy of a CDK4/6 inhibitor. We report a subanalysis of data from patients (N = 339) enrolled in the central and south European countries of the SERCE (Southern Europe, RUC, Central Europe) cluster of CompLEEment-1. PATIENTS AND METHODS: Men and women of any menopausal status with HR+/HER2- ABC received once-daily oral ribociclib 600 mg (3-weeks on/1-week-off), plus letrozole 2.5 mg continuously. Men/premenopausal women also received a GnRH-agonist. The primary outcome was the number of patients with adverse events (AEs) over a timeframe of approximately 36 months. Time-to-progression, overall response rate, and clinical benefit rate were also measured. RESULTS: Safety results in the SERCE subgroup were consistent with those in the pivotal clinical trials of ribociclib in combination with endocrine therapy. Treatment-related AEs leading to dose adjustments/interruption occurred in 63.1% of patients but led to treatment discontinuation in only 10.6%. The most common treatment-related AEs of grade ≥ 3 were neutropenia and transaminase elevations. There were no fatal treatment-related events. CONCLUSIONS: These findings from the SERCE subgroup support the safety and manageable tolerability of ribociclib in a broad range of patients with HR+/HER2- ABC more representative of patients in real-world clinical practice.

Management Strategies for Hyperglycemia Associated with the α-Selective PI3K Inhibitor Alpelisib for the Treatment of Breast Cancer.

Alpelisib is an α-selective phosphatidylinositol 3-kinase inhibitor used for treating hormone receptor-positive (HR+), human epidermal growth receptor 2-negative (HER2-), PIK3CA-mutated locally advanced or metastatic breast cancer following disease progression on or after endocrine therapy. Hyperglycemia is an on-target effect of alpelisib affecting approximately 60% of treated patients, and sometimes necessitating dose reductions, treatment interruptions, or discontinuation of alpelisib. Early detection of hyperglycemia and timely intervention have a key role in achieving optimal glycemic control and maintaining alpelisib dose intensity to optimize the benefit of this drug. A glycemic support program implemented by an endocrinology-oncology collaborative team may be very useful in this regard. Lifestyle modifications, mainly comprising a reduced-carbohydrate diet, and a designated stepwise, personalized antihyperglycemic regimen, based on metformin, sodium-glucose co-transporter 2 inhibitors, and pioglitazone, are the main tools required to address the insulin-resistant hyperglycemia induced by alpelisib. In this report, based on the consensus of 14 oncologists and seven endocrinologists, we provide guidance for hyperglycemia management strategies before, during, and after alpelisib therapy for HR+, HER2-, PIK3CA-mutated breast cancer, with a focus on a proactive, multidisciplinary approach.

Demographic Characteristics and Treatment Patterns Among Patients Receiving Palbociclib for HR+/HER2- Advanced Breast Cancer: A Nationwide Real-World Experience.

BACKGROUND: This nationwide retrospective study reports data on the real-world use of the selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib in a large population of advanced breast cancer (ABC) patients during a 2-year period in Hungary. METHODS: All patients with ABC who received palbociclib between May 1, 2017 and June 30, 2019 were included in the analysis. Patient demographic and clinical characteristics, disease-related factors and treatment patterns were examined during the early access program and in the regular reimbursement period. RESULTS: Altogether, 962 patients were included (mean age: 60.6 years). A total of 399 patients (41%) were treated with palbociclib plus aromatase inhibitors (P+AI), and 563 patients (59%) received palbociclib and fulvestrant (P+F). The most commonly prescribed AI was letrozole (n=359; 90%). Of those with metastatic disease (n=733; 76%), 241 patients (33%) had visceral metastases and 449 (61%) had bone-only disease. The majority of patients (79%) received palbociclib as first- or second-line therapy for ABC. The starting dose of palbociclib was 125 mg in 98% of patients; dose reductions were required in 32% of patients receiving P+AI and 31% of those treated with P+F. At the time of data collection, palbociclib therapy was ongoing in 270 patients (68%) in the P+AI group and 245 patients (44%) in the P+F group. CONCLUSIONS: This nationwide analysis is the first to provide insights into the real-world use of palbociclib in a large patient population from a Central-Eastern European country. The findings confirm the good tolerability of palbociclib with similar dose reduction rates to those reported from registration trials.

Pathologic Complete Response Rates After Neoadjuvant Pertuzumab and Trastuzumab with Chemotherapy in Early Stage HER2-Positive Breast Cancer - Increasing Rates of Breast Conserving Surgery: A Real-World Experience.

Purpose: The neoadjuvant use of pertuzumab and trastuzumab with chemotherapy improves the pathologic complete response (pCR) in early HER2+ breast cancer. The aim of this study was to determine the pCR rate obtained with dual HER2 blockade in routine clinical practice. The secondary and tertiary objective was to investigate the impact of neoadjuvant systemic therapy (NST) on performing breast-conserving surgery and survival data. Methods: This was a multicentre, retrospective, observational study in patients with stage II and III HER2+ early breast cancer who received pertuzumab and trastuzumab-based NST. Data were collected from patients' medical records. Results: Eighty-two patients were included in the study treated in 8 cancer centers in Hungary between March 2015 and January 2020. The study included women with a median age of 50.3 years. The majority of the patients (95%) received a sequence of anthracycline-based chemotherapy followed by docetaxel. pCR was achieved in 54% of the cases. As a result of NST a significant increase of conservative breast surgeries (33% vs. 3.6% planned, p = 0.0001) was observed. Ki67 expression and neutrophil-to-lymphocyte ratio (NLR) significantly predicted pCR. None of the variables were independent predictors of DFS. Conclusion: The pCR rate achieved in our study demonstrates the reproducibility of trial data in a real-world population. The rate of breast-conserving surgery was significantly increased.

Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study.

BACKGROUND: Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer. METHODS: PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II-III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1-21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). FINDINGS: Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9-29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2-90·6) for palbociclib plus endocrine therapy and 88·5% (85·8-90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76-1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3-4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths. INTERPRETATION: At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing. FUNDING: Pfizer.

[Systemic treatment of breast cancer: professional guideline]. / Az emlorák szisztémás kezelése: szakmai irányelvek.

Since the III. Breast Cancer Consensus Conference, a number of new evidence based on clinical trial results have been published which justified updating the 2016 recommendation. In addition to classical prognostic factors, some multigenic tests, which we have incorporated into the recommendation, will play an important role in therapeutic decision-making. The professional guide primarily reflects the resolutions and recommendations of the current ESMO, NCCN, ABC4, as well as the St. Gallen Consensus Conference. From a didactic point of view, the text follows first the line of early and then locally advanced breast cancer, locoregionally recurrent and metastatic breast cancer. Within these, we discuss each group according to therapeutic options.

Long-Term Dynamic Changes in Cosmetic Outcomes and Patient Satisfaction after Implant-Based Postmastectomy Breast Reconstruction and Contralateral Mastopexy with or without an Ultrapro Mesh Sling Used for the Inner Bra Technique. A Retrospective Correlational Study.

Immediate implant-based postmastectomy breast reconstruction (IPMBR) with contralateral symmetrization has mostly short-term limited evidence of cosmetic outcomes. Because 84% of early-stage breast cancer patients have overall survival of more than 10 years, reconstructed breast symmetry should provide long-lasting results and acceptable patient satisfaction. Ageing, changes in body weight, and biomechanical changes after IPMBR and symmetrization may contribute to symmetry worsening. This non-interventional single-centre retrospective correlational study presents the clinical and aesthetic results of synthetic ULTRAPRO® mesh inner bra sling.

[Immunotherapy possibilities and results in breast cancer]. / Immunterápiás lehetõségek és eredmények emlõdaganatban.

In recent years, a number of tumor types have shown significant therapeutic benefit with immunotherapy. Breast cancer has not been regarded traditionally as a typical immunogenic tumor, however, based on results so far, immunotherapy may play a role in the therapy. The most important change in attitude is that the target of therapy is not the disease but the host. A better understanding of the host's immune system and the process between the tumor and host provides an opportunity for therapeutic intervention, in this case (re-)activating anti-tumor immune processes. The purpose of this summary is to briefly summarize for clinicians the basics of anti-tumor immunity process, the available clinical results and the major therapeutic options in this field.

Influence of mutagenic versus non-mutagenic pre-operative chemotherapy on the immune infiltration of residual breast cancer.

Background: Chemotherapeutic agents are often mutagenic. Induction of mutation associated neo-epitopes is one of the mechanisms by which chemotherapy is thought to increase the number of tumor-infiltrating lymphocytes. It is not known, however, whether treatment with various chemotherapeutic agents with different mutagenic capacity induce a significantly different number of stromal tumor-infiltrating lymphocytes (StrTIL) in residual cancer.Methods: One hundred and twenty breast carcinoma cases with residual disease that were treated with one of three types of pre-operative chemotherapy regimens were selected for the study. The percentage of StrTIL was evaluated in pretreatment core biopsies (pre-StrTIL) and post-treatment surgical tumor samples (post-StrTIL). TIL changes (ΔStrTIL) were calculated from the difference between post-StrTIL and pre-StrTIL.Results: When analyzing the pre-StrTIL and post-StrTIL among the three treatment groups, we detected significant StrTIL increase independently of the treatment applied. Based on distant metastases-free survival analysis, both post-StrTIL and ΔStrTIL was found to be independent prognostic factor in HR negative cases. Conclusions: Significant increase of StrTIL in the residual disease was observed in patients treated with the highly (platinum), moderately (cyclophosphamide) and marginally mutagenic chemotherapeutic agents (taxane, anthracycline). Increase in StrTIL in residual cancer compared to pretreatment tumor tissue is associated with improved distant metastasis-free survival in cases with HR negative breast carcinoma.

Evaluation of the central pedicled, modified Wise-pattern technique as a standard level II oncoplastic breast-conserving surgery: A retrospective clinicopathological study of 190 breast cancer patients.

Involving 207 breast cancer patients a retrospective study was performed to facilitate the acceptance of the central pedicled, modified Wise-pattern therapeutic mammoplasty technique as a standard volume-displacement level II oncoplastic breast-conserving surgery (OBCS). The overall local recurrence rate was 5.8% with an average follow-up of 43.9 months. The median time to the initiation of the adjuvant treatment was 4.9 weeks. Due to positive surgical margins, 13 (6.84%) completional surgeries were performed. In total, 45 complications (12.9%) were recorded. The median values of the esthetic outcomes represented improved cosmetic results. The modified Wise-pattern technique could be a standard, safe and repeatable level II volume-displacement OBCS.

A long-term retrospective comparative study of the oncological outcomes of 598 very young (≤35 years) and young (36-45 years) breast cancer patients.

BACKGROUND: Breast cancer diagnosed in very young women (VYWBC; ≤35 years) and young women (YWBC; 36-45 years) tends to be heterogeneous. The current study aimed to compare the clinicopathological characteristics and long-term clinical outcomes between YWBC and VYWBC subgroups. PATIENTS AND METHODS: The institutional prospectively led database was retrospectively analysed from 2000 to 2014 at the National Institute of Oncology, Hungary. A total of 297 patients were assigned to the VYWBC group, and 301 patients were assigned to the YWBC group. RESULTS: The median follow-up period was 69 months for the VYWBC group and 79 months for the YWBC group. Significant differences were observed based on breast cancer subtype. The proportion of Triple-negative and ER-negative patients was higher in the VYWBC group than in the YWBC group (P = 0.00008). The incidence of distant metastasis was significantly higher in the VYWBC group (P = 0.01). Significant differences in the frequency of chemotherapy (P = 0.049) and endocrine therapy (P = 0.037) were observed between the two groups. The YWBC group exhibited significantly better overall survival (OS) and disease-free survival (DFS) rates than did the VYWBC group (P = 0.00005 and P = 0.00004, respectively). CONCLUSION: Breast cancers in VYWBC are biologically different from those in YWBC and tend to be more aggressive. Younger age was associated with worse OS and DFS. Young women with breast cancer should be subgrouped into VYWBC and YWBC populations, and these subgroups should be targeted by specialized clinical trials and further investigations.

Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer.

BACKGROUND: PIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The PI3Kα-specific inhibitor alpelisib has shown antitumor activity in early studies. METHODS: In a randomized, phase 3 trial, we compared alpelisib (at a dose of 300 mg per day) plus fulvestrant (at a dose of 500 mg every 28 days and once on day 15) with placebo plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status. The primary end point was progression-free survival, as assessed by the investigator, in the cohort with PIK3CA-mutated cancer; progression-free survival was also analyzed in the cohort without PIK3CA-mutated cancer. Secondary end points included overall response and safety. RESULTS: A total of 572 patients underwent randomization, including 341 patients with confirmed tumor-tissue PIK3CA mutations. In the cohort of patients with PIK3CA-mutated cancer, progression-free survival at a median follow-up of 20 months was 11.0 months (95% confidence interval [CI], 7.5 to 14.5) in the alpelisib-fulvestrant group, as compared with 5.7 months (95% CI, 3.7 to 7.4) in the placebo-fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001); in the cohort without PIK3CA-mutated cancer, the hazard ratio was 0.85 (95% CI, 0.58 to 1.25; posterior probability of hazard ratio <1.00, 79.4%). Overall response among all the patients in the cohort without PIK3CA-mutated cancer was greater with alpelisib-fulvestrant than with placebo-fulvestrant (26.6% vs. 12.8%); among patients with measurable disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisib-fulvestrant group vs. 0.7% in the placebo-fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the alpelisib-fulvestrant group, as compared with 0.3% of those in the placebo-fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued alpelisib and placebo owing to adverse events were 25.0% and 4.2%, respectively. CONCLUSIONS: Treatment with alpelisib-fulvestrant prolonged progression-free survival among patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. (Funded by Novartis Pharmaceuticals; SOLAR-1 ClinicalTrials.gov number, NCT02437318.).

First Line Sorafenib Treatment for Metastatic Medullary Thyroid Cancer: Efficacy and Safety Analysis.

BACKGROUND: Medullary thyroid cancer (MTC) is a rare disease, the prognosis of advanced and metastatic disease is poor and few therapeutic options are available in this setting. Based on the results of phase II and III studies with sorafenib in differentiated thyroid cancer and the lack of availability of registered tyrosine kinase inhibitors, vandetabin and cabozantinib in Hungary, we designed a uncontrolled, prospective efficacy and safety study of patients with metastatic MTC treated with first-line sorafenib in five Hungarian oncology centers. METHODS: Ten consecutive patients with progressive or symptomatic metastatic MTC were included and started sorafenib 400  mg twice a day between June 2012 and March 2016. The primary end point was median progression-free survival (mPFS). Secondary endpoints included disease control rate, biochemical response, symptomatic response and toxicity. RESULTS: Four patients achieved partial remission (40%) according to RECIST 1.1 evaluation. Five patients had stable disease beyond 12 months (50%) and one patient had progressive disease (10%). Median PFS was 19.1 months. The disease control rate was 90%. Association between radiologic response and biochemical or symptomatic response was inconsistent. Most common side effects were Grade 1-2 fatigue (60%), palmar-plantar erythrodysesthesia, rash/dermatitis 50-50%, alopecia 40%. CONCLUSIONS: In our prospective case series in patients with MTC first-line sorafenib showed at least similar efficacy as in other small phase II trials and case reports. Based on comparable efficacy with registered tyrosine kinase inhibitors and it's manageable toxicity profile, we believe that sorafenib has role in the sequential treatment of MTC.

Predictive Value of Early Skin Rash in Cetuximab-Based Therapy of Advanced Biliary Tract Cancer.

Randomized trials in advanced biliary tract cancer (BTC) did not show benefit of cetuximab addition over chemotherapy. This is probably due to the lack of predictive biomarkers. The aim of this study was to explore possible predictive factors. Between 2009 and 2014, 57 patients were treated in 3-week cycles with cetuximab (250 mg/m2/week, loading dose: 400 mg/m2), gemcitabine (1000 mg/m2 on day 1 and 8), and capecitabine (1300 mg/m2/day on days 1-14). The objective response rate (ORR), progression-free (PFS) and overall survival (OS) and the adverse events (AEs) were evaluated. An exploratory analysis was performed to find possible predictive factors on clinicopathological characteristics, routine laboratory parameters and early AEs, which occurred within 2 months from the beginning of treatment. The ORR was 21%. The median PFS and OS were 34 (95% CI: 24-40) and 54 (43-67) weeks, respectively. The most frequent AEs were skin toxicities. In univariate analysis performance status, previous stent implantation, thrombocyte count at the start of therapy, early neutropenia and skin rash statistically significantly influenced the ORR, PFS and/or OS. In multivariate Cox regression analysis only normal thrombocyte count at treatment start and early acneiform rash were independent markers of longer survival. In patients showing early skin rash compared to the others the median PFS was 39 vs. 13 weeks and the median OS was 67 vs. 26 weeks, respectively. It is suggested that early skin rash can be used as a biomarker to select patients who would benefit from the treatment with cetuximab plus chemotherapy.

Recent Advances in the Neoadjuvant Treatment of Breast Cancer.

In the last few decades, neoadjuvant therapy for breast cancer has gained considerable therapeutic importance. Despite extensive clinical investigations, it has not yet been clarified whether neoadjuvant therapy would result in improved survival in comparison with the standard adjuvant setting in any subgroups of patients with breast cancer. Chemotherapy is especially effective in the treatment of endocrine insensitive tumors, and such ther-apeutic benefit can be assumed for patients with triple-negative, or hormone receptor-negative and human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, dose escalation, modification of the therapeutic regimens according to early tumor response, as well as the optimal sequence of administration are still matters of debate. There is a current debate between clinical experts regarding the concomitant and sequential administration of carboplatin and capecitabine, respectively, as part of the standard neoadjuvant treatment, as well as the use of bevacizumab, as part of the preoperative treatment. In case of HER2 positive tumors, an anti-HER2 agent can be administered as part of the preoperative treatment, and according to preliminary clinical data, dual HER2 blockade can also be reasonable. Further, chemotherapy-free regimens can be justified in highly endocrine sensitive tumors, while immune modulating agents may also gain particular importance in the case of certain subtypes of breast cancer. Several small-molecule targeted therapies are under clinical investigation and are expected to provide new neoadjuvant treatment options. However, novel, more predictive biomarkers are required for further evaluation of the neoadjuvant therapies, as well as the effect of novel targeted agents intended to be incorporated into neoadjuvant therapy.