Spatial predictors of immunotherapy response in triple-negative breast cancer.

Immune checkpoint blockade (ICB) benefits some patients with triple-negative breast cancer, but what distinguishes responders from non-responders is unclear1. Because ICB targets cell-cell interactions2, we investigated the impact of multicellular spatial organization on response, and explored how ICB remodels the tumour microenvironment. We show that cell phenotype, activation state and spatial location are intimately linked, influence ICB effect and differ in sensitive versus resistant tumours early on-treatment. We used imaging mass cytometry3 to profile the in situ expression of 43 proteins in tumours from patients in a randomized trial of neoadjuvant ICB, sampled at three timepoints (baseline, n = 243; early on-treatment, n = 207; post-treatment, n = 210). Multivariate modelling showed that the fractions of proliferating CD8+TCF1+T cells and MHCII+ cancer cells were dominant predictors of response, followed by cancer-immune interactions with B cells and granzyme B+ T cells. On-treatment, responsive tumours contained abundant granzyme B+ T cells, whereas resistant tumours were characterized by CD15+ cancer cells. Response was best predicted by combining tissue features before and on-treatment, pointing to a role for early biopsies in guiding adaptive therapy. Our findings show that multicellular spatial organization is a major determinant of ICB effect and suggest that its systematic enumeration in situ could help realize precision immuno-oncology.

Atezolizumab and chemotherapy for advanced or recurrent endometrial cancer (AtTEnd): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: At the time of AtTEnd trial design, standard treatment for advanced or recurrent endometrial cancer included carboplatin and paclitaxel chemotherapy. This trial assessed whether combining atezolizumab with chemotherapy might improve outcomes in this population. METHODS: AtTEnd was a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done in 89 hospitals in 11 countries across Europe, Australia, New Zealand, and Asia. Enrolled patients were aged 18 years or older, and had advanced or recurrent endometrial carcinoma or carcinosarcoma, an Eastern Cooperative Oncology Group performance status of 0-2, and received no previous systemic chemotherapy for recurrence. Patients were randomly assigned (2:1) using an interactive web response system (block size of six) to either atezolizumab 1200 mg or placebo given intravenously with chemotherapy (carboplatin at area under the curve of 5 or 6 and paclitaxel 175 mg/m2 intravenously on day 1 every 21 days) for 6-8 cycles, then continued until progression. Stratification factors were country, histological subtype, advanced or recurrent status, and mismatch repair (MMR) status. Participants and treating clinicians were masked to group allocation. The hierarchically tested co-primary endpoints were progression-free survival (in patients with MMR-deficient [dMMR] tumours, and in the overall population) and overall survival (in the overall population). Primary analyses were done in the intention-to-treat population, defined as all randomly assigned patients who gave their full consent to participation in the study and data processing. Safety was assessed in all patients included in the intention-to-treat population who received at least one dose of study treatment. Here, we report the primary progression-free survival and the interim overall survival results. This study is ongoing and is registered with ClinicalTrials.gov, NCT03603184. FINDINGS: Between Oct 3, 2018, and Jan 7, 2022, 551 patients were randomly assigned to atezolizumab (n=362) or placebo (n=189). Two patients in the atezolizumab group were excluded from all analyses due to lack of consent. Median follow-up was 28·3 months (IQR 21·2-37·6). 81 (23%) patients in the atezolizumab group and 44 (23%) patients in the placebo group had dMMR disease by central assessment. In the dMMR population, median progression-free survival was not estimable (95% CI 12·4 months-not estimable [NE]) in the atezolizumab group and 6·9 months (6·3-10·1) in the placebo group (hazard ratio [HR] 0·36, 95% CI 0·23-0·57; p=0·0005). In the overall population, median progression-free survival was 10·1 months (95% CI 9·5-12·3) in the atezolizumab group and 8·9 months (8·1-9·6) in the placebo group (HR 0·74, 95% CI 0·61-0·91; p=0·022). Median overall survival was 38·7 months (95% CI 30·6-NE) in the atezolizumab group and 30·2 months (25·0-37·2) in the placebo group (HR 0·82, 95% CI 0·63-1·07; log-rank p=0·048). The p value for the interim analysis of overall survival did not cross the stopping boundary; therefore, the trial will continue until the required number of events are recorded. The most common grade 3-4 adverse events were neutropenia (97 [27%] of 356 patients in the atezolizumab group vs 51 [28%] of 185 in the placebo group) and anaemia (49 [14%] vs 24 [13%]). Treatment-related serious adverse events occurred in 46 (13%) patients in the atezolizumab group and six (3%) patients in the placebo group. Treatment-related deaths occurred in two patients (pneumonia in one patient in each group). INTERPRETATION: Atezolizumab plus chemotherapy increased progression-free survival in patients with advanced or recurrent endometrial carcinoma, particularly in those with dMMR carcinomas, suggesting the addition of atezolizumab to standard chemotherapy as first-line treatment in this specific subgroup. FUNDING: F Hoffmann-La Roche.

Safety and efficacy analysis of neoadjuvant pertuzumab, trastuzumab and standard chemotherapy for HER2-positive early breast cancer: real-world data from NeoPowER study.

BACKGROUND: The addition of pertuzumab (P) to trastuzumab (H) and standard chemotherapy (CT) as neoadjuvant treatment (NaT) for patients with HER2 + breast cancer (BC), has shown to increase the pathological complete response (pCR) rate, without main safety concerns. The aim of NeoPowER trial is to evaluate safety and efficacy of P + H + CT in a real-world population. METHODS: We retrospectively reviewed the medical records of stage II-III, HER2 + BC patients treated with NaT: who received P + H + CT (neopower group) in 5 Emilia Romagna institutions were compared with an historical group who received H + CT (control group). The primary endpoint was the safety, secondary endpoints were pCR rate, DRFS and OS and their correlation to NaT and other potential variables. RESULTS: 260 patients were included, 48% received P + H + CT, of whom 44% was given anthraciclynes as part of CT, compared to 83% in the control group. The toxicity profile was similar, excluding diarrhea more frequent in the neopower group (20% vs. 9%). Three patients experienced significant reductions in left ventricular ejection fraction (LVEF), all receiving anthracyclines. The pCR rate was 46% (P + H + CT) and 40% (H + CT) (p = 0.39). The addition of P had statistically correlation with pCR only in the patients receiving anthra-free regimens (OR = 3.05,p = 0.047). Preoperative use of anthracyclines (OR = 1.81,p = 0.03) and duration of NaT (OR = 1.18,p = 0.02) were statistically related to pCR. 12/21 distant-relapse events and 14/17 deaths occurred in the control group. Patients who achieve pCR had a significant increase in DRFS (HR = 0.23,p = 0.009). CONCLUSIONS: Adding neoadjuvant P to H and CT is safe. With the exception of diarrhea, rate of adverse events of grade > 2 did not differ between the two groups. P did not increase the cardiotoxicity when added to H + CT, nevertheless in our population all cardiac events occurred in patients who received anthracycline-containing regimens. Not statistically significant, higher pCR rate is achievable in patients receiving neoadjuvant P + H + CT. The study did not show a statistically significant correlation between the addition of P and long-term outcomes.

Management of cutaneous adverse events caused by antineoplastic therapies: a single-center experience.

INTRODUCTION: Cutaneous adverse events can occur in patients treated with antineoplastic treatments, albeit their incidence has not been defined yet. The clinical presentation of CAEs related to anticancer treatments can vary. The purpose of our study is to characterize skin toxicities during oncological treatments, manage such adverse events to improve patients' quality of life, and ensure therapeutic adherence. METHODS: We conducted a single-center prospective study which provided the enrollment of all patients referred to the Skin Toxicity Outpatient Clinic for the occurrence of cutaneous adverse events secondary to an ongoing antineoplastic treatment, between July 2021 and June 2023. We analyzed clinical features, and we described our therapeutic approach. RESULTS: Based on the type of drug assumed, chemotherapy-induced skin toxicity in 24 (38.7%) of the 62 evaluated patients, target therapies in 18 (29.0%), CDK4/6 cyclin inhibitors in 12 (19.4%), and immunotherapy in 6 (9.7%), while skin adverse events secondary to hormone therapy were seen in two patients. The most common cutaneous adverse event in our experience was rosaceiform rash of the face, followed by eczematous rash, hand-foot syndrome, and folliculitis. CONCLUSION: The present study is aimed at describing the variability and heterogeneity of clinical manifestations of different pharmacological classes used in oncological patients, as well as the different pathogenesis of skin damage. Chemotherapy very frequently causes skin toxicities that are often underestimated by clinicians. Their adequate recognition and optimal treatment lead to total recovery and allow better adhesion to chemotherapy.

Updated progression-free survival and final overall survival with maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial.

OBJECTIVE: In the PAOLA-1/ENGOT-ov25 trial (NCT02477644), adding maintenance olaparib to bevacizumab provided a substantial progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and homologous recombination deficiency (HRD)-positive tumors, irrespective of clinical risk. Subsequently, a clinically meaningful improvement in overall survival was reported with olaparib plus bevacizumab in the HRD-positive subgroup. We report updated progression-free survival and overall survival by clinical risk and HRD status. METHODS: Patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab received maintenance olaparib (up to 24 months) plus bevacizumab (up to 15 months in total) or placebo plus bevacizumab. This post hoc analysis evaluated 5-year progression-free survival and mature overall survival in patients classified by clinical risk and HRD status. RESULTS: Of 806 randomized patients, 74% were higher-risk and 26% were lower-risk. In higher-risk HRD-positive patients, the hazard ratio (HR) for progression-free survival was 0.46 (95% confidence interval (95% CI) 0.34 to 0.61), with 5-year progression-free survival of 35% with olaparib plus bevacizumab versus 15% with bevacizumab alone; and the HR for overall survival was 0.70 (95% CI 0.50 to 1.00), with 5-year overall survival of 55% versus 42%, respectively. In lower-risk HRD-positive patients, the HR for progression-free survival was 0.26 (95% CI 0.15 to 0.45), with 5-year progression-free survival of 72% with olaparib plus bevacizumab versus 28% with bevacizumab alone; and the HR for overall survival was 0.31 (95% CI 0.14 to 0.66), with 5-year overall survival of 88% versus 61%, respectively. No benefit was seen in HRD-negative patients regardless of clinical risk. CONCLUSION: This post hoc analysis indicates that in patients with newly diagnosed advanced HRD-positive ovarian cancer, maintenance olaparib plus bevacizumab should not be limited to those considered at higher risk of disease progression. Five-year progression-free survival rates support long-term remission and suggest an increased potential for cure with particular benefit suggested in lower-risk HRD-positive patients.

Randomized phase II trial of farletuzumab plus chemotherapy versus placebo plus chemotherapy in low CA-125 platinum-sensitive ovarian cancer.

OBJECTIVE: The primary purpose of this study was to determine if farletuzumab, an antifolate receptor-α monoclonal antibody, improved progression-free survival (PFS) versus placebo when added to standard chemotherapy regimens in patients with platinum-sensitive recurrent ovarian cancer (OC) in first relapse (platinum-free interval: 6-36 months) with low cancer antigen 125 (CA-125) levels. METHODS: Eligibility included CA-125 ≤ 3 x upper limit of normal (ULN, 105 U/mL), high-grade serous, platinum-sensitive recurrent OC, previous treatment with debulking surgery, and first-line platinum-based chemotherapy with 1st recurrence between 6 and 36 months since frontline platinum-based treatment. Patients received investigator's choice of either carboplatin (CARBO)/paclitaxel (PTX) every 3 weeks or CARBO/pegylated liposomal doxorubicin (PLD) every 4 weeks x6 cycles in combination with either farletuzumab [5 mg/kg weekly] or placebo randomized in a 2:1 ratio. Maintenance treatment with farletuzumab (5 mg/kg weekly) or placebo was given until disease progression or intolerance. RESULTS: 214 patients were randomly assigned to farletuzumab+chemotherapy (142 patients) versus placebo+chemotherapy (72 patients). The primary efficacy endpoint, PFS, was not significantly different between treatment groups (1-sided α = 0.10; p-value = 0.25; hazard ratio [HR] = 0.89, 80% confidence interval [CI]: 0.71, 1.11), a median of 11.7 months (95% CI: 10.2, 13.6) versus 10.8 months (95% CI: 9.5, 13.2) for farletuzumab+chemotherapy and placebo+chemotherapy, respectively. No new safety concerns were identified with the combination of farletuzumab+chemotherapy. CONCLUSIONS: Adding farletuzumab to standard chemotherapy does not improve PFS in patients with OC who were platinum-sensitive in first relapse with low CA-125 levels. Folate receptor-α expression was not measured in this study. (Clinical Trial Registry NCT02289950).

Post-operative residual disease and number of cycles of neoadjuvant chemotherapy in advanced epithelial ovarian carcinoma.

BACKGROUND: The optimal number of neoadjuvant chemotherapy cycles in patients with advanced ovarian cancer is still disputed. OBJECTIVE: To evaluate the impact of the number of neoadjuvant chemotherapy cycles and role of optimal cytoreduction on the prognosis of patients with advanced ovarian cancer. METHODS: Clinical and pathological details were examined. Patients were evaluated combining the number of cycles of neoadjuvant chemotherapy-namely, 'interval debulking surgery' after up to four neoadjuvant chemotherapy cycles, and 'delayed debulking surgery' after more than four cycles of therapy. RESULTS: A total of 286 patients were included in the study. Complete cytoreduction with no residual peritoneal disease (CC0) was achieved in 74 (74%) patients with interval debulking surgery and 124 (66.7%) patients with delayed interval debulking. Of those with residual disease, there were 26/88 (29.5%) patients in the interval debulking surgery group and 62/88 (70.5%) patients in the delayed debulking surgery group. Comparison of patients with delayed debulking-CC0 and interval debulking-CC0 showed no difference in progression-free survival (p=0.3) or overall survival (p=0.4), while significantly worse outcomes were observed in patients with interval debulking-CC1 (p=0.02 and p=0.04, respectively). Specifically, patients with interval debulking-CC1 had an approximately 67% increased risk of disease progression (p=0.04; HR=2.01 (95% CI 1.04 to 4.18)) and a 69% higher risk of death than patients with delayed debulking-CC0 (p=0.03; HR=2.34 (95% CI 1.11 to 4.67)). CONCLUSION: Increasing the number of neoadjuvant chemotherapy cycles does not worsen patient outcomes if complete resection is achieved. Nevertheless, additional prospective trials are necessary to establish the optimum number of neoadjuvant chemotherapy cycles.

Ribociclib plus letrozole in male patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: subgroup analysis of the phase IIIb CompLEEment-1 trial.

PURPOSE: CompLEEment-1 (NCT02941926) is a single-arm, open-label, multicentre phase IIIb study investigating the safety and efficacy of ribociclib plus letrozole (RIB + LET) in a large, diverse cohort who have not received prior endocrine therapy (ET) for advanced disease. We present an exploratory analysis of male patients. METHODS: Eligible patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), who had no prior ET and ≤ 1 line of prior chemotherapy for advanced disease, received RIB + LET. Male patients also received goserelin or leuprolide. Primary endpoint was safety and tolerability; efficacy was a secondary endpoint. RESULTS: In total, 39/3246 patients were male. Baseline characteristics were similar to the overall population. Male patients experienced fewer treatment-related adverse events (AEs) and treatment-related serious AEs compared with the overall population; fewer male patients had treatment-related AEs leading to discontinuation, adjustment/interruption, or additional therapy. One male patient died as a result of a serious AE that was not considered to be treatment-related. The most common AE was neutropenia; the incidence of grade ≥ 3 neutropenia in males (41.0%) was lower than in the overall population (57.2%). Median follow-up was 25.4 months; median time to progression was not reached in males versus 27.1 months for the overall population. CONCLUSION: The clinical benefit and overall response rates in males were consistent with the overall population. This analysis demonstrates the safety and efficacy of ribociclib in a close-to-real-world setting, supporting the use of RIB + LET in male patients with HR+, HER2- ABC. TRIAL REGISTRATION NUMBER: NCT02941926 (Registered 2016).

Management of malignant cutaneous wounds in oncologic patients.

PURPOSE: Neoplastic wounds may develop as a result of primary tumor growth in the skin, due to metastasis, or due to skin invasion by tumors emerging from deeper levels. Malignant wounds may present as a crater-like ulcer, or as raised nodules with a cauliflower-like appearance. They are associated with malodor, necrosis, pain, bleeding, and secondary infection. The aim of our study is to better characterize fungating wounds and their management. METHODS: We retrospectively reviewed the database of the Wound Care Unit of the University of Bologna in order to identify individuals affected by neoplastic wound, between January 2019 and February 2021. RESULTS: We identified 9 females and 2 males with a mean age of 63 years; all were referred by the Oncology Unit. Management differed depending on the characteristics of the patients and the ulcers. Complete healing of the wound, following the parallel complete remission of the lymphoproliferative neoplasia, was observed in one individual. Among the others, one died because of breast cancer, while cutaneous lesions in 2 individuals deteriorated after 1 year of follow-up. Remission/relapse of the ulcer following the treatment course administered for the lymphoma were observed in one patient. CONCLUSIONS: Treatment of malignant fungating wounds is challenging. Considering the neoplastic nature of the wounds, complete healing or improvement cannot be expected with the application of classically prescribed dressing for wounds. A mostly palliative treatment, focusing on maintaining the patient's quality of life, is a reasonable choice.

A Long-Term Extension Study of Bevacizumab in Patients With Solid Tumors.

BACKGROUND: Bevacizumab has been studied in numerous clinical trials in multiple types of cancer; however, patients may receive bevacizumab over an extended period of time. This study assessed the long-term safety and tolerability of bevacizumab among patients with solid tumors. MATERIALS AND METHODS: Patients enrolled in a Roche/Genentech-sponsored trial who had derived benefit from bevacizumab therapy as monotherapy or in combination with anticancer drugs were eligible for continuation of bevacizumab in this long-term extension (LTE) study. The primary endpoints were the incidence of adverse events (AEs) of Common Terminology Criteria for AEs (CTCAE) grade ≥3 related to bevacizumab treatment, serious AEs (SAEs), and deaths. RESULTS: Ninety-five patients with the following cancer types were enrolled in the LTE: ovarian cancer or peritoneal carcinoma (n = 41), non-small cell lung cancer (n = 16), glioblastoma multiforme (n = 14), breast cancer (n = 11), colorectal cancer (n = 7), or renal cell carcinoma (n = 6). The median (range) duration of bevacizumab treatment was 15.6 (0.0-81.0) months during the LTE and 57.5 (16.4-134.9) months overall (parent trial + LTE), with three patients receiving bevacizumab for >10 years. Overall, 17 patients (17.9%) experienced SAEs, and 21 (22.1%) had a bevacizumab-related AE of CTCAE grade ≥3 (proteinuria and hypertension were the most common). Four patients died: three from disease progression and one from an AE considered unrelated to bevacizumab. CONCLUSION: The safety outcomes observed support the tolerability of long-term bevacizumab in patients with various solid tumors, with a median extended treatment duration of almost 5 years overall and >10 years in some individual patients. ClinicalTrials.gov identifier: NCT01588184. IMPLICATIONS FOR PRACTICE: In this long-term extension study of patients with solid tumors, the median duration of bevacizumab treatment (including parent trials) was just under 5 years, with a long-term exposure in some patients of 7 to >10 years. Grade ≥3 adverse events related to bevacizumab were consistent with the established safety profile, with proteinuria and hypertension being the most common. Patients received bevacizumab over an extended period of time (beyond the length of most clinical trials), and the overall safety outcomes observed support the tolerability of long-term bevacizumab treatment in patients with solid tumors, with clinical benefit achieved over an extended period.

Full population results from the core phase of CompLEEment-1, a phase 3b study of ribociclib plus letrozole as first-line therapy for advanced breast cancer in an expanded population.

PURPOSE: CompLEEment-1 is a phase 3b trial in an expanded patient population with hormone receptor-positive (HR +), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC), the largest current trial of cyclin-dependent kinase 4 and 6 inhibitors in ABC. METHODS: Patients treated with ≤ 1 line of prior chemotherapy and no prior endocrine therapy for ABC received ribociclib 600 mg/day (3-weeks-on/1-week-off) plus letrozole 2.5 mg/day and additionally monthly goserelin/leuprolide in men and pre-/perimenopausal women. Eligibility criteria allowed inclusion of patients with stable CNS metastases and an Eastern Cooperative Oncology Group performance status of 2. Primary objectives were safety and tolerability, and secondary objectives were efficacy and quality of life (QoL). RESULTS: Overall, 3,246 patients were evaluated (median follow-up 25.4 months). Rates of all-grade and grade ≥ 3 treatment-related adverse events (AEs) were 95.2% and 67.5%, respectively. Treatment-related discontinuations due to all grade and grade ≥ 3 AEs occurred in 12.9% and 7.3% of patients, respectively. Rates of all-grade AEs of special interest (AESI) were as follows: neutropenia (74.5%), increased alanine aminotransferase (16.2%), increased aspartate aminotransferase (14.1%), and QTcF prolongation (6.7%); corresponding values for grade ≥ 3 AESI were 57.2%, 7.7%, 5.7%, and 1.0%, respectively. Median time to progression was 27.1 months (95% confidence interval, 25.7 to not reached). Patient QoL was maintained during treatment. CONCLUSION: Safety and efficacy data in this expanded population were consistent with the MONALEESA-2 and MONALEESA-7 trials and support the use of ribociclib plus letrozole in the first-line setting for patients with HR + , HER2- ABC. TRIAL REGISTRATION: linicalTrials.gov NCT02941926.

COVID-19 free oncologic surgical hub: The experience of reallocation of a gynecologic oncology unit during pandemic outbreak.

INTRODUCTION: During the SARS-CoV-2 pandemic, the majority of healthcare resources of the affected Italian regions were allocated to COVID-19 patients. Due to lack of resources and high risk of death, most cancer patients have been shifted to non-surgical treatments. The following reports our experience of a Gynaecologic Oncology Unit's reallocation of resources in a COVID-19 free surgical oncologic hub in order to guarantee standard quality of surgical activities. MATERIALS AND METHODS: This is a prospective observational study performed in the Gynaecologic Oncology Unit, on the outcomes of the reallocation of surgical activities outside the University Hospital of Bologna, Italy, during the Italian lockdown period. Here, we described our COVID-19 free surgical oncologic pathway, in terms of lifestyle restrictions, COVID-19 screening measures, and patient clinical, surgical and follow up outcomes. RESULTS: During the lockdown period (March 9th - May 4th, 2020), 83 patients were scheduled for oncological surgery, 51 patients underwent surgery. Compared to pre-COVID period, we performed the same activities: number of cases scheduled for surgery, type of surgery and surgical and oncological results. No cases of COVID-19 infection were recorded in operated patients and in medical staff. Patients were compliant and well accepted the lifestyle restrictions and reorganization of the care. CONCLUSIONSONCLUSIONS: Our experience showed that the prioritization of oncological surgical care and the allocation of resources during a pandemic in COVID-19 free surgical hubs is an appropriate choice to guarantee oncological protocols.

Sharing real-world experiences to optimize the management of olaparib toxicities: a practical guidance from an Italian expert panel.

Olaparib is the first poly(ADP-ribose) polymerase inhibitor approved as maintenance therapy of recurrent ovarian cancer (OC) patients with a BRCA mutation. To achieve the maximum clinical benefit, adherence to olaparib must be persistent. However, in clinical practice, this is challenged by the frequent suboptimal management of toxicities. In view of the expanding use of olaparib also in Italy, physicians must learn how to adequately and promptly manage drug toxicities not to unnecessarily interrupt or reduce the dose. The experts agreed that nausea,vomiting, anemia, and fatigue are the most frequent events experienced by OC patients on olaparib, and that these toxicities usually develop early during treatment, are mainly of grade 1-2 and transient and can be managed with simple non-pharmacological interventions. By sharing their real-world experiences, the panel prepared, for each toxicity, an algorithm organized by grade and besides the procedures indicated in the local label, included supportive care interventions based also on nutritional and lifestyle modifications and psycho-oncology consultation. Moreover, in view of the tablet entry into the Italian market, the full and reduced dosages of capsules and tablets were compared. This practical guidance is intended to be a tool to support especially less-experienced physicians in the management of these complex patients, with the aim to help preventing the worsening of patients' conditions and the unnecessary interruption/reduction of olaparib dosage, which may jeopardize treatment efficacy.

Palbociclib plus endocrine therapy in HER2 negative, hormonal receptor-positive, advanced breast cancer: A real-world experience.

Data from 423 human epidermal growth factor receptor 2-negative (HER2-), hormone receptor-positive (HR+) advanced breast cancer (aBC) patients treated with palbociclib and endocrine therapy (ET) were provided by 35 Italian cancer centers and analyzed for treatment outcomes. Overall, 158 patients were treated in first line and 265 in second/later lines. We observed 19 complete responses and 112 partial responses. The overall response rate (ORR) was 31% (95% confidence interval [CI], 26.6-35.4) and clinical benefit was 52.7% (95% CI, 48-57.5). ORR was negatively affected by prior exposure to everolimus/exemestane ( p = 0.002) and favorably influenced by early line-treatment ( p < 0.0001). At 6 months, median progression-free survival was 12 months (95% CI, 8-16) and median overall survival was 24 months (95% CI, 17-30). More favorable outcomes were associated with palbociclib in early lines, no visceral metastases and no prior everolimus/exemestane. The main toxicity reported was neutropenia. Our results provide further support to the use of palbociclib with ET in HER2-, HR+ aBC. Differences in outcomes across patients subsets remain largely unexplained.

Validation of the AJCC prognostic stage for HER2-positive breast cancer in the ShortHER trial.

BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) staging has introduced prognostic stage based on anatomic stage combined with biologic factors. We aimed to validate the prognostic stage in HER2-positive breast cancer patients enrolled in the ShortHER trial. METHODS: The ShortHER trial randomized 1253 HER2-positive patients to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Patients were classified according to the anatomic and the prognostic stage. Distant disease-free survival (DDFS) was calculated from randomization to distant relapse or death. RESULTS: A total of 1244 patients were included. Compared to anatomic stage, the prognostic stage downstaged 41.6% (n = 517) of patients to a more favorable stage category. Five-year DDFS based on anatomic stage was as follows: IA 96.6%, IB 94.1%, IIA 92.4%, IIB 87.3%, IIIA 81.3%, IIIC 70.5% (P < 0.001). Five-year DDFS according to prognostic stage was as follows: IA 95.7%, IB 91.4%, IIA 86.9%, IIB 85.0%, IIIA 77.6%, IIIC 67.7% (P < 0.001). The C index was similar (0.69209 and 0.69249, P = 0.975). Within anatomic stage I, the outcome was similar for patients treated with 9 weeks or 1 year trastuzumab (5-year DDFS 96.2% and 96.6%, P = 0.856). Within prognostic stage I, the outcome was numerically worse for patients treated with 9 weeks trastuzumab (5-year DDFS 93.7% and 96.3%, P = 0.080). CONCLUSIONS: The prognostic stage downstaged 41.6% of patients, while maintaining a similar prognostic performance as the anatomic stage. The prognostic stage is valuable in counseling patients and may serve as reference for a clinical trial design. Our data do not support prognostic stage as guidance to de-escalate treatment. TRIAL REGISTRATION: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

DPYD*6 plays an important role in fluoropyrimidine toxicity in addition to DPYD*2A and c.2846A>T: a comprehensive analysis in 1254 patients.

Dihydropyrimidine dehydrogenase (DPYD) is a highly polymorphic gene and classic deficient variants (i.e., c.1236G>A/HapB3, c.1679T>G, c.1905+1G>A and c.2846A>T) are characterized by impaired enzyme activity and risk of severe adverse drug reactions (ADRs) in patients treated with fluoropyrimidines. The identification of poor metabolizers by pre-emptive DPYD screening may reduce the rate of ADRs but many patients with wild-type genotype for classic variants may still display ADRs. Therefore, the search for additional DPYD polymorphisms associated with ADRs may improve the safety of treatment with fluoropyrimidines. This study included 1254 patients treated with fluoropyrimidine-containing regimens and divided into cohort 1, which included 982 subjects suffering from gastrointestinal G≥2 and/or hematological G≥3 ADRs, and cohort 2 (control group), which comprised 272 subjects not requiring dose reduction, delay or discontinuation of treatment. Both groups were screened for DPYD variants c.496A>G, c.1236G>A/HapB3, c.1601G>A (DPYD*4), c.1627A>G (DPYD*5), c.1679T>G (DPYD*13), c.1896T>C, c.1905 + 1G>A (DPYD*2A), c.2194G>A (DPYD*6), and c.2846A>T to assess their association with toxicity. Genetic analysis in the two cohorts were done by Real-Time PCR of DNA extracted from 3 ml of whole blood. DPYD c.496A>G, c.1601G>A, c.1627A>G, c.1896T>C, and c.2194G>A variants were found in both cohort 1 and 2, while c.1905+1G>A and c.2846A>T were present only in cohort 1. DPYD c.1679T>G and c.1236G>A/HapB3 were not found. Univariate analysis allowed the selection of c.1905+1G>A, c.2194G>A and c.2846A>T alleles as significantly associated with gastrointestinal and hematological ADRs (p < 0.05), while the c.496A>G variant showed a positive trend of association with neutropenia (p = 0.06). In conclusion, c.2194G>A is associated with clinically-relevant ADRs in addition to the already known c.1905+1G>A and c.2846A>T variants and should be evaluated pre-emptively to reduce the risk of fluoropyrimidine-associated ADRs.

Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study.

BACKGROUND: In the neoadjuvant setting, blockade of HER2 plus use of an aromatase inhibitor in patients with HER2-positive and oestrogen receptor (ER)-positive breast cancer leads to a pathological complete response in 21% of patients. Convergence of HER2 and ER signals on RB1 suggests that a combined pharmacological intervention directed to these targets could be synergistic. To test this approach, we combined palbociclib to block RB1, fulvestrant to block ER, and trastuzumab with pertuzumab to block HER2 in patients with HER2-positive, ER-positive breast cancer. METHODS: NA-PHER2 is a multicohort, open-label, exploratory, phase 2 study done at seven sites in Italy. Patients were eligible for the first cohort if they had previously untreated, histologically confirmed, unilateral, invasive, HER2-positive, ER-positive breast cancer and were suitable for neoadjuvant therapy. Patients were treated every 3 weeks with intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and intravenous pertuzumab (840 mg loading dose in the first cycle and then at 420 mg) for six cycles plus oral palbociclib (125 mg once a day for 21 days in a 4-week cycle) and intramuscular fulvestrant (500 mg) every 4 weeks for five cycles. The coprimary endpoints were change from baseline in Ki67 expression at 2 weeks of treatment and at surgery (16 weeks after treatment) and changes in apoptosis from baseline to surgery. Secondary endpoints were clinical objective response (according to modified Response Evaluation Criteria in Solid Tumors) and pathological complete response. All patients who met eligibility criteria were assessed for the primary and secondary endpoints. All patients who received at least one cycle of therapy were assessed for safety. This trial is registered with ClinicalTrials.gov, number NCT02530424. The trial is ongoing and two further cohorts are being enrolled. FINDINGS: Between May 20, 2015, and Feb 8, 2016, we enrolled 36 patients, of whom one was deemed ineligible for the study and five were found to be HER2-negative on retrospective analysis. Thus, 35 patients were included in safety analyses and 30 were assessed for the primary and secondary endpoints. At baseline, geometric mean Ki67 expression was 31·9 (SD 15·7), versus 4·3 (15·0) at week 2 (n=25; p<0·0001) and 12·1 (20·0) at time of surgery (n=22; p=0·013). The geometric mean for apoptosis was 1·2 (SD 0·3) at baseline versus 0·4 (0·4; p=0·019) at surgery. A clinical objective response immediately before surgery was achieved by 29 (97%; 95% CI 83-100) of 30 patients. At surgery, eight (27%; 95% CI 12-46) patients had a pathological complete response in breast and axillary nodes. The most frequent grade 3 adverse events were neutropenia (ten [29%]), diarrhoea (five [14%]), and stomatitis, increased alanine aminotransferase, and hypersensitivity reactions (one [3%] of each event). No grade 4 or serious adverse events were recorded in the study and there were no deaths. INTERPRETATION: The combination of palbociclib, fulvestrant, trastuzumab, and pertuzumab had a significant effect on the expression of Ki67 at 2 weeks and at surgery. Triple targeting of ER, HER2, and RB1 in HER2-positive and ER-positive breast cancer could be an effective chemotherapy-free treatment strategy. Further clinical testing and additional molecular characterisation is necessary, not only in hormone receptor-positive tumours but also in tumours without HER2 amplification. FUNDING: Pfizer and Roche.

Efficacy and Safety of Pertuzumab and Trastuzumab Administered in a Single Infusion Bag, Followed by Vinorelbine: VELVET Cohort 2 Final Results.

BACKGROUND: VELVET Cohort 1 demonstrated the applicability of pertuzumab, trastuzumab, and vinorelbine as an alternative first-line treatment regimen for patients with HER2-positive locally advanced or metastatic breast cancer (MBC) who cannot receive docetaxel. Co-infusion of pertuzumab and trastuzumab may reduce clinic time and medical resource utilization. We report results from Cohort 2, in which pertuzumab and trastuzumab were co-infused, followed by vinorelbine. PATIENTS AND METHODS: During cycle 1, patients with HER2-positive locally advanced or MBC received loading doses of pertuzumab (840 mg) and trastuzumab (8 mg/kg) on consecutive days, followed by vinorelbine (25 mg/m2) on days two and nine. From cycle 2 onwards, patients received a co-infusion of pertuzumab (420 mg) and trastuzumab (6 mg/kg) on day one, followed by vinorelbine (30-35 mg/m2) on days one and eight (or days two and nine). The primary endpoint was objective response rate (ORR) in patients with measurable disease. Secondary endpoints included progression-free survival (PFS) and safety. RESULTS: Cohort 2 enrolled 107 patients. The ORR was 63.7% (95% confidence interval [CI] 53.0-73.6) in patients with measurable disease (91/107; 85.0%). Median PFS was 11.5 months (95% CI 10.3-15.8). The most common adverse events [AEs] were diarrhea (57.9%), neutropenia (57.0%), and nausea (41.1%). Grade ≥3 AEs occurred in 85 patients (79.4%) and serious AEs in 44 patients (41.1%). Eighteen patients (16.8%) had AEs suggestive of congestive heart failure. CONCLUSION: These results support the feasibility of pertuzumab and trastuzumab co-infusion from a safety perspective and support Cohort 1 conclusions that vinorelbine offers an alternative chemotherapy companion for pertuzumab and trastuzumab. The Oncologist 2017;22:1160-1168 IMPLICATIONS FOR PRACTICE: Combined treatment with pertuzumab, trastuzumab, and docetaxel is the standard of care for first-line HER2-positive metastatic breast cancer. However, some patients cannot, or choose not to, receive docetaxel. VELVET Cohort 2 results support the results from Cohort 1 that suggest that pertuzumab plus trastuzumab and vinorelbine is a suitable alternative for these patients. In addition to this, results from Cohort 2 support the feasibility of administering pertuzumab and trastuzumab together in a single infusion bag, which has the potential to offer greater patient convenience and reduce active health care professional time and medical resource utilization compared with administering them separately.

Trastuzumab resumption after extremely severe cardiotoxicity in metastatic breast cancer patient: a case report.

BACKGROUND: Trastuzumab-related cardiotoxicity has been reported in patients receiving trastuzumab concurrently with other agents, especially with anthracyclines. Cardiac function damage is generally rare, precox and mild with trastuzumab alone. CASE PRESENTATION: We report the case of a 49 year-old woman affected by metastatic breast cancer who developed trastuzumab-related cardiogenic shock due to pump failure (with LVEF of about 15%) after three months of treatment. After a long hospitalization in the cardiac intensive care unit and a proper treatment, LVEF increased to 50% and, due to a severe progression of disease, trastuzumab was resumed and continued for more than one year. CONCLUSION: This is a case of particularly severe cardiotoxicity related to trastuzumab treatment, which was recovered with pharmacological treatment and the temporary discontinuation of the treatment. Trastuzumab was safely resumed after clinical and echocardiographic parameters improvement.