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BACKGROUND: Despite the increase in chances of cure for early breast cancer (EBC) patients, approximately 20–45% of them will experience a disease recurrence, particularly bone metastases in 60–80% of cases, which occur more frequently in luminal subtypes. Endocrine therapy (ET) has always been the milestone of adjuvant treatment for hormone receptor-positive EBC patients, leading to indubitable reduction of disease recurrence risk. However, adjuvant aromatase inhibitors (AIs) therapy may promote a progressive decrease in bone mineral density (BMD), which can lead to osteoporosis. The increased bone resorption associated with osteoporosis may provide fertile soil for cancer growth and accelerate the development of bone metastases. PATIENTS AND METHODS: In this single-institution cohort study, we performed a retrospective analysis of “luminal-like” EBC patients who experienced bone recurrence after a subsequent disease free interval. The aim of the study was to evaluate the median time to skeletal recurrence (TSkR). RESULTS: 143 patients experienced bone recurrence. Median TSkR was 54 months (95%CI: 45–65). Among patients who received adjuvant AIs median TSkR was 35 months (95%CI: 25–54), while among patients who did not was 61 months (95%CI: 50–80) (HR = 1.45 [95%CI: 0.97–2.17], p = 0.0644). After adjusting for TNM stage (AJCC 8th edition), adjuvant AIs treatment was significantly related to a shorter TSkR (HR = 1.60 [95%CI: 1.06–2.42], p = 0.0244). Adjuvant Tamoxifen, adjuvant AIs/Tamoxifen and no-treatment did not revealed to be associated to TSkR. CONCLUSIONS: In this cohort of EBC patients with bone recurrence, AIs treatment seems to be related to a shorter TSkR. AIs-induced bone resorption might represent the underlying mechanism.

One of the major challenges related to solvent-based taxanes administration in clinical practice is the high rate of hypersensitivity reactions (HSRs). Nab-paclitaxel is a solvent-free, albumin-bound, paclitaxel, which minimize the risk of HSR occurrence. In this single-institution, retrospective analysis, we evaluated stage IIIc–IV epithelial ovarian cancer (EOC) patients, treated with first-line carboplatin/nab-paclitaxel (± bevacizumab), after the occurrence of an HSR with solvent-based paclitaxel (and/or docetaxel). Between April 2012 and December 2018, ten patients (20.8%) received carboplatin/nab-paclitaxel (± bevacizumab) after the occurrence of an HSR to solvent-based taxanes. Among the evaluable patients, ORR was 100%. At median follow-up of 28.5 months, median PFS was 16.7 months, and median OS was 65.4 months, respectively. Median received dose intensity (DI) was 86% and 80% of the projected DI for nab-paclitaxel and carboplatin, respectively. There were no treatment-related grade 4 adverse events. Most relevant treatment-related grade 3 adverse events were: asthenia (10%), hypertransaminasemia (10%), neutropenia (20%), thrombocytopenia (20%), and anemia (10%). No HSR recurrence was observed. The high rate of HSR occurrence could limit first-line treatment options in clinical practice. Carboplatin/nab-paclitaxel association could represent a valid treatment option in this setting.

Between January 2003 and January 2015, women at genetic risk of developing breast and/or ovarian cancer were selected for a surveillance program. The monitoring strategy consisted of the association of breast ultrasound (US), every six months, and Rx-mammography (XM) and breast MRI (MRI) to be performed annually. To date, 29 women have been included in the surveillance program: BRCA1 mutation carriers, 18; BRCA2 mutation carriers, 11. Eight women (28%) had already developed breast and/or ovarian cancer, while 21 (72%) were unaffected carriers. At a median surveillance time of 33 months (range 0-144), 4 incidental breast cancers were diagnosed in 4 BRCA1/2 mutation carriers (4/29, 14%), 2 BRCA1+ and 2 BRCA2+; 3/21 (14%) unaffected carriers and 1/8 (13%) previously affected carriers. Two cancers (50%) were detected by all three diagnostic tools; 2 (50%) were identified only by US and MRI in patients aging 33 and 43, respectively. Characteristics of patients with breast cancer diagnosed during surveillanceagemutated geneprevious cancerUSXMMRIhistologysurveillance time (months)33BRCA2-+-+ductal74+43BRCA2-+-+ductal40+45BRCA1-+++ductal60+40BRCA1yes+++ductal74+ One of these four patients, affected by breast cancer, died at 31 months of overall survival; three underwent surgery, chemotherapy and radiotherapy and are still disease free, in follow-up at 59, 28 and 26 months, respectively. In conclusion, 29 BRCA1/2 carriers have been included in the surveillance program, the median age was 42.5 months (range 27-68) and the median surveillance time was 33 months (range 0-144). Our preliminary data confirm the 3% expected rate of diagnosed cancers and the effectiveness of performing the triple diagnostic surveillance with US, XM and MRI. Citation Format: Sidoni T, Cocciolone V, Cannita K, Di Giacomo D, Ciccozzi A, Bafile A, Pizzorno L, Resta V, Marsecano C, Ferrari F, Di Cesare E, Ficorella C, Ricevuto E. Surveillance program for women carrying BRCA1/BRCA2 genetic predisposition. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-14.

The most frequent site of recurrence in breast cancer (BC) is the bone, particularly in patients with ‘luminal-like’ disease. Denosumab has been shown to prevent aromatase inhibitors (AIs) induced bone resorption in postmenopausal early BC patients and reduce skeletal-related events (SREs) in bone metastatic breast cancer (BMBC). A ‘real life’ analysis of 90 BMBC patients treated with denosumab was performed. Eighty-six patients (95.6%) had ‘luminal-like’ disease, 72 (80%) had bone metastases at the time of first recurrence of disease. Among 50 patients with metachronous ‘luminal-like’ disease, 40 (80%) had first recurrence to the bone. Among these patients median time to skeletal recurrence (TSkR) was shorter for patients who were previously exposed to AIs compared to those who were not (53.0 vs. 102.0 months, respectively; P=0.0300) and longer for patients previously treated with tamoxifen compared to those who were not (102.0 vs. 59.0 months, respectively; P=0.0466). Both of them were not confirmed at multivariate analysis. In the overall population, 17 first SREs were observed (16 radiation therapy) and median time to first SRE was not reached. A statistically significant difference in the incidence of SREs was detected only between patients with exclusively osteolytic bone metastases vs. those without (P=0.013). The presence of exclusively-osteolytic bone metastases was the only factor significantly associated with a shorter time to first SRE (P=0.011). The only G3 toxicity reported was hypocalcemia in one patient. No osteonecrosis of the jaw events (ONJ) occurred. This study demonstrated that a pro-active attitude enables the treatment of the majority of patients with denosumab without significant class-related toxicities. The majority of SREs were from radiation therapy, so pain still remains the clinical hallmark of bone metastases, particularly for osteolytic ones. The suggestion that estrogen deprivation with AIs can favor a ‘bone-related’ risk conditions for developing bone metastases must be considered with caution and surely needs further validations.

Summary We describe a metastatic colorectal cancer patient, treated with first-line 5-fluorouracil, irinotecan, bevacizumab, and oxaliplatin (FIr-BFOx) therapy, with aggressive and resistant disease. KRAS , NRAS , BRAF , and PI3KCA were analyzed in primary tumor and liver metastasis. KRAS c.34G>A mutation was detected in primary tumor and liver metastasis, which additionally revealed 2 rare PI3KCA mutations (c.1633G>C and c.1645G>C). The c.1645G>C was never reported in colorectal cancer. Akt/p-Akt Ser473 , phosphatase and tensin homolog, mismatch repair, and epidermal growth factor receptor expression was evaluated. Normal mismatch repair and epidermal growth factor receptor expression was detected. Akt was shown by primary tumor and liver metastasis, whereas p-Akt Ser473 was identified only in the latter, despite positive phosphatase and tensin homolog expression. Patient showed 7 months of progression-free survival and 15 months of overall survival, lower than median values reported in KRAS exon 2–mutant patients treated with the same therapy. Results lead to the hypothesis of a putative role of these mutations in worsening of the disease and are open to further confirmatory studies.

Angiogenesis plays an essential role in the growth and progression of breast cancer. This observational single center study evaluated the efficacy and safety of a new weekly schedule of bevacizumab/paclitaxel combination in the first‐line treatment of unselected, HER2‐negative, metastatic breast cancer (MBC) patients, in a real‐life setting. Thirty‐five patients (median age 56 years, range 40–81) with HER2‐negative MBC were treated with paclitaxel (70 mg/m2) dd 1,8,15 q21 (60 mg/m2 if ≥65 years or secondary Cumulative Illness Rating Scale) plus bevacizumab (10 mg/kg) every 2 weeks. Twenty‐two patients (63%) had ≥2 metastatic sites and 15 (43%) visceral disease. Eleven patients (31%) had a triple‐negative breast cancer (TNBC). A clinical complete response (cCR) was observed in 6 (17%) cases after a median of seven cycles, a partial response (PR) in 22 (63%), and a stable disease (SD) in 6 (17%) cases; the overall clinical benefit rate was 97%. In TNBC subgroup, cCR occurred in 1 (9%) case, PR in 8 (73%), and SD in 2 (18%). At a median follow‐up of 13 months (range 1–79 months), the median progression‐free survival was 11 months and the median overall survival was 36 months. No grade 4 adverse events occurred. The main grade 3 toxicities observed were neutropenia (11.4%), hypertension (5.7%), stomatitis (2.8%), diarrhea (2.8%), and vomiting (2.8%). The administration of weekly paclitaxel plus bevacizumab in this real‐life experience shows similar efficacy than previously reported schedules, with a comparable dose intensity and a good toxicity profile.

Author Summary Background. Anthracyclines and taxanes are effective drugs in breast cancer (BC), but their toxicity profiles limit their use in combination. A dose-finding study was performed to determine maximum tolerated doses (MTDs) of nonpegylated liposomal doxorubicin (TLC-D99) and docetaxel (DTX) as a dose-dense schedule, to maintain dose intensity, and to limit toxicity, particularly cardiac. Methods. Twenty-four patients were enrolled, 12 with metastatic BC, 5 with locally advanced BC, and 7 with early BC. An intra- and interpatient approach was planned in two sequential steps. In the first step, TLC-D99 was administered at dose levels of 40, 45, and 50 mg/m2 plus DTX at a fixed dose of 50 mg/m2. In the second step, TLC-D99 was administered at the dose established in the first step plus DTX at dose levels of 55, 60, and 65 mg/m2. Every treatment cycle was delivered on day 1 every 14 days. Pegylated granulocyte colony-stimulating factor was scheduled on day 2. Dose-limiting toxicities (DLTs) were defined as G4 hematological; G3 nonhematological; ≥10% or ≥20% left ventricular ejection fraction (LVEF) reduction if the final value was Results. Five DLTs occurred (20.8%). No cardiac event of congestive heart failure was reported; 2 events of grade 3 cardiac dysfunction (8.3%), including a ≥20% LVEF reduction in 1 patient and symptomatic arrhythmia in another; 2 incidences of G4 neutropenia (8.3%); and 1 occurrence of G3 asthenia (4.2%) were reported. MTDs were not reached. The recommended doses were established as TLC-D99 50 mg/m2 and DTX 65 mg/m2. Cumulatively, mild (G1–G2) cardiac dysfunction was observed in 58.4% of patients: G1 cardiac arrhythmia was noted in 50%, G1–G2 general cardiac toxicity occurred in 25%, and concomitant toxicity was present in 17%. cTnI never increased. pBNP was increased in 25% and was associated with limiting arrhythmia in 4% and cardiac dysfunction in 16%. Conclusion. Dose-dense TLC-D99 50 mg/m2 and DTX 65 mg/m2 can be safely administered in combination every 2 weeks for breast cancer, with the highest projected dose intensity for each drug at 25 and 32.5 mg/m2 per week, respectively.

The treatment with poly ADP-ribose polymerase (PARP) inhibitors represents a peculiar targeted therapy specifically destroying cancer cells harboring a relevant DNA damage repair dysfunction, through the inhibition of a different other pathway of DNA repair, thus realizing the synthetic lethality. PARP inhibitors target key enzymes of the base excision repair pathway, involved in repairing DNA single-strand breaks, more specifically when the preferred homologous recombination (HR) mechanism for repairing double-strand breaks is lost due to BRCA1 dysfunction. HR defects such as occurring in cancers harboring BRCA1/BRCA2 predisposition are extremely sensitive to PARP inhibitors.

BACKGROUND: Among the different chemotherapeutic options available for adjuvant treatment of early breast cancer (EBC), anthracycline-containing regimens represent prevalent choices. OSCAR/ABC is an observational, prospectic, multicentric study aimed at evaluating, in the clinical practice, the relevance of cardiac dysfunction and congestive heart failure (CHF) associated to “free choice”, anthracycline-containing adjuvant regimens and to identify patients at increased cardiac risk. PATIENTS AND METHODS: patients candidate to receive adjuvant anthracycline-containing chemotherapy, will be enrolled in the study. Data on demographic and clinical characteristics of patients (age, cardio-vascular comorbidity) tumor features (TNM, histotype, ER and PgR status, Ki67, and HER2 status), type of adjuvant regimen and tolerability of treatment will be collected and centrally registered at the Consorzio Interuniversitario Nazionale per ***1a Bio-Oncologia (CINBO) using e-CRFs. Data on type, sites and doses of radiotherapy performed will be collected, to evaluate the possible impact on cardiac function. Primary aim of the study is to evaluate the prevalence of cardiac dysfunction and CHF among the whole population enrolled, particularly according to risk criteria and type of administered chemotherapy. Cardiac dysfunction is defined as limiting cardio-vascular toxicity (≥ Grade 3 dyspnea, arrhytmia, hypertension) and/or asymptomatic LVEF reduction ≥20% (if >50% at the baseline) or ≥10% (if ≤50% at baseline); CHF is defined as clinical diagnosis and/or symptomatic LVEF reduction ≥20% (if >50% at the baseline) or ≥10% (if ≤50% at baseline). Assessment of cardiac risk involves the evaluation of age (< vs ≥ 65 years), cardio-vascular comorbidities (requiring treatment or not) and Left-Ventricular Ejection Fraction LVEF (> vs ≤ 55%) at diagnosis. Clinical and instrumental cardiac evaluation (ECG, Ecocardiography) will be performed at study entry, on-treatment and up to 5 years thereafter. Secondary objective of the study is to evaluate the clinical properness of different adjuvant anthracyclines-containing chemotherapy options, with regard to prevalence of therapeutic regimens, safety, efficacy (DFS and OS) and costs analysis. Cardiac safety and general toxicity on-treatment will be evaluated according to NCI criteria. The expected enrollment is 1,200 patients in 36 months. From September 2010 to May 2011, 7 of the 13 Centers involved in the study are active, with 65 enrolled patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-01-04.

Abstract #2157 Background: Liposomal-Encapsulated Doxorubicin (LED) shows equivalent efficacy, better cardiac tolerability at higher cumulative dose than conventional anthracyclines in breast cancer treatment. Methods: Sixteen pts were enrolled in a dose-finding study of LED (TLC-D99 Myocet ®) associated to Docetaxel (TXT). Twelve pts were treated with a fixed TXT dose (50 mg/m2) and TLC-D99 at three dose levels, 40-45-50 mg/m2, days 1 and 15 every 2 weeks using an intra- and inter-patient approach; four pts wrere treated at the TLC-D99 recommended dose (50 mg/m2). Cardiac monitoring of LVEF was performed every two cycles; Precursor Brain Natriuretic Peptide (proBNP) and cardiac Troponin (c-TnI) before and after 24 h chemotherapy was evaluated. Results: Breast cancer (BC) disease extension: metastatic (MBC), 8; locally advanced BC, 5; T2-T3 BC, 3. Previous chemotherapy: untreated, 11 pts; adjuvant, 5 pts. Enrolled pts for each dose-level: I, 7; II, 9; III, 14. Newly treated pts: I dose-level, 7; II dose-level, 3; III dose-level, 6. Valuable cycles for each dose-level in a total 77 cycles: I, 14; II, 21; III, 42. DLTs were observed in 3 pts, 21%, and 3 cycles, 4%: 2 cardiac, characterized by a 19% LVEF decrease and a symptomatic arrhythmia; one G4 hematologic resistant to G-CSF. DLTs for each dose-level by pts and cycles, respectively: I, 14% (1/7 pts) and 7% (1/14 cycles); II, no DLT in 9 pts and 21 cycles; III, 14% (2/14 pts) and 5% (2/42 cycles). Cumulative G3-4 toxicities by pts and cycles, respectively: cardiac arrhythmia 6% and 1,3%, cardiac general (symptomatic LVEF decrease), 6% and 1,3%; alopecia 81% and 65%; neutropenia resistant to G-CSF, 6% and 1,3%. Cardiac DLTs were observed in 2 elderly pts (>65 y). The 2 cardiac DLTs were observed in 2 out of 3 pts with pre-existing diastolic dysfunction. No pathologic increase of c-TnI levels was detected. Seven pts showed increased pro-BNP after chemotherapy; 1 of these with increased pro-BNP after chemotherapy, persistent the day 1 of each subsequent chemotherapy showed a DLT; G2 toxicities by patients and cycles, respectively: asthenia 37% and 18%, stomatitis/mucositis 12% and 5%, nausea 31% and 12%. Median rDI of TLC-D99 was 25 mg/m2/w and TXT 25 mg/m2/w for pts, respectively. Preliminary efficacy in 16 assessable pts: LA-BC and MBC, 1 CR (pCR) 7 PR (OR 62%), 4 SD and 1 PD; T2-T3 BC, 2 PR and 1 SD. Conclusion: dose-dense TLC-D99/Docetaxel association can be safely recommended at the dose of 50 mg/m2 for each drug. Docetaxel intensification is ongoing. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2157.