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Background: The androgen receptor (AR) is expressed in >75% of hormone receptor (HR)+ tumors. AR signaling has been associated with resistance to endocrine therapy (ET). Aromatase inhibitors (AIs) divert estrogen precursors to androgens; in preclinical models enzalutamide (ENZA) blocked both estrogen- and androgen-mediated growth of HR+ cells. In a phase 1 study of ET+ENZA in breast cancer, doubling the dose of exemestane (EXE) to 50 mg was necessary to restore exposure observed with 25 mg.1 Methods: This placebo (PBO)–controlled phase 2 trial randomized patients (pts) with HR+/HER2-normal advanced/metastatic breast cancer (MBC) to either 25 mg EXE+PBO or 50 mg EXE+160 mg ENZA daily (NCT02007512). Two parallel cohorts enrolled pts who had no prior ET (C1) or who had received 1 prior ET for MBC (C2). Randomization was stratified on resistance to prior ET and prior exposure to AI. Tissue samples for biomarker development were mandatory. Brain metastases or a history of seizure was exclusionary. One prior chemotherapy regimen for MBC was permitted. Response was assessed every 8 weeks for 48 weeks, then every 12 weeks. Crossover to ENZA+EXE was allowed at disease progression. A gene signature–based biomarker (Bmkr) indicating AR signaling predictive of response to ENZA was developed using a training set of RNAseq data from 2/3 of randomized pts and validated using a test set of data from the remaining 1/3 of pts. Progression-free survival (PFS) according to RECIST v1.1 was the primary endpoint in the intent-to-treat (ITT) population and in the Bmkr+ subgroup of each cohort. Secondary endpoints included clinical benefit rate at 24 weeks (CBR24), best overall response, and safety. Results: A total of 247 pts were randomized (C1, n=127; C2, n=120). In C1, 50 pts (39.4%) were Bmkr+; in C2, 35 pts (29.2%) were Bmkr+. Statistically significant improvements in median PFS and CBR24 were observed only in the Bmkr+ population with no prior ET (Table). The most common adverse events (AEs) reported in the ENZA+EXE arms were nausea (39%) in C1 and fatigue (37%) in C2. In C1, 9 pts (15%) and 10 pts (16%) discontinued the study due to AEs in the ENZA+EXE and PBO+EXE arms, respectively. In C2, 11 pts (18%) and 5 pts (8%) discontinued due to AEs in the ENZA+EXE and PBO+EXE arms, respectively. Conclusions: In the first reported randomized trial of ENZA in HR+ MBC, ENZA+EXE was well tolerated with no new safety signals. The study met its primary endpoint in pts with Bmkr+ MBC with no prior ET. 1. Schwartzberg et al. Clin Cancer Res. 2017 Mar 9 [Epub ahead of print]. C1: No Prior ETC2: 1 Prior ET ITTBmkr+ITTBmkr+EXE+ENZA | PBOENZA | PBOENZA | PBOENZA | PBO n=63 | n=64n=24 | n=26n=60 | n=60n=15 | n=20Primary endpointPFS, median, months11.8 | 5.816.5 | 4.33.6 | 3.96.0 | 5.3(95% CI)(7.3, 15.9) | (3.5, 10.9)(11.0, NR) | (1.9, 10.9)(1.9, 5.5) | (2.6, 5.4)(2.3, 26.7) | (1.8, 6.7)Hazard ratio0.820.441.020.55(95% CI)(0.54, 1.26)(0.21, 0.96)(0.66, 1.59)(0.23, 1.36)P value0.36310.03350.92120.1936Secondary endpointCBR24, n (%)39 (62) | 29 (45)20 (83) | 10 (38)12 (20) | 19 (32)6 (40) | 6 (30)(95% CI)(49, 74) | (33, 58)(63, 95) | (20, 59)(11, 32) | (20, 45)(16, 68) | (12, 54)P value0.06090.00120.14430.5374 Citation Format: Krop I, Abramson V, Colleoni M, Traina T, Holmes F, Estevez L, Hart L, Awada A, Zamagni C, Morris P, Schwartzberg L, Chan S, Wheatley D, Gucalp A, Biganzoli L, Steinberg J, Gianni L, Trudeau M, Tudor IC, Markova D, Barry E, Tarazi J, Stewart R, Winer E, Yardley DA. Results from a randomized placebo-controlled phase 2 trial evaluating exemestane ± enzalutamide in patients with hormone receptor–positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS4-07.

1023 Background: GDC-9545 is a potent, orally available, selective estrogen receptor degrader developed for the treatment of ER-positive (ER+) breast cancer alone or combined with CDK4/6 inhibitors. A first-in-human study evaluated 10-250 mg GDC-9545; tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and clinical results support expansion cohorts at ≥30 mg (Jhaveri et al., 2019). Methods: This study evaluated PK, PD, and efficacy of GDC-9545 alone and combined with palbociclib, ± LHRH agonist. Eligible patients (pts) had ER+ (HER2-) metastatic breast cancer (MBC) with ≤ 2 prior therapies in the advanced or metastatic setting. No prior treatment with CDK4/6 inhibitor was allowed in pts receiving palbociclib. Results: Eight-five pts were enrolled in 2 cohorts: GDC-9545 100 mg given once daily ± LHRH agonist (Cohort A), and GDC-9545 100 mg +125 mg palbociclib on a 21 day on/7 day off schedule ± LHRH agonist (Cohort B). Of the 39 pts in Cohort A, adverse events (AE) occurring in ≥10% of pts were fatigue, cough, back pain, pain in extremity, and arthralgia. Related AEs were generally Grade (G) 1-2; there were 3 related G3 AEs of fatigue, transaminase increased, and diarrhea. Two pts had GDC-9545 reduced, one due to G3 diarrhea and another due to G3 transaminitis. Of the 46 pts in Cohort B, AEs in ≥10% of pts were neutropenia, fatigue, bradycardia, diarrhea, constipation, dizziness, nausea, anemia, asthenia, thrombocytopenia, pruritus, and visual impairment. Twenty-six (57%) pts had G≥3 AEs. G≥3 neutropenia was reported in 23 (50%) pts. One pt had palbociclib reduced due to G3 febrile neutropenia. Eleven (13%) of 85 pts had G1 asymptomatic bradycardia considered related to GDC-9545. No pts in either cohort discontinued study treatment due to AEs. PK analysis and clinical data demonstrate no clinically relevant drug-drug interactions between GDC-9545 and palbociclib. Reduced ER, PR, and Ki67 levels, and an ER activity signature, were observed in paired pre- and on-treatment biopsies (n = 12). Eighteen of 33 pts in Cohort A had either confirmed partial responses or were on study 24 weeks (clinical benefit rate 55%). Clinical benefit was observed in pts with prior fulvestrant treatment and with detectable ESR1 mutations at enrollment. Clinical benefit data for both cohorts are anticipated to be mature in April 2020. Conclusions: GDC-9545 was well-tolerated as a single agent and in combination with palbociclib with encouraging PK, PD, and anti-tumor activity in ER+ MBC to support Phase III development. Clinical trial information: NCT03332797 .

Purpose There are currently no targeted therapies approved for triple-negative breast cancer (TNBC). A tumor necrosis factor α ( TNFα)–based gene expression signature (GS) predictive of sensitivity to LCL161, inhibitor of apoptosis antagonist, was translated into a clinical assay and evaluated in a neoadjuvant trial. Patients and Methods Women with localized TNBC (T2/N0–2/M0) were prospectively stratified by GS status and randomly assigned (1:1) to receive oral LCL161 (1,800 mg once per week) and intravenous paclitaxel (80 mg/m2 once per week; combination arm) or paclitaxel alone (control arm) for 12 weeks, followed by surgery. The primary objective was to determine whether neoadjuvant LCL161 enhances efficacy of paclitaxel, defined by > 7.5% increase in the pathologic complete response (pCR, breast) rate, stratified by GS. Results Of 209 patients enrolled (207 with valid GS scores), 30.4% had GS-positive TNBC. In the GS-positive group, pCR was higher in the combination versus the control arm (38.2% v 17.2%), with 88.8% posterior probability of > 7.5% increase in pCR. However, in the GS-negative group, the pCR was lower in the combination group (5.6% v 16.4%), with 0% posterior probability of > 7.5% increase in pCR. A higher incidence of grade 3 or 4 adverse events in the combination arm included neutropenia (24.5%) and diarrhea (5.7%). Overall, 19 patients (18.1%) in the combination arm discontinued treatment because of adverse events, including pyrexia (n = 5), pneumonia (n = 4), and pneumonitis (n = 4), versus five patients (4.9%) in the control arm. Conclusion This neoadjuvant trial provides evidence supporting a biomarker-driven targeted therapy approach for selected patients with GS-positive TNBC and demonstrates the utility of a neoadjuvant trial for biomarker validation and drug development, but also highlights toxicity risk. Future neoadjuvant clinical trials should carefully weigh these considerations for targeted therapy development in biomarker-defined TNBC.

Aberrations in the PI3K signaling pathway are frequently observed in patients with breast cancer. Because of that, PI3K inhibitors are attractive options for the treatment of breast cancer because PI3K is the most proximal component of the pathway other than receptor tyrosine kinases. Buparlisib is a potent and highly specific oral pan-class I PI3K inhibitor, which is currently under investigation in patients with breast cancer. In this article, we describe the PI3K signaling pathway, the prognostic value of PI3K pathway mutations, as well as the mechanism of action of buparlisib. Lastly, we discuss preliminary results of preclinical and clinical studies showing the efficacy and safety profile of this agent in breast cancer patients.

Background: Activation of the PI3K/AKT/mTOR and cyclin D–CDK4/6–INK4–Rb pathways, including through alteration of PIK3CA and CCND1, has been implicated in resistance to aromatase inhibitors. BYL719 (BYL), an α-isoform selective PI3K inhibitor, demonstrated clinical activity as a single agent and in combination with hormone therapy in pts with advanced HR+ breast cancer (BC), while the CDK4/6 inhibitor LEE011 (LEE) showed evidence of clinical activity as a single agent in pts with advanced solid tumors and in combination with letrozole (LET) in pts with heavily pretreated advanced ER+ BC. In ER+ BC models, the triple combination of LEE, BYL, and LET had enhanced activity vs each agent alone. A Ph Ib/II, 3-arm study is currently investigating the combination of LEE, BYL, and LET in pts with ER+ BC. Here we report on safety, preliminary efficacy, and molecular analysis from Arm (A)1 (LEE + LET) and A2 (BYL + LET) of the Ph Ib part of the study. Methods: Postmenopausal pts with advanced ER+, HER2– BC receive daily oral LEE (3-wks-on/1-wk-off; A1) or BYL (continuous; A2), plus fixed, daily LET (2.5 mg, continuous) in 28-day cycles. Primary objective: determine the MTD and/or RP2D of each combination. A Bayesian Logistic Regression Model using the escalation with overdose control principle and real-time PK guide dose escalation. Secondary objectives: safety, PK, and preliminary efficacy. Potential biomarkers that are predictive of response are also being assessed by next-generation sequencing of tumor samples. Results: As of March 28, 2014, 10 pts received 600 mg LEE plus LET (A1), and 7 pts 300 mg BYL plus LET (A2). At study entry, all pts had stage IV disease; number of prior endocrine regimens for advanced disease was: 0–1 (47%); 2–3 (35%); 4–5 (18%); 35% of pts had previously received PI3K/AKT/mTOR pathway inhibitors for advanced disease. Of the 15 pts evaluable for dose determination (10 in A1 and 5 in A2), 1 dose-limiting toxicity was observed (A1: Grade [G]4 neutropenia; data cut-off: May 15). Most common (all grade >30%) study drug-related AEs (all grade/G3–4) were: A1: neutropenia (90%/50%) and nausea (40%/0%); A2: hyperglycemia (57%/14%), decreased appetite, diarrhea, and nausea (43%/0% each). PK of LEE and BYL on Days 1 and 21, and LET on Day 1, are comparable with historic single-agent data. PK of LET at steady state is being evaluated. In A1, of 6 pts with known response, 1 pt had a PR, 2 pts had SD, 1 pt without measurable disease had NCRNPD, and 2 pts had PD. In A2, of 5 pts with known response, 2 pts had SD, and 3 pts had NCRNPD. Biomarker analysis showed that 2 pts in A2 with SD who are still on study (1 with 25% tumor shrinkage) had PIK3CA mutations. Conclusion: LET plus LEE or BYL had an acceptable safety profile and preliminary clinical activity in pts with ER+/HER2– advanced BC. Dose escalation continues, and upon determination of the MTD/RP2D in A1 and A2, enrollment into A3 (LEE + BYL + LET) will begin to determine the MTD/RP2D. Genetic alterations in PIK3CA were observed in A2. Analysis of baseline aberrations in the cyclin D–CDK4/6–INK4–Rb pathway in A1 and A3 are ongoing and will be updated. The Ph II part of the trial will compare LET plus LEE or BYL with the triple combination. Citation Format: Dejan Juric, Erika Hamilton, Laura Garcia Estévez, Richard H De Boer, Ingrid Mayer, Mario Campone, Shizuka Asano, Suraj Bhansali, Vickie Zhang, Becker Hewes, Pamela Munster. Phase Ib/II study of LEE011 and BYL719 and letrozole in ER+, HER2– breast cancer: Safety, preliminary efficacy and molecular analysis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-24.

DOI: 10.1038/s41598-017-04033-9 https://www.nature.com/articles/s41598-017-04033-9 Filiació URV: SI Metastatic cancer patients require a continuous monitoring during the sequential treatment cycles to carefully evaluate their disease evolution. Repetition of biopsies is very invasive and not always feasible. Herein, we design and demonstrate a 3D-flow focusing microfluidic device, where all optics are integrated into the chip, for the fluorescence quantification of CTCs in real samples. To test the chip performance, two cell membrane targets, the epithelial cell adhesion molecule, EpCAM, and the receptor tyrosine-protein kinase, HER2, are selected. The efficiency of the platform is demonstrated on cell lines and in a variety of healthy donors and metastatic-breast cancer patients.

Aim To assess the safety and tolerability of adjuvant subcutaneous trastuzumab (Herceptin ® SC, H SC), delivered from an H SC Vial via hand-held syringe (Cohort A) or single-use injection device (Cohort B), with or without chemotherapy, for human epidermal growth factor receptor 2 (HER2)-positive stage I to IIIC early breast cancer (EBC) in the phase III SafeHer study (NCT01566721). Methods Patients received 600 mg fixed-dose H SC every 3 weeks for 18 cycles. The chemotherapy partner was at the investigators' discretion (H SC monotherapy was limited to ≤10% of the population). Data from the first H SC dose until 28 days (plus a 5-day window) after the last dose are presented. Results are descriptive. Results In the overall population, 2282/2573 patients (88.7%) experienced adverse events (AEs). Of the above, 128 (5.0%) patients experienced AEs leading to study drug discontinuation; 596 (23.2%) experienced grade ≥ 3 AEs and 326 (12.7%) experienced serious AEs. Grade ≥ 3 cardiac disorders were reported in 24 patients (0.9%), including congestive heart failure in eight (0.3%). As expected, the AE rates varied according to the timing of chemotherapy in both cohorts, with higher rates in concurrent versus sequential chemotherapy subgroups. In the concurrent chemotherapy subgroup, AEs were more common during the actual period of concurrent chemotherapy compared with the period when patients did not receive concurrent chemotherapy. Conclusion SafeHer confirms the safety and tolerability of the H SC 600 mg fixed dose for 1 year (every 3 weeks for 18 cycles) as adjuvant therapy with concurrent or sequential chemotherapy for HER2-positive EBC. These primary analysis results are consistent with the known safety profile for intravenous H and H SC.

Background: The PI3K/AKT/mTOR signaling pathway plays a key role for the growth and survival of breast cancer cells and aberrations such as phosphatidylinositol-3-kinase (PI3KCA) mutations are common. BKM120 is an oral pan-class I PI3KCA inhibitor. The aim of this study was to evaluate neoadjuvant treatment with BKM120 in PI3KCA mutated early breast cancer in order to assess the effect in PI3K/Akt/mTOR signalling pathway. Methods: Patients (pts) with previously untreated invasive, non-metastatic histologically confirmed breast cancer, with a tumor size ≥ 1,5cm and non-urgent surgical treatment were enrolled. Only women with ER+ / HER2- and PI3KCA gene mutated were eligible. Patients received treatment with BKM120 (100mg/day; administered orally) during 4 weeks. Subsequently, surgery was performed. Inmunohistochemical analysis of pAkt and pS6 (the H-score intensity x%) as well as KRAS mutation were evaluated on tumor tissue at surgery. H score < 150 was related with inactivation of PI3K signalling pathway. Results: To date 24 patients has been included in the study (median age, 52,5 years; range 38-69 years;). 13 out of 24 (54%) had PI3KCA mutated and 8 have completed BKM120 treatment. PI3KCA mutation: Exon 20, 4 pts; exon 9, 2 pts; exon 4, 1 pts and exon 20 and 9, 1 pts. One patient discontinued treatment due to adverse event (nausea grade 2). The most relevant adverse events included transitory increase of transaminases. No serious or grade 4 adverse events were observed. Preliminary results of 7 pts showed inactivation of pAkt (H score < 150) in 2 pts with no change in the reminder 5 pts (median H score 300). Conclusion: Our preliminary data shown that four weeks of BKM120 treatment do not inactivate PI3K/Akt/mTOR signalling pathway, measured throughout pAkt in ER+/HER2-/PI3KCA mutated breast cancer pts. However, we cannot draw any conclusion because the small number of pts included so far. KRAS mutation and pS6 analysis will be presented along with updated results. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-15-09.

Background: HER2 amplification is frequent in DCIS and is associated with poor prognosis features. This study aimed to determine the molecular effects in Ras/Raf/MAK and PI3K/AKT signaling pathway of the HER2 inhibitor lapatinib in patients with HER2 positive DCIS as well as correlation with radiological and pathological response. Patients and Methods: Patients (pts) with HER2 positive DCIS received 1500 mg daily of lapatinib for 4 consecutive weeks prior to surgical resection. Changes in tumor volume were evaluated by MRI. The molecular effects of lapatinib on apoptotic level (TUNEL), cell proliferation (Ki67) and HER2 signaling pathway were determined in pre and post-treatment tumor biopsies. Results: A total of 20 pts were included. Lapatinib was well tolerated with only minor and transient side effects reported. The agent effectively modulated HER2 signaling by affecting cell cycle kinetics through decreasing cytoplasm pERK1 in 11 pts with no change or slight increase activation in 5 pts. Of those 11 pts: eight had parallel inactivation of pHER2, two pts had paradoxical activation of pAkt and three pts had an increase in apoptotic level. In addition, seven pts also presented with decrease in MRI signal intensity and tumor size. Conclusions: Four weeks of lapatinib for patients with HER2-positive DCIS result in significant antiproliferative changes through RAS/MAPK signaling pathway together with a decrease in MRI signal. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-15.

Chemotherapy remains as the only systemic treatment option available for basal-like breast cancer (BC) patients. Preclinical models and several phase II studies suggested that platinum salts are active drugs in this BC subtype though there is no randomized study supporting this hypothesis. This study investigates if the addition of carboplatin to a combination of an alkylating agent together with anthracyclines and taxanes is able to increase the efficacy in the neoadjuvant treatment context. Patients with operable breast cancer and immunophenotypically defined basal-like disease (ER-/PR-/HER2- and cytokeratin 5/6+ or EGFR+) were recruited. Patients were randomized to receive EC (epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) for 4 cycles) followed either by D (docetaxel 100 mg/m(2) × 4 cycles; EC-D) or DCb (docetaxel 75 mg/m(2) plus carboplatin AUC 6 × 4 cycles; EC-DCb). The primary end point was pathological complete response (pCR) in the breast following the Miller and Payne criteria. Ninety-four patients were randomized (46 EC-D, 48 EC-DCb). pCR rate in the breast was seen in 16 patients (35 %) with EC-D and 14 patients (30 %) with EC-DCb (P value = 0.61). pCR in the breast and axilla was seen in 30 % of patients in both arms. The overall clinical response rate was 70 % (95 % CI 56-83) in the EC-D arm and 77 % (95 % CI 65-87) in the EC-DCb arm. Grade 3/4 toxicity was similar in both arms. The addition of carboplatin to conventional chemotherapy with EC-D in basal-like breast cancer patients did not improve the efficacy probably because they had already received an alkylating agent. These findings should be taken into consideration when developing new agents for this disease.

Use of breast magnetic resonance imaging (MRI) to detect breast cancer has generated significant debate. We analyze the role of breast MRI in the detection of additional disease and the need to perform additional biopsies in early breast carcinoma patients. In addition, we correlate the detection of new foci with tumor pathological features.Early breast carcinoma patients that had undergone an MRI as well as a mammography as diagnostic procedures were included in the study. The following pathologic features were studied: carcinoma type, histological grade, estrogen receptors (ER), progesterone receptors (PR), HER2 and Ki67. Univariate analysis was conducted to ascertain significant correlation among detection of new foci and each of the tumor pathological features.Data from 98 patients have been analyzed: median age 49 years (range 35-79); carcinoma type: (a) infiltrative ductal carcinoma (n = 73, 74 %), (b) infiltrative lobular cancer (n = 12, 12 %), (c) ductal carcinoma in situ (n = 6, 6 %); amplified HER2 (n = 18, 18 %); grade III (n = 33, 33 %); Ki67 ≥ 25 % (n = 33, 33.67 %); positive ER and PR (n = 79, 80 %); triple negative tumors (n = 8, 8 %). MRI detected additional disease in 38 cases (39.58 %), and 20 led to an additional biopsy (20.4 %). Thirty-eight patients (39 %) underwent mastectomy. We found a statistically significant correlation between new foci in MRI and high Ki67 ≥ 25 % (p0.005). No other statistically significant correlation was established.MRI detected additional disease in 39 % cases, requiring an additional biopsy 20 %. Tumors with high proliferative index were significantly correlated with the detection of new foci in MRI.

Purpose: The Her2/neu gene is amplified and/or its protein is overexpressed in 15-25% of invasive breast cancer, but in Ductal Carcinoma In Situ (DCIS) this expression is highly increased (60-80%). We review our rate of DCIS with Her2 amplified in a prospective series of women with new diagnosis of DCIS. Methods: Patients with new diagnosis of DCIS by biopsy were studied. The status of Her2 was evaluated by fluorescence in situ hybridization (Vysis path vision HER-2 DNA probe kit) and was considered amplified if the ratio HER2/CEP17 was >2.0. The status of estrogen and progesterone receptors were analyzed by inmunohistochemistry (IHQ). Data evaluating architectural pattern and histological grade were also collected. Results: Data from 53 patients with DCIS were included (two patients with combined invasive ductal carcinoma detected at time of surgery and 51 cases of pure DCIS). HER2 was amplified in 20 patients (37%), with HER2/CEP17 ratios between 2.16 to 14.00. A total of 29 patients had grade III DCIS, and of those 18 (62%) had Her2 amplified. 17 patients (32%) were estrogen and progesterone receptors negative (10 with Her2 amplified). We have not observed any correlation about architectural pattern (comedo, cribriform, micropapillary, solid/necrotic) and amplification of Her2. Conclusion: In our series of DCIS patients the Her2 amplification was less commonly found compared to prior studies (37% vs >60%). Most of DCIS were grade 3 (90%) and no relation was found among the architectural pattern and amplification of Her2. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-15-06.

Background: DCIS is a heterogeneous disease, with increasing incidence. Up to 37% of DCIS overexpress HER2. Lapatinib is a tyrosine kinase inhibitor that directly inhibits HER2 receptor signaling by blocking the receptor's kinase activity. This work tested the hypothesis that Lapatinib inhibits Ras/Raf/MAK and PI3K/AKT signaling in HER2 positive DCIS. Patients and Methods: Patients with HER2 positive (FISH rate >2.2) DCIS diagnosed by core needle biopsy with low risk of having a hidden invasive component were eligible. Neoadjuvant Lapatinib 1500mg daily was administered for 4 weeks prior to surgical resection. EGFR was analyzed by FISH in the biopsy specimen. Ki67, PTEN, AKT, pAKT and pERK were evaluated by IHQ. PI3KCA mutations were screened at exons 9 and 20 by PCR. Apoptosis was analyzed by TUNEL assay. All biological markers were measured before and after Lapatinib treatment. Results: Eleven pts with HER2 positive DCIS have been included to date. Median FISH amplification was 7 (range 2, 70-14). Evaluation pre-Lapatinib showed that: none of the pts had EGFR amplification; six pts (54%) had a Ki67 >25%; pAKT was overexpressed in 3 pts (27%) and pERK in 2 pts (18%); PTEN was deleted in 3 pts (27%). PI3KCA mutations were detected in only 1 pt (9%). After Lapatinib treatment, 9 pts were evaluable. We observed a trend for inactivation of the Ras/Raf/MAK signaling pathway in 7 pts (70%) patients. Interestingly, 3 of these pts had paradoxical activation of PI3K/Akt suggesting a compensatory feed back loop. One out of these 3 pts has PTEN deleted. In addition, 3 pts (33%) showed an increase in the apoptotic index. Conclusions: In our study, four weeks of Lapatinib against HER2 positive DCIS resulted in inactivation of Ras/Raf/MAK pathway; however an activation of the PI3K/Akt was seen as the same time in 3 pts. Nevertheless this trend needs to be confirmed with the inclusion of more pts. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-06-17.

Purpose The aim of this study was to evaluate the efficacy and safety of capecitabine in combination with vinorelbine in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. Patients and Methods In this prospective, multicenter, open-label phase II trial, patients received capecitabine (2000 mg/m2 daily, taken in 2 oral doses) on days 1-14 and vinorelbine (25 mg/m2 intravenous infusion) on days 1 and 8. Cycles were repeated every 3 weeks up to a maximum of 6 cycles, unless disease progression or unacceptable toxicity occurred or patient consent was withdrawn. Results Thirty-one patients were included and received 152 cycles of chemotherapy, with a median of 3 cycles per patient. All patients were evaluated for efficacy and toxicity in an intent-to-treat analysis. The overall response rate was 49% (95% CI, 30%-67%), including 4 complete (13%) and 11 partial (36%) responses. With a median follow-up time of 9 months, the median time to disease progression was 7.6 months (95% CI, 5.7-9.8 months), and the median survival time was 27.2 months. The most frequent severe hematologic toxicities were neutropenia (48% of patients) and leukopenia (10% of patients). Vomiting (16% of patients) was the most common nonhematologic toxicity, while asthenia, bone pain, dyspnea, plantar-palmar erythrodysesthesia, nausea, and transaminase elevation were observed in 6%-10% of patients. There was 1 death from septic shock. Conclusion Capecitabine in combination with vinorelbine is an effective and safe schedule for patients with MBC pretreated with anthracycline-and taxane-containing regimens.

This review examines all randomized studies that evaluated the role of taxanes in the neoadjuvant treatment of breast cancer and have reported results in terms of efficacy and tolerance. The primary objective of this review was to evaluate whether, at this point in time, there is sufficient evidence to support the routine use of taxanes in the neoadjuvant treatment of breast cancer. Other objectives were to determine the optimal schedule in which to administer taxanes and anthracyclines and whether the addition of other antitumor drugs improves the efficacy of these anthracycline/taxane-based schedules. A literature search revealed 9 major randomized clinical trials published to date. To facilitate analysis, they were classified according to their protocol design. Five trials evaluated the effect of the addition of a taxane to an anthracycline-based schedule, either concomitantly or sequentially. The remaining 4 trials contained taxanes in both treatment arms in an attempt to optimize the administration schedule of anthracyclines and taxanes, or to improve efficacy by adding a further antitumor drug. This type of analysis has provided the opportunity to draw some conclusions regarding the optimal use of taxanes.

Six major randomized clinical trials evaluating the role of taxanes in the adjuvant setting of breast cancer have demonstrated significant improvements in terms of efficacy in favour of the taxane treatment arm. In all cases, different anthracycline-based regimens were used as the control arm. Nevertheless, many clinicians are still not sufficiently convinced to incorporate the routine use of taxanes in the adjuvant treatment of breast cancer. There are two main objections, first the possible lack of effectiveness of chemotherapy in hormone-receptor positive tumors and second, some of the anthracycline-based control arms used in these trials were not the optimal ones. In this review, we have searched and analyzed all randomized studies that evaluated the role of taxanes in the adjuvant setting of breast cancer patients and have reported results in terms of efficacy or tolerance. The suitability of the control arm, the prospective definition of patient's subgroups and the statistical methodology were taking into account. The objective of this review was to analyze if, at this point in time, there is sufficient evidence to support the routine use of taxanes in the adjuvant setting of breast cancer, and if it is valid for all subgroups including hormone-receptor and Her2/neu positive breast cancer patients. Other objectives of this review were to define the optimal regimen for administration of taxanes, how the tolerability of taxanes may be improved and also, to investigate any potential differences in efficacy or tolerability between docetaxel and paclitaxel.

At the present time, there is not a standard regimen in upfront metastatic setting for breast cancer. A wide variety of regimens which includes anthracyclines, taxanes, gemcitabine or capecitabine are currently used, however, there is evidence to support the use of many of these drugs in early breast cancer and consequently limiting their use in first line treatment. The aim of this review is to evaluate every randomized phase III trials conducted in first line metastatic breast cancer. For this reason, all randomized studies that evaluated the role of chemotherapy in advanced breast cancer were analyzed and classified according to their protocol design. So far, sixteen major randomized clinical trials have evaluated the role of chemotherapy as front line in metastatic breast cancer. Some of them have analyzed a different anthracyclines-based regimen as the control arm versus new combinations or new drugs. In others, the aim is to evaluate the most effective therapy after progression to an adjuvant anthracyclines-containing regimen. The suitability of the control arm, the prospective definition of patient's subgroups as well as the statistical methodology have been taken into account.

The purpose of this phase II study was to evaluate the efficacy and safety of neoadjuvant docetaxel/gemcitabine treatment in a biweekly regimen.Patients with stage II/III breast cancer were treated with docetaxel (65 mg/m(2)) followed by gemcitabine (2500 mg/m(2)) every 2 weeks for 6 cycles. Patients with a clinical response or stable disease underwent mastectomy or breast-conserving surgery plus axillary dissection. After surgery, patients received 4 cycles of standard doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 21 days.Thirty-five patients were included in the trial. The overall response rate was 71.4% (95% CI: 53.7-85.4), with 8 complete and 17 partial responses. Breast conservation was possible in 59% of the patients. Toxicity was manageable.We consider biweekly docetaxel and gemcitabine could be an active and tolerable regimen option in the neoadjuvant setting sequentially with standard adjuvant doxorubicin-cyclophosphamide in patients with stage II or III breast cancer.

Breast cancer is a major public health problem. Despite remarkable advances in early diagnosis and treatment, one in three women may have metastases since diagnosis. Better understanding of prognostic and predictive factors allows us to select the most appropriate adjuvant therapy in each patient. In these guidelines, we summarize current evidence for the medical management of early-stage breast cancer.

Taking into account what we presently know aboaut neoadjuvant chemotherapyn in breast cancer, the following conclusions may be drawn

Neoadjuvant chemotherapy (NC) is standard therapy for patients with locally advanced breast cancer and is increasingly used for early-stage operable disease. The aim of NC is a pathological complete response (pCR) in the breast and axillary lymph nodes, which is the best predictor of improved outcome and prolonged survival. The taxanes docetaxel and paclitaxel are potent agents in breast cancer management, with promising single-agent activity and acceptable tolerability in the neoadjuvant setting. In this review of the taxanes as NC for operable and inoperable breast cancer, we include all fully published Phase II-III studies enrolling ≥30 patients. Current evidence suggests that the sequential administration of taxane- and anthracycline-based therapy may be superior to concomitant administration. Indeed, until the recent Phase III Aberdeen study (n = 162), it was uncertain whether NC could prolong survival. In this study, sequential docetaxel after anthracycline-based NC significantly enhanced the clinical response rate and pathological complete response, and yielded a significant 3-year survival advantage, versus anthracycline-based NC alone. Recently, the Phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B27 trial (n = 2411) showed that sequential docetaxel after doxorubicin-cyclophosphamide significantly increased both clinical and pathological response rates for operable breast cancer, with the benefit evident in both estrogen receptor-positive and estrogen receptor-negative patients. This apparent superiority of a sequential anthracycline-taxane regimen is limited to docetaxel, with no similar Phase III trials of paclitaxel versus a non-taxane-based comparator having been conducted to date. In conclusion, current evidence supports the inclusion of a taxane in NC schedules for patients with large and locally advanced breast cancer.

Background: Angiosarcomas are malignant neoplasms of endothelial cells. Angiosarcoma of the breast is a rare neoplasm that behaves in a highly malignant fashion. It must be differentiated from benign vascular proliferations and from mammary carcinoma. Methods: We report on a 49-year-old-woman who presented with a large mass involving the left breast. Results: The lesion had an erythematoviolaceous hue and livedoid pattern at the periphery. Histopathologic study showed an epithelioid malignant neoplasm, and immunohistochemical studies demonstrated that neoplastic cells expressed immunoreactivity for endothelial cell markers. Conclusions: A diagnosis of epithelioid angiosarcoma of the breast was established. The patient was treated with radical mastectomy, but she refused any other additional therapy.

Breast cancer is a leading cause of malignancy-related death in women. The prognosis for patients with breast cancer is determined by well established pathologic features associated with poor outcome such as histological grade, tumor size, and node involvement. The proto-oncogene HER2/neu or its protein receptor HER2 is amplified/overexpressed in nearly 25–30% of breast tumors. It is now recognized that breast tumors that overexpress the HER2 receptor are associated with poor prognosis and outcome. The discovery of monoclonal antibodies targeted against the transmembrane protein p185HER2/neu of HER2/neu represents a new tool for the treatment of breast cancer patients with tumors that overexpress this receptor. Trastuzumab is a recombinant humanized monoclonal antibody against the HER2 receptor that has been shown to be very active in both preclinical and clinical trials. In metastatic disease, the addition of trastuzumab to current chemotherapy has proven to be beneficial compared with chemotherapy alone. Clinical trials with different trastuzumab combination chemotherapies in metastatic settings are ongoing. In addition, trastuzumab therapy is now being tested beyond advanced disease; several trials in America and Europe are designed to add trastuzumab to adjuvant chemotherapy for patients with early nonmetastatic breast cancer. The efficacy and safety of trastuzumab in clinical trials are reviewed in this report.

Background: ET is the standard of care for HR+ ABC; however, disease progression eventually occurs. Breast cancer driver mutations can include alterations in the cyclin D–cyclin-dependent kinase (CDK)4/6–inhibitor of CDK4 (INK4; p16)–retinoblastoma pathway and in upstream pathways such as the phosphatidylinositol 3-kinase (PI3K) pathway. Doublet combination strategies with selective CDK4/6 inhibitors such as ribociclib (RIB) have demonstrated increased progression-free survival (PFS) in Phase III studies of HR+ ABC. Here, we evaluate the clinical activity of RIB-based ET combinations in Phase I clinical trials, including in tumors with various molecular alterations. Methods: Postmenopausal women with HR+, HER2– ABC received RIB with letrozole (LET; 2.5 mg continuous; NCT01872260; previously untreated or first-line patients [pts]), exemestane (EXE; 25 mg continuous; NCT01857193; aromatase inhibitor [AI]-refractory disease), or fulvestrant (FUL; 500 mg; NCT02088684; AI-refractory disease). RIB was administered at 600 mg/day 3 weeks on/1 week off (all combinations) or 400 mg/day continuously (additional subgroup in the RIB + FUL study). Fresh or archival tumor tissue was collected from all pts. Clinical activity and next-generation sequencing (NGS) data from pretreatment tumor samples were assessed. Results: Preliminary clinical activity was observed with all 3 combinations, with clinical benefit rates (CBR; including stable disease for ≥24 weeks) of: RIB + LET (N=47 pretreated or first-line pts) 60%, RIB + EXE (N=14 pretreated pts) 50%, and RIB + FUL (N=28 pretreated pts; n=13 at 600 mg/day RIB, n=15 at 400 mg/day RIB) 52%. Best overall responses of complete response [CR] or partial response [PR] were observed in 14 pts (RIB + LET), 4 pts (RIB + EXE), and 5 pts (RIB + FUL). In a first-line subset of pts (N=28), RIB + LET had a median PFS of 25.3 months. Most common Grade 3/4 adverse events for all 3 combinations were neutropenia and leukopenia. NGS data were available for 33, 6, and 16 pts treated with RIB + LET, RIB + EXE, and RIB + FUL, respectively. CR and/or PR were observed in pts with PIK3CA and/or CCND1 (cyclin D) alterations treated with RIB + LET (9/19 pts and 4/9 pts, respectively); and RIB + FUL (1/10 pts and 2/5 pts, respectively). Integrated biomarker analyses from all 3 trials will be provided at the time of the meeting. Conclusions: RIB + ET doublet combinations are well tolerated, with encouraging clinical activity that includes responses and durable PFS in heavily pretreated pts, and are consistent with previously reported first-line data (NCT01958021). Preliminary biomarker analyses suggest pts with PIK3CA and/or CCND1 alterations derive treatment benefit from RIB + ET combinations. Other genetic alterations are being evaluated. Citation Format: Dejan Juric, Mario Campone, Pamela Munster, Roohi Ismail-Khan, Laura Garcia Estévez, Mariana Chavez-MacGregor, Antonio Frassoldati, Rina Hui, Ingrid A. Mayer, Javier Cortés, Anthony Gonçalves, Richard H. De Boer, Luc Dirix, Sara M. Tolaney, Soo Chin Lee, Michela Maur, Yingbo Wang, Faye Su, Jason R. Dobson, Caroline Germa, Becker Hewes, Aditya Bardia. Ribociclib + endocrine therapy (ET) doublet combinations in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): Phase I clinical activity and impact of molecular alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT087. doi:10.1158/1538-7445.AM2017-CT087

The survival of patients with advanced non-small cell lung cancer remains poor. Cisplatin-based chemotherapy produces a modest benefit in survival compared with that observed with best supportive care. Gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN), a novel nucleoside antimetabolite, is active and well tolerated. The combination of gemcitabine/cisplatin has shown a significant improvement in response rate and survival over cisplatin alone. Phase III trials comparing gemcitabine/cisplatin with older combinations such as cisplatin/etoposide or mitomycin/ifosfamide/cisplatin have shown a higher activity for gemcitabine/cisplatin; however, the best way to combine these drugs remains unclear. In addition, the 3-week schedule has obtained a higher dose intensity with less toxicity and similar efficacy as the 4-week schedule. The role of carboplatin in combination with new drugs is still under evaluation. Gemcitabine/carboplatin seems to be a good alternative, with the advantage of ambulatory administration and lower nonhematologic toxicity. The 4-week schedule has produced frequent grade 3/4 neutropenia and thrombocytopenia in some studies. The 3-week schedule, using gemcitabine on days 1 and 8 and carboplatin on day 1, is a convenient and well-tolerated regimen. The toxicity profile is acceptable without serious symptoms. This schedule could be considered a good option as a standard regimen. Semin Oncol 28 (suppl 10):4-9.

Third-generation aromatase inhibitors (AIs) have proven to be superior to tamoxifen in terms of time to disease progression in patients with hormone receptor (HR) positive (HR+) status and, nowadays, are used in the adjuvant and neoadjuvant settings, and first-line therapy for advanced breast cancer. Letrozole is a third generation AI, as are anastrozole and exemestane. In the past, clinical studies had demonstrated that letrozole was effective as a second-line treatment of metastatic breast cancer. In this paper, pharmacokinetic and pharmacodynamic properties of letrozole are reviewed along with its activity in preclinical and clinical settings. Additionally, the results of important clinical trials such as Breast International Group (BIG) 1-98, which tested the optimal initial adjuvant endocrine treatment and the sequential therapy with letrozole and tamoxifen, MA-17 that evaluates the benefits of extended adjuvant therapy, and other important studies in advanced and neoadjuvant disease, are reviewed. Safety comparisons of treatments are also addressed. Interestingly, about 50% of human epidermal growth factor receptor 2-positive (HER2+) breast cancers are HR+. However, HER2 positivity is a marker of antiestrogen treatment resistance. Because of this, a dual treatment is a logical approach when both receptors are overexpressed. The combination of lapatinib and letrozole leads to a significant improvement in the overall disease outcome. Also, the combination of everolimus plus letrozole has been tested in this setting. In fact, the coadministration of both agents seems to increase the efficacy of letrozole in newly-diagnosed HR+ patients. Once resistance to sequential trastuzumab and AI as monotherapy has been found, trastuzumab and letrozole combined in HR+ and HER2+ patients with advanced breast cancer can overcome resistance to both drugs administered as single agents, according to recently reported results.

Patients with metastatic breast cancer have a wide number of treatment options, including medical, surgical, and supportive care measures. Treatment decisions are based in predictive and prognostic factors and the informed choice of the patients. SEOM has elaborated these guidelines with evidence-based recommendations for the diagnostic work-up, treatment (chemotherapy, endocrine therapy and targeted therapies) and supportive care for the management of these patients.

To evaluate the sequential administration of doxorubicin (A) and cyclophosphamide (C) followed by weekly docetaxel in women with stage II to IIIA breast cancer.Patients received 60 mg/m(2) of A and 600 mg/m(2) of C every three weeks for four cycles followed by 12 infusions of weekly docetaxel at a dose of 36 mg/m(2) and with a 2-week resting period.Sixty-three women were included. On an intention-to- treat basis, clinical response rate was 90% (95% CI: 83-98), with 46% complete responses. Breast-conserving surgery could be performed in 43 patients (68%). Complete pathological responses in the breast were confirmed in 17% of patients. No correlations between levels of expression of topoisomerase II alpha, survivin or p27 and the pathological response were detected. The study treatment was generally well tolerated.Neoadjuvant AC followed by weekly docetaxel is a feasible regimen for patients with early-stage breast cancer.

Combined treatments together with surgery, radiotherapy, chemotherapy, and endocrine therapy have contributed substantially to the improved survival rate in breast cancer. For more than 2 decades, tamoxifen has been the standard endocrine agent for hormone receptor-positive tumors. Third-generation aromatase inhibitors have, however, now proven to be superior to tamoxifen in the adjuvant and, more recently, the neoadjuvant treatment of postmenopausal patients. They have especially improved the surgical management of large or inoperable locally advanced breast tumors. Other advantages of neoadjuvant endocrine therapy are just emerging, but there are still many unanswered questions regarding its optimal use in this setting. A need to define how to select the patients who will benefit most from these therapies, the optimal duration of treatment, the best method to evaluate the treatment response achieved, the existence of predictive factors for response, or the superiority of certain endocrine agents over others has been observed. Other questions regarding which complementary local and systemic treatments should be administered after neoadjuvant endocrine therapy or which efficacy endpoints should be evaluated in clinical trials are also of interest. To answer as many of these questions as possible, we have carried out a critical analysis of the current literature on the use of endocrine therapy in the neoadjuvant setting of breast cancer. In this review, we outline the rationale for its use, and consider data published to date to further clarify how to optimize its administration.

The clinical decision to treat early-stage breast cancer with adjuvant chemotherapy is sometimes a difficult one because 70-80% of patients who receive chemotherapy would probably have survived without it. To help clinicians in this decision-making process, different tools or 'decision aids' have been developed for the treatment of early breast cancer over the years. Some of these tools include clinical treatment guidelines and computer-based programs as well as different prognostic and/or predictive tests such as those based on gene expression profiles or the presence minimum invasive disease. All of these tools try to individualize as much as possible the estimation of the risk of breast cancer relapse and death and to facilitate the clinical decision about giving additional treatment, and ultimately the most appropriate treatment to be given. Thus, it is important for clinicians to be aware of not only the existence of these tools or 'decision aids', but also to know how they have been developed, how frequently there are revised and if they have been validated. In order to address all these concerns, we have carried out a critical review of the most important prognostic tests and clinical guidelines for the treatment of early breast cancer. Information regarding their development process as well as frequency of revision, validations that have been performed and main limitations of each tool were gathered and critically analyzed.

The purpose of this study is to evaluate the efficacy and safety of a biweekly neoadjuvant docetaxel/gemcitabine regimen in patients with histologically confirmed stage II and III breast cancer. In addition, a cDNA microarray study attempted to correlate pretreatment gene-expression profile with clinical and pathologic responses. Docetaxel 65 mg/m 2 was given in a 60-minute intravenous infusion followed by gemcitabine 2,500 mg/m 2 in a 30-minute intravenous infusion every 2 weeks for six cycles; prophylaxis with growth factors was allowed. Four cycles of standard AC (doxorubicin 60 mg/m 2 and cyclophosphamide 600 mg/m 2 every 21 days) was routinely delivered to all patients postsurgery. Thirty patients are accrued on-study so far. The overall response rate for 24 evaluable patients was 79% (95% confidence interval, 9.7 to 53.5) with six complete responses and 13 partial responses. One patient (4%) out of 23 achieved a pathologic complete response in the breast at the time of definitive surgery. Breast conservation procedure was possible in 14 patients (61%). A total of 161 cycles has been delivered. Grade 1/2 alopecia and a mild grade 1/2 LDH increase were the most frequently reported adverse events (78% and 55% of cycles, respectively). Grade 3/4 neutropenia was reported in 18 cycles (11%). These preliminary results show that biweekly docetaxel and gemcitabine is an optimal regimen as neoadjuvant treatment of stage II and III breast cancer. In spite of the large tumor size, breast conservation was possible in 61% of the patients. In general, toxicity was very manageable.

This phase II study was designed to evaluate the response rate (RR) and toxicity of gemcitabine/vinorelbine in patients with metastatic breast cancer. All patients had previously received anthracyclines. Treatment consisted of gemcitabine 1200 mg/m2 and vinorelbine 30 mg/m2 on days 1 and 8, every 3 weeks. Twenty-five patients were enrolled. Median age was 59 years (range, 33-73 years). Ten patients had received only adjuvant therapy with anthracyclines. The remaining 15 patients had received chemotherapy for metastatic disease, including taxanes in 11 cases. Four patients could not be evaluated for response. By intent-to-treat analysis, the overall RR was 44% (95% CI, 24.4%-65%). Median duration of response and median time to treatment failure were 21 and 17 weeks, respectively. The main toxicity was hematologic, with grade 3/4 neutropenia occurring in 13 patients and 1 patient developing febrile neutropenia. Two deaths from pneumonia occurred. These results reveal an encouraging activity with a reasonable toxicity profile in a patient population with an unfavorable prognosis. Our group is conducting a randomized study to compare this combination with vinorelbine alone in patients with metastatic breast cancer after failure to respond to anthracyclines and taxanes

143 Background: Activation of the PI3K/AKT/mTOR and cyclin D–CDK4/6–INK4–Rb pathways has been implicated in endocrine therapy resistance in pts with advanced HR+ breast cancer (BC). BYL719 (BYL), an α-isoform selective PI3K inhibitor and LEE011 (LEE), a CDK4/6 inhibitor have demonstrated clinical activity in pts with advanced HR+ BC and advanced solid tumors, respectively. In preclinical HR+ BC models, the combination of LEE, BYL, and letrozole (LET) had enhanced antitumor activity vs either agent alone. Here we report results from Arm (A)1 (LEE + LET) and A2 (BYL + LET) of the Ph Ib part of a Ph Ib/II, 3-arm study of LEE, BYL, and LET in pts with advanced ER+ BC (CLEE011X2107/NCT01872260). Methods: Postmenopausal women with advanced ER+, HER2− BC receive daily oral doses of LEE (3-wks on/1-wk off; A1) or BYL (continuous; A2), plus fixed, daily LET (2.5 mg, continuous), as part of a 28-day cycle. Primary objective: determine the MTD and/or RP2D of A1 and A2. Dose escalation is guided by a Bayesian Logistic Regression Model using the escalation with overdose control principle and real-time PK. Safety and preliminary efficacy are also assessed. Results: As of March 28, 2014, 10 pts have been treated with 600 mg LEE + LET (A1), and 7 pts with 300 mg BYL + LET (A2). One DLT was observed (A1: Grade [G]4 neutropenia; data cut-off: May 15). Common (all grade >30%) study drug-related AEs (all grade/G3–4) were: A1: neutropenia (90%/50%) and nausea (40%/0%); A2: hyperglycemia (57%/14%), decreased appetite, diarrhea, and nausea (43%/0% each). PK for LEE and BYL on Days 1 and 21, and LET on Day 1, are comparable to historic single-agent data. PK of LET at steady state is being evaluated. In A1, 6 pts had known responses: 1 PR, 2 SD, 1 NCRNPD, and 2 PD. In A2 5 pts had known responses: 2 SD, and 3 NCRNPD. Conclusions: LET plus LEE or BYL had an acceptable safety profile and preliminary signs of clinical activity have been observed. Upon determination of the MTD/RP2D in A1 and A2, enrollment into A3 (LEE + BYL + LET) will commence. The randomized Ph II part of the trial will compare LET + LEE or BYL with LET + LEE + BYL. MONALEESA-2 (CLEE011A2301/NCT01958021), a Ph III, randomized, double-blind, placebo-controlled study of LEE + LET in untreated advanced HR+ BC is currently recruiting pts. Clinical trial information: NCT01872260.

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor (HGF) with many applications in cancer therapy. The most important applications are reduction in the incidence of febrile neutropenia, acceleration of neutrophil recovery after chemotherapy or bone marrow transplantation, and mobilization of progenitor cells. Many cutaneous adverse reactions associated with HGF have been reported in recent years, including injection site reactions, pyoderma gangrenosum, Sweet's syndrome, cutaneous leucocytoclastic vasculitis, and widespread folliculitis. The presence of large histiocytes on the dermis between collagen bundles has been proposed as a characteristic histopathologic finding in cutaneous eruptions secondary to granulocyte colony-stimulanting factor and granulocyte-macrophage colony-stimulating factor. We report on a patient with a high-risk ductal infiltrating carcinoma of the breast who received high-dose chemotherapy (HDC) with peripheral blood progenitor cell (PBPC) rescue. The patient received G-CSF after PBPC for a faster granulocyte recovery. She developed a cutaneous eruption located on back, buttocks, axillae, groin and sites where electrocardiography electrodes had been placed. From the histopathological point of view, the eruption was characterized by the presence of numerous large, atypical histiocytes in the dermis with several mitotic figures, mimicking involvement of the dermis by a malignant process.

e11531 Background: The international guidelines include the use of Oncotype DX as a predictor of chemotherapy (CT) benefit in hormonal sensitive breast cancer patients (pts) with node negative and node positive (1-3 positive nodes) disease.The aim of this study was to assess the distribution of the RS in breast cancer pts regardless lymph nodes status, and the association with treatment recommendations. Methods: Retrospectivedata from 131 pts with invasive breast cancer for which the OncotypeDX Assay had been ordered, and pathology data were available. Estrogen (ER) and progesterone (PR) receptor was assessed by IHC (cut-off 10% nuclear staining). Ki67 by IHC [high (≥14%) and low (< 14%)]. Positive-lymph nodes pts was classified as isolated tumoral cells (ITC), micrometastasis (MIC) and macrometasis (MAC). Results: Median age: 51 (range: 35-78); premenopausal status: 74 pts (56%). Median tumor size: 1.5 cm (0.3- 6); Median Ki 67 index: 15 (3-63); Median ER: 93 (35-100) and PR: 85(0-100). 42 pts (32%) had positive-lymph nodes: 6 ITC (14%), 14 MIC (33%) and 22 MAC (52%). RS was low in 82 (63%) cases, intermediate 39 (30%), and high 10 (7%). RS according to nodal status was: positive nodes, 31 pts (74%) low RS, 10 pts (24%) intermediate and 1 pts (2%) high; negative nodes: 50 pts (57%) low RS, 26 (29%) intermediate and 12 pts (14%) high RS. ER and Ki67 was similar between both lymph-nodes groups whereas a higher PR expression (median 90) was seen in positive-lymph nodes vs 76 in negative nodes. First recommendation in positive-lymph nodes: hormonotherapy (HT) 33%, CT 55% and 12% no defined (ND); after RS, HT 83% and CT 17% (p=0.021). Negative nodes first recommendation: HT 68%, CT 23% and ND 14%; after RS, HT 68% and CT 32%. Conclusions: Although based on a small case series, the results show that a substantial number (73%) pts with positive-lymph nodes have low RS, indicating minimal if any benefit from adjuvant CT. The proportion of patients with low scores is higher than in the validation studies and selection bias can’t be excluded. The wide range of RS in both negative and positive-lymph nodes breast cancer confirm the important role of Oncotype DX in treatment decision- making.

Purpose: To analyze the role of MRI in the detection of additional disease and the need to perform additional biopsies in early breast carcinoma patients. In addition, to correlate the detection of new foci with tumor pathological features.Methods: Early breast carcinoma patients that had undergone a MRI as well as a mammography as diagnostic procedures were included in the study. The following pathologic features were studied: carcinoma type, histological grade, estrogen (ER)/progesterone (PR) receptors, HER2 and Ki67. HER2 status was established by FISH, while ER, PR and Ki67 status were established by inmunohistochemistry. Univariate analysis was conducted to ascertain significant correlation among detection of new foci and each of the tumor pathological features.Results: To date, data from 98 patients have been analyzed: median age 49 years (range: 35-79); carcinoma type: a) infiltrative ductal carcinoma (n=73, 74%), b) infiltrative lobular cancer (n=13, 13%), c)ductal carcinoma in situ (n= 6, 6%); amplified HER2 (n=18, 18%); grade III (n=33, 33%);Ki67 ≥ 25%(n=33, 33%); positive ER and PR (n=78, 79%); triple negative tumors (n=8, 8%). MRI detected additional disease in 38 cases (39%) that led to an additional biopsy in 20 cases (20%). Thirty-nine patients (39%) underwent mastectomy. A statistically significant correlation was established between the finding of new foci in MRI and high proliferative tumors through the biomarker Ki67 (cutoff ≥ 25%) (p Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4018.

10693 Background: X monotherapy is consistently effective and very well tolerated in pretreated MBC. N is also commonly used in this indication. In several studies, the combination of X + N led to response rates ranging from 43–67% in first-line MBC. As there are few data on the combination in pts with pretreated MBC, we evaluated the efficacy and safety of X + N in a multicenter phase II trial of pts previously treated with anthracycline- and taxane-containing regimens. Methods: Women >18 years of age with pretreated MBC, PS 0–2 and adequate organ function were enrolled to receive a 3-weekly regimen of XN: X 1000mg/m2 twice daily on days 1–14 and N 25mg/m2 on days 1&8, every 3 weeks up to a maximum of 6 cycles, disease progression or unacceptable toxicities. Results: A total of 32 pts were enrolled, median age 58 years (range 41–77), PS 0(74%), 1(19%), postmenopausal (61%). The most frequent sites of metastases were: liver (68%), nodes (36%), lung (36%). 58% of pts had ≥2 metastatic sites. 27 patients (87%) previously failed on anthracycline and taxane chemotherapy regimens. 152 cycles were administered with a median of 3 cycles/pt (range 1–10). Median relative dose intensity was 0.86 (0.51–1.01] for N and 0.85 (0.26–1.03] for X. All pts were evaluable for safety. The most common grade 3/4 clinical adverse events were vomiting (15%), asthenia (9%), and hand-foot syndrome (6%). Grade 3/4 hematological toxicities were: neutropenia (47%), leucopenia (9%), thrombocytopenia (3%). One pt died due to septic shock after the first cycle. 29 pts are evaluable for efficacy: the overall response rate was 52% (4 CR, 11 PR), with stable disease in 8 pts (28%). Median TTP was 7.5 months [95% CI, 5.7–9.8]. Conclusions: Our preliminary data indicate that the combination of X and N has promising clinical activity and good safety in pts with MBC who have failed prior taxane- and anthracycline-containing regimens. No significant financial relationships to disclose.

Forty consecutive patients with HD were treated with ABVD or EBVD (doxorubicin 25 mg/m2 or 4-epi-doxorubicin 37.5 mg/m2, bleomycin 10 mg/m2, vinblastine 6 mg/m2 and dacarbazine 375 mg/m2 day 1 and 14 every 28 days). Patients (pts) obtaining a complete remission (CR) after 4 cycles received up to 8 cycles, and pts obtaining a partial remission (PR) received up to 10 cycles. Two pts did not respond after 4 cycles and received a second line regimen. Twenty-two pts were male and 18 female. Median age was 36 years (13_77). 56% had nodular sclerosis, 19% mixed cellularity, 14% lymphocyte depletion and 11% lymphocyte predominance. Staging showed IE-A to III-A: 20 pts, III-B to IV-A, B: 20 pts. 12 received ABVD or EBVD after radiotherapy (RT) failure. With 4 cycles of CT 75% of pts achieved a CR (67% ABVD, 82% EBVD), this rate was increased to 95% (89% ABVD, 100% EBVD) after 8 or 10 cycles. With a median follow-up of 81 m (21_141) the freedom for progression (FFP) survival at 12 years is 86%. ABVD (or EBVD) is as or perhaps more effective and less toxic than MOPP as first line therapy in HD. In our series previous RT did not influence the results.

Introduction Human epidermal growth factor receptor 2 (HER2) amplification is frequent in ductal carcinoma in situ (DCIS) of the breast and is associated with poorly differentiated tumors and adverse prognosis features. This study aimed to determine the molecular effects of the HER2 inhibitor lapatinib in patients with HER2 positive DCIS. Methods Patients with HER2 positive DCIS received 1,500 mg daily of lapatinib for four consecutive weeks prior to surgical resection. Magnetic resonance imaging (MRI) was used to determine changes in tumor volume. The molecular effects of lapatinib on HER2 signaling (PI3K/AKT and RAS/MAPK pathways), cell proliferation (Ki67 and p27) and apoptosis (TUNEL) were determined in pre and post-lapatinib treatment samples. Results A total of 20 patients were included. Lapatinib was well tolerated with only minor and transient side effects. The agent effectively modulated HER2 signaling decreasing significantly pHER2 and pERK1 expression, together with a decrease in tumor size evaluated by MRI. There was no evidence of changes in Ki67. Conclusions Four weeks of neoadjuvant lapatinib in patients with HER2-positive DCIS resulted in inhibition of HER2 and RAS/MAPK signaling pathway. Trial registration 2008-004492-21 (Registered June 25th 2008). Electronic supplementary material The online version of this article (doi:10.1186/bcr3695) contains supplementary material, which is available to authorized users.