Background: Onco-cardiology is a developing interdisciplinary field aiming to help oncologists to cope with the cardiovascular complications and comorbidities of patients followed for malignancies. Side effects of cytotoxic chemotherapies and targeted treatments are put into focus.

Background: Neutropenic sepsis is a frequent complication of cytotoxic chemotherapy delivered for cancer patients. Its management is well determined by clinical guidelines. Non-neutropenic sepsis is another potential complication in cancer patients. Its management is less established in the medical literature. Materials and Methods: Three cases are presented to illustrate favourable evolution of non-neutropenic biliary-, uro- and bronchogenic-sepsis in cancer patients with poor prognosis. Results: All three patients had a survival over six months after the management of the septic complication. Two of them received subsequent systemic anticancer treatment. Conclusions: Survival benefit offered by the management of cancer-related non-neutropenic sepsis may be comparable to the benefit obtained by systemic anticancer treatments. Cost-effectiveness of sepsis management may be better than that of anticancer treatments.

Background: Standard adjuvant or neo-adjuvant chemotherapy of primary breast cancers consists of docetaxel and the combination of anthracyclin-cyclophosphamide in two steps. According to international literature, the neo-adjuvant treatment of triple negative tumours by the combination of docetaxel-carboplatin allows a high rate of pathological complete remission and the adjuvant treatment of small, node negative HER2+ tumours by the combination of paclitaxel-trastuzumab allows a negligible recurrence rate together with a very good tolerance. Methods: Our aim was the retrospective analysis of the alternative chemotherapy regimens in our patient population. Results: The neo-adjuvant docetaxel-carboplatin allowed a 55% pathological complete remission rate among 20 patients. With the adjuvant paclitaxel-trastuzumab, we did not notice any recurrence among 5 patients at a median follow-up of 18 months. Conclusion: Our results correspond to the literature data. The spread of the protocols in the clinical practice is proposed.

A szerzők két esetet mutatnak be. A 69 éves nőbetegnél helyileg előrehaladott és pulmonalis, illetve multiplex cerebralis metasztázisokat adó triple negatív ductalis emlődaganatot diagnosztizáltak. A tünetmentes cerebralis metasztázisok komplett radiológiai remisszióját észlelték szisztémás carboplatin-docetaxel (75 mg/m2) kemoterápia mellett. A beteg később palliatív koponyabesugárzást és 2. vonalú kemoterápiát kapott. A diagnózistól számítva másfél évet élt, részlegesen megőrzött önállósággal. Az 57 éves nőbetegnél meningitis carcinomatosát, nyirokcsomóés multiplex ossealis metasztázist adó hormonérzékeny lobularis emlődaganatot mutattak ki. A nyirokcsomó-metasztázis megjelenése előtt intrathecalis methotrexat kemoterápiát alkalmaztak, amely mellett neurológiai tünetei megszűntek. A zsigeri metasztázis kifejlődésekor szisztémás ifosfamid (1000 mg/m2, 1–3. nap) – etoposid (100 mg/m2, 1–3. nap) kemoterápiát kapott, amely mellett a nyirokcsomóáttét komplett klinikai remisszióját és a neurológiai tünetmentesség stabilitását észlelték. A meningitis carcinomatosa diagnózisától számítva több mint egy évet élt, önálló életvitellel. Mindkét eset a szisztémás kemoterápia lehetséges hatásosságát mutatja intracranialis metasztázisokat adó emlődaganatok kezelésében. Orv. Hetil., 2016, 157(45), 1809–1813.

Abstract Background Palbociclib (P) is an oral CDK4/6 inhibitor. In PALOMA-1/TRIO-18, a randomized phase 2 trial, addition of P to letrozole (L) significantly prolonged progression-free survival (PFS) (20 mo with P+L vs 10 mo with L alone; HR = 0.488, P=0.0004; Finn et al, Lancet Oncol, 2015) in postmenopausal women with estrogen-receptor-positive (ER+), HER2-negative advanced breast cancer (ABC) in the first-line setting. At the time of final PFS analysis, overall survival (OS) was immature. Objectives It is clinically important to understand whether patients (pts) benefit from standard of care endocrine therapy (ET) after they progressed on P+L as first-line treatment for ABC. We report patterns of post-progression treatment in the next line of therapy immediately following participation in the PALOMA-1 trial. Methods Postmenopausal women with ER+ and HER2- ABC who had not received any treatment for their advanced disease were randomized to receive P+L (N = 84) or L alone (N = 81) in the first-line setting. The primary endpoint was investigator-assessed PFS. Tumor assessment was performed every 8 weeks. Post-progression treatment data was captured and analyzed. Results As of the data cut-off (Nov 29, 2013), 40 progression events had occurred in the P+L arm and 59 in the L alone arm. 50% of pts in the P+L arm vs. 64% in the L alone arm received ET after progression on study treatment. 60% of pts in the P+L arm vs. 66% in the L alone arm received chemotherapy (CT) after progression on study treatment. The time to 1st subsequent ET/ CT after progression on study treatment, duration of 1st subsequent ET/CT, and choice of 1st subsequent ET/ CT are shown in Table 1. Table 1 P + LL N=84N=81Patients (pts) with Disease Progression, NN (%)a40 (47.6)59 (72.8)Pts who received subsequent Endocrine Therapy (ET) after progression on study treatment, n(%)b20 (50.0)*38 (64.4)*Time from randomization to 1st subsequent ET (days), median (range)465.5 (239-1100)368.5 (65-1102)Duration of 1st subsequent ET (days), median (range)**153 (24-592)151 (16-1135)Choice of 1st subsequent ET, n(%)bFulvestrant9 (22.5)15 (25.4)Exemestane6 (15.0)9 (15.3)Medroxyprogesterone4 (10.0)1 (1.7)Letrozole1 (2.5)5 (8.5)Tamoxifen08 (13.6)Pts who received subsequent Chemotherapy (CT) after progression on study treatment, n(%)b24 (60.0)*39 (66.1)*Time from randomization to 1st subsequent CT (days), median (range)388.5 (69-918)281 (46-1013)Duration of 1st subsequent CT (days), median (range)**92 (1-457)120 (1-1143)Choice of 1st subsequent CT, n(%)bCapecitabine1 (2.5)10 (17.0)Mitoxantrone13 (32.5)1 (1.7)Paclitaxel013 (22.0)Other10 (25)15 (25.4)apercentages are based on N as denominator; bpercentages based on NN as denominator; *some patients had both ET and CT after progression; **calculated as treatment stop date minus treatment start date +1; if treatment was ongoing at time of data cut-off, stop date was imputed as Nov 29, 2013. Conclusions P+L delayed the time to ET/CT as compared to L alone. Pts benefited from standard of care ET/CT after they progressed on P+L as first-line treatment for ABC as demonstrated by the length of time on subsequent therapies; no difference was observed from the L alone arm. Clinical Trial Information: NCT00721409 Funding Source: Pfizer. Citation Format: Finn RS, Crown JP, Ettl J, Pinter T, Thummala A, Shparyk Y, Patel R, Randolph S, Kim S, Huang X, Nadanaciva S, Huang Bartlett C, Slamon DJ. Treatment patterns of post-disease progression in the PALOMA-1/TRIO-18 trial. [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 P4-13-02.

Abstract Background: BCIRG-006 was study designed to assess the relative efficacy and safety of two trastuzumab-based regimens compared to a standard (non-trastuzumab) regimen in the adjuvant treatment of early HER2+ breast cancer. We present the final, protocol-specified analysis of the long-term results from this trial that was initially developed to determine how to maximize adjuvant treatment efficacy and safety in these patients. Material & Methods: Between April, 2001 and March, 2004, we randomized 3,222 HER2+ operable breast cancer patients with axillary lymph node-positive or high risk node-negative disease, to either standard AC (60/600mg/m2 q3wk x 4) followed by T (100mg/m2 q3wk x 4) (AC-T) or two trastuzumab-based regimens. The trastuzumab-based regimens were AC followed by T (100mg/m2 q3wk x 4) and trastuzumab (H) x 1 year (AC-TH), or TCarbo (75mg/m2/AUC6 q3wk x 6) and H x 1 year (TCH). Patients were prospectively stratified by number of positive nodes (0, 1-3 vs ≥4) and hormone receptor status and those with ER and/or PR positive disease received hormone-directed therapy for 5yrs post chemotherapy. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety, with extensive cardiac evaluation (symptomatic events and asymptomatic, sustained LVEF declines). Results: Baseline characteristics of the study population were well balanced in the three study arms. At a median follow-up of 10.3 years, a persistent significant DFS benefit is seen in both trastuzumab-containing arms compared to AC-T with only 10 DFS events separating the two trastuzumab-based regimens: AC-TH (HR=0.70, 95%CI [0.60, 0.83]; p<0.001)) and TCH (HR=0.76, 95% CI [0.65, 0.90]; p<0.001). At this final analysis, the DFS HRs for AC-TH and TCH are closer than those observed in any prior protocol-directed study analyses (at 5 years follow-up the HRs were 0.64 and 0.75 for AC-TH and TCH respectively). Also, an OS benefit was observed in both AC-TH (HR=0.64, 95% CI [0.52, 0.79]; p<0.001)) and TCH (HR=0.76, 95% CI [0.62, 0.93]; p=0.0081). Importantly, TCH has significantly lower symptomatic CHF events by five-fold compared to AC-TH; 21 (2.0%) for AC-TH vs. 4 (0.4%) for TCH; p=0.0005. The AC-T control arm had 8 (0.8%) symptomatic CHF events. The incidence of patients with a relative LVEF decline >10% is doubled in the AC-TH compared to TCH regimens (206 vs 97; p<0.0001). Discussion: The long-term 10 years final results of the BCIRG 006 trial confirm the significant benefit of trastuzumab in the adjuvant treatment of HER2+ breast cancers, no significant efficacy difference between AC-TH and TCH as well as a significant symptomatic and asymptomatic cardiac safety benefit in the non-anthracycline, TCH trastuzumab-based regimen. Citation Format: Slamon DJ, Eiermann W, Robert NJ, Giermek J, Martin M, Jasiowka M, Mackey JR, Chan A, Liu M-C, Pinter T, Valero V, Falkson C, Fornander T, Shiftan TA, Bensfia S, Hitier S, Xu N, Bée-Munteanu V, Drevot P, Press MF, Crown J, On Behalf of the BCIRG-006 Investigators. Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC→T) with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2+ early breast cancer. [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 S5-04.

BACKGROUND:Pegfilgrastim's role in reducing the risk of febrile neutropenia (FN) in patients with colorectal cancer (CRC) receiving chemotherapy plus bevacizumab was not previously evaluated in a prospective study. The present phase III, double-blind trial evaluated the efficacy of pegfilgrastim versus placebo in reducing the incidence of grade 3/4 FN in patients with advanced CRC receiving bevacizumab combined with first-line chemotherapy (FOLFOX [leucovorin, 5-fluorouracil, oxaliplatin] or FOLFIRI [leucovorin, 5-fluorouracil, irinotecan]). PATIENTS AND METHODS:Patients aged ≥ 18 years with locally advanced or metastatic CRC were randomized 1:1 to placebo or 6 mg of pegfilgrastim ∼24 hours after receiving chemotherapy plus bevacizumab every 14 days. The study treatment period included 4 cycles, but patients could continue treatment for ≤ 60 months. The primary endpoint was incidence of grade 3/4 FN in the first 4 cycles. The secondary endpoints included the objective response rate (ORR), overall survival, and progression-free survival, analyzed at the end of the long-term follow-up period. RESULTS:A total of 845 patients were randomized from November 2009 to January 2012 (422, pegfilgrastim; 423, placebo). Pegfilgrastim significantly reduced the incidence of grade 3/4 FN in the first 4 treatment cycles (pegfilgrastim, 2.4%; 95% confidence interval [CI], 1.1%-4.3%; placebo, 5.7%; 95% CI, 3.7%-8.3%; odds ratio [OR], 0.41; P = .014). No significant differences were observed between the 2 arms in ORR (OR, 1.15; P = .330), overall survival (hazard ratio, 0.94; P = .440), and progression-free survival (hazard ratio, 0.93; P = .300). CONCLUSION:Pegfilgrastim reduced the FN incidence in patients with advanced CRC receiving chemotherapy and bevacizumab. Administration of pegfilgrastim was tolerable and did not negatively affect the tumor response or survival in this patient population.

Background: BCIRG-006 was study designed to assess the relative efficacy and safety of two trastuzumab-based regimens compared to a standard (non-trastuzumab) regimen in the adjuvant treatment of early HER2+ breast cancer. We present the final, protocol-specified analysis of the long-term results from this trial that was initially developed to determine how to maximize adjuvant treatment efficacy and safety in these patients. Material u0026 Methods: Between April, 2001 and March, 2004, we randomized 3,222 HER2+ operable breast cancer patients with axillary lymph node-positive or high risk node-negative disease, to either standard AC (60/600mg/m2 q3wk x 4) followed by T (100mg/m2 q3wk x 4) (AC-T) or two trastuzumab-based regimens. The trastuzumab-based regimens were AC followed by T (100mg/m2 q3wk x 4) and trastuzumab (H) x 1 year (AC-TH), or TCarbo (75mg/m2/AUC6 q3wk x 6) and H x 1 year (TCH). Patients were prospectively stratified by number of positive nodes (0, 1-3 vs ≥4) and hormone receptor status and those with ER and/or PR positive disease received hormone-directed therapy for 5yrs post chemotherapy. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety, with extensive cardiac evaluation (symptomatic events and asymptomatic, sustained LVEF declines). Results: Baseline characteristics of the study population were well balanced in the three study arms. At a median follow-up of 10.3 years, a persistent significant DFS benefit is seen in both trastuzumab-containing arms compared to AC-T with only 10 DFS events separating the two trastuzumab-based regimens: AC-TH (HR=0.70, 95%CI [0.60, 0.83]; p 10% is doubled in the AC-TH compared to TCH regimens (206 vs 97; p Discussion: The long-term 10 years final results of the BCIRG 006 trial confirm the significant benefit of trastuzumab in the adjuvant treatment of HER2+ breast cancers, no significant efficacy difference between AC-TH and TCH as well as a significant symptomatic and asymptomatic cardiac safety benefit in the non-anthracycline, TCH trastuzumab-based regimen. Citation Format: Slamon DJ, Eiermann W, Robert NJ, Giermek J, Martin M, Jasiowka M, Mackey JR, Chan A, Liu M-C, Pinter T, Valero V, Falkson C, Fornander T, Shiftan TA, Bensfia S, Hitier S, Xu N, Bee-Munteanu V, Drevot P, Press MF, Crown J, On Behalf of the BCIRG-006 Investigators. Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC→T) with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2+ early breast cancer. [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 S5-04.

Nowadays the main task of scientists is to find natural ways of improving plant productivity that lead to environmentally friendly agriculture. Biofertilizers have a great potential to achieve this aim but unfortunately there is little information about their application in grape growing in Hungary. For this reason, a foliar nutrition experiment was conducted to investigate the effect of two biofertilizers (an algae product and a biostimulator, containing amino acids) on yield, leaf nutrient concentration, and quality parameters of Blaufrankish grape variety. The study was conducted in 2012 at Noszvaj in northeastern Hungary in a 24-year-old grapevine plantation on cv. Blaufrankish. Treatments (application time and doses) were adjusted to the phenological phases of grapevine. Effect of treatments was monitored by soil and leaf analysis, grape quality measurements, and field observations. Treatments increased the yield but did not affect the fruit quality compared to the control. The applied products significantly increased the bunch weight and the size of berries. Applied biofertilizers had no effect on leaf nutrient concentration. According to our field observations, it seemed that treated vines had larger and greener leaves.

Background: Palbociclib (P) an oral selective, reversible CDK4/6 inhibitor, inhibits cell proliferation by halting cell cycle progression. PALOMA-1/TRIO-18, a randomized ph 2 study evaluated the efficacy and safety of P + letrozole (L) in women with post-menopausal ER + , HER2-advanced breast cancer (ABC). Progression-free survival was doubled over L alone. Neutropenia was the most frequently reported adverse event (AE). In preclinical studies evaluating the bone marrow, P did not appear to affect well-differentiated progenitor cells or mature peripheral neutrophils but induces quiescence (G1 arrest) of early multipotent progenitor cells (S Johnson, JCI 2010). These findings suggest P may induce neutropenia by a different mechanism than chemotherapy (CT).

3575 Background: The literature reports that adding biologics to chemotherapy (ctx) may increase the incidence of clinically significant neutropenia. his trial was conducted to evaluate the efficacy of PEG in reducing the incidence of febrile neutropenia (FN) in pts with locally-advanced (LA) or metastatic (m)CRC receiving first-line treatment with either FOLFOX/B or FOLFIRI/B. Methods: Key eligibility: ≥ 18 years old; measurable, nonresectable CRC per RECIST 1.1. Pts were randomly assigned 1:1 to either placebo or 6 mg PEG ~24 h after ctx/B. The study treatment period included four Q2W cycles, but pts could continue their assigned regimen until progression. Pts were stratified by region (North America vs rest of world), stage (LA vs mCRC), and ctx (FOLFOX vs FOLFIRI). Estimated sample size (N = 800) was based on the expected incidence of grade 3/4 FN (primary endpoint) across the first 4 cycles of ctx/B, powered for PEG superiority over placebo. Other endpoints included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: 845 pts were randomized (Nov 2009 to Jan 2012) and received study treatment; 783 pts completed 4 cycles of ctx/B. Median age was 61 years; 512 (61%) pts were male; 819 (97%) had mCRC; 414 (49%) received FOLFOX, and 431 (51%) received FOLFIRI. Grade 3/4 FN (first 4 cycles) for placebo vs PEG was 5.7% vs 2.4%; OR 0.41; p = 0.014. A similar incidence of other ≥ grade 3 adverse events was seen in both arms (28% placebo; 27% PEG). See table for additional results. Conclusions: PEG significantly reduced the incidence of grade 3/4 FN in this pt population receiving standard ctx/B for CRC. Follow-up is ongoing. Clinical trial information: NCT00911170. [Table: see text]

Background: PD 0332991 (palbociclib), a selective inhibitor of CDK-4/6, prevents DNA synthesis by blocking cell cycle progression. Preclinical studies identified luminal ER+ breast cancer cell lines with elevated expression of cyclin-D1, Rb and reduced p16 expression as being associated with palbociclib sensitivity (Finn et al. 2009). In addition, synergistic activity was seen in vitro when combined with tamoxifen. As a result of these data Phase Ib safety testing was performed, and led to this randomized Phase II study using a recommended Phase II dose of palbociclib (P) 125 mg QD for 3 weeks followed by 1 week off plus letrozole (L) 2.5 mg QD continuously. Methods: This Phase II trial was designed as a two-part study evaluating P+L in front-line ER+/HER2- metastatic breast cancer (MBC). Part 1 enrolled post-menopausal patients (pts) with this subtype using ER+/HER2- biomarkers while Part 2 enrolled pts with the same MBC subtype additionally screened for CCND1 amplification and/or loss of p16. The primary endpoint was investigator assessed progression-free survival (PFS) defined as time from randomization to objective progression or death. Secondary endpoints included objective response rate, overall survival, safety, and correlative biomarker studies. In both parts, post-menopausal women with ER+/HER2- MBC were randomized 1:1 to receive either P+L or L alone. Pts continued until disease progression, unacceptable toxicity, or consent withdrawal and were followed for tumor assessments every 2 months. The trial had 80% power to detect a 50% improvement in median PFS (hazard ratio 0.67 [P+L vs. L] with a 1-sided alpha=0.10). Results: A total of 165 pts were randomized in this Phase II study; 66 pts in Part 1 and 99 pts in Part 2. Baseline characteristics were balanced between treatment arms. The final analysis of primary endpoint showed a statistically significant improvement in PFS for the P+L arm (20.2 months) vs. L arm (10.2 months) with hazard ratio (HR)=0.488 (95% CI: 0.319, 0.748) and 1-sided p=0.0004. The treatment effects were also demonstrated when Part 1 and Part 2 were analyzed separately (HR=0.299 [95% CI: 0.156, 0.572]; 1-sided p=0.0001 for Part 1 and HR=0.508 [95% CI: 0.303, 0.853]; 1-sided p=0.0046 for Part 2). The OS analysis with 61 events demonstrated a trend in favor of P+L vs. L (37.5 months vs. 33.3 months, respectively; HR=0.813; p=0.2105). The most common adverse events in the P+L arm were neutropenia, leukopenia, fatigue, and anemia. Conclusions: P+L demonstrated a statistically significant improvement in PFS and showed significant clinical benefit as first-line treatment of ER+/HER2- advanced BC. A Phase III study of P+L in this same MBC population is ongoing. Citation Format: Richard S. Finn, John P. Crown, Istvan Lang, Katalin Boer, Igor M. Bondarenko, Sergey O. Kulyk, Johannes Ettl, Ravindranath Patel, Tamas Pinter, Marcus Schmidt, Yaroslav V. Shparyk, Anu R. Thummala, Nataliya L. Voytko, Xin Huang, Sindy T. Kim, Sophia S. Randolph, Dennis J. Slamon. Final results of a randomized Phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT101. doi:10.1158/1538-7445.AM2014-CT101

Background: PD 0332991, a selective inhibitor of CDK 4/6, prevents cellular DNA synthesis by blocking cell cycle progression.Preclinical studies in a BC cell line panel identified the luminal ER subtype, elevated expression of cyclin D1 and Rb protein, and reduced p16 expression as being associated with sensitivity to PD 0332991 (Finn et al. 2009).Synergistic activity was also observed in vitro when combined with tamoxifen.Based on these observations, a phase 1/2 study in combination with letrozole was initiated.We present results from the randomized phase 2 portion.Methods: The phase 2 portion is a two-part study; Part 1, ER + /HER2-selected; Part 2, further biomarkers.We present results from Part 1.The primary endpoint is progression-free survival (PFS); secondary endpoints include response rate, overall survival, safety, and correlative biomarker studies.Post-menopausal women with ER + /HER2-advanced BC were randomized 1:1 to receive either letrozole 2.5 mg QD plus PD 0332991 125 mg QD on Schedule 3/1 (L + P) or letrozole 2.5 mg QD alone (L).Pts continue on assigned study treatment until disease progression, unacceptable toxicity, or consent withdrawal, and are followed for tumor assessments every 2 months.Results: 66 pts were randomized.Baseline characteristics were balanced between the two arms.As of the data cut-off, median duration of treatment was 47 wks for the L + P arm and 24 wks for the L arm.The most commonly reported treatment-related AEs in the combination arm were neutropenia, leukopenia, and fatigue.The response rate was 27% vs. 23% (out of 26 and 22 pts with measurable disease, L + P vs. L, respectively), clinical benefit rate (PR + SD ≥24 weeks) was 59% vs. 44%, respectively.Two vs. 7 pts had best response of progressive disease for L + P vs. L, respectively.PFS was significantly greater in the L + P arm vs. L (HR = 0.38; 95% CI, 0.17 to 0.86; p = 0.015).There were 20 vs. 8 pts ongoing on assigned treatment.Conclusions: The combination of PD 0332991 and letrozole is well tolerated with encouraging clinical benefit, confirming the preferential sensitivity of ER+ BC observed in preclinical models.

Background: PD 0332991 is an orally bioavailable selective inhibitor of CDK 4/6 and prevents cellular DNA synthesis by prohibiting progression of the cell cycle from G1 into the S phase. Preclinical evaluations suggest that reduction in CDKN2A (p16) expression and cyclin D1 (CCND1) overexpression confer susceptibility to PD 0332991 (Finn 2009). In addition, PD 0332991 was synergistic in combination with tamoxifen in vitro in ER+ human breast cancer cell lines. Based on these observations, a phase 1/2 study in combination with letrozole as first-line therapy for advanced ER+ post-menopausal breast cancer was initiated. The phase 1 part of the study (completed) determined the recommended phase 2 dose to be PD 0332991 125 mg QD on Schedule 3/1 (3 weeks on treatment followed by 1-week off treatment) in combination with letrozole 2.5 mg QD. The combination was generally well tolerated and encouraging antitumor activity was observed. We present preliminary data from the randomized Phase 2 portion comparing letrozole alone to letrozole plus PD 0332991. Methods: The Phase 2 portion of the study is designed as a two-part study; we present data from Part 1. In both parts, eligible patients are randomized 1:1 to letrozole 2.5 mg QD alone (control) or PD 0332991 125 mg QD on schedule 3/1 and letrozole 2.5 mg QD (treatment, tx). Part 1enrolled post-menopausal women with ER+, HER2− cancer using only ER+, HER2−as a selection criteria. Part 2 is now enrolling post-menopausal women with ER+, HER2− breast cancer with CCND1 amplification and/or loss of p16 by FISH (target N=150). The primary endpoint is progression-free survival (PFS); secondary endpoints include overall survival, response rate, safety, and correlative studies. Pts are stratified for disease site and length from prior adjuvant therapy. Pts continue assigned study treatment until disease progression, unacceptable toxicity, or consent withdrawal and are followed every 2 months to assess disease status. Tumor tissue was required for participation. Results: 66 patients have been randomized in Part 1. At the time of data cut-off (April 2011) median duration of treatment is 20 (range 4–64) wks for control and 27 (2-59) wks for tx. Dose reductions occurred in 9 pts on the tx arm and none on the control arm. There are no complete responses. The number of partial responses for pts with measurable disease are similar between arms (4/22 control vs 5/24 in tx). The number of pts with stable disease> 24 weeks was higher in the tx arm (5 vs 8). The number of pts with best response of progressive disease is lower in the treatment arm (2 vs 6). PFS data are immature. Twelve pts remain on control vs. 21 on tx. As in the Phase I portion of the study, the most common treatment-related AEs were neutropenia and leucopenia without febrile neutropenia. Biomarker studies for CCND1 amplification, p16 loss, RB status, and Ki67 are ongoing. Conclusion: The combination of PD 0332991 and letrozole is well tolerated as first-line treatment of ER+, HER2− post-menopausal breast cancer. Updated efficacy data and biomarker data will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-05.

LBA5002 Background: Abagovomab, a murine monoclonal anti-idiotypic antibody directed against CA125, has been shown to induce an active immune response against CA125 tumor-associated antigen in advanced ovarian cancer patients. Methods: Abagovomab (A) has been tested in a randomized (2:1) double-blind, placebo (P) controlled, multicenter phase II/III trial in patients with FIGO stage III/IV ovarian cancer after complete response to platinum-taxane first-line chemotherapy. A (2 mg/1 ml) or P was given subcutaneously every 2 weeks for 6 weeks (induction phase); then every 4 weeks (maintenance phase) until recurrence, or up to 21 months after the last patient had been randomized. Primary endpoint is progression-free survival (PFS); secondary endpoints are OS and immunological response. An estimated 870 patients, with a mean follow-up of 18 months, were needed to observe at least 535 recurrences, which provides a power >90% in rejecting the null hypothesis of equality between A and P on PFS according to a hazard ratio (HR) of 1.33, in which median P PFS time is 18 months, significance level (a) 5% (two-sided), and the overall dropout rate 10%. Primary analysis was run on PFS in the ITT population. The design included a prospective stratification in randomization for the following prognostic factors: FIGO stage (III-IV); tumor size after debulking (residual tumor <1 cm, >1 cm); and CA125 serum level after the third cycle (<35 U/ml, >35 U/ml). The Cox proportional hazards model was used for adjusting the primary analysis. Results: 888 patients were enrolled by December 2008, 593 in A arm and 295 in P arm. The median follow-up was 28.1 months and the mean number treatment administrations was 18. Baseline characteristics were balanced between arms. Overall tolerability profile was consistent with previous A studies. Median (95% CI) PFS was 13.24 (10.612-13.602) months for A arm and 13.21 (10.612-16.000) months for P arm; HR=1.099 (0.919-1.315); p=0.301. Conclusions: Treatment with A did not translate into a prolonged PFS.

TPS100 Background: PD 0332991 is an orally bioavailable selective inhibitor of CDK4/6 and prevents cellular DNA synthesis by prohibiting progression of the cell cycle from G1 to S phase. Preclinical evaluations suggest that reduction in CDKN2A (p16) expression and cyclin D1 (CCND1) overexpression confer susceptibility to PD 0332991 (Finn et al. Breast Cancer Res 2009;11:R77). In addition, PD 0332991 was synergistic in combination with tamoxifen in vitro in ER+ human breast cancer cell lines (Ibid.). Based on these observations, a phase I/II study (ClinicalTrials.gov ID: NCT00721409 ) in combination with letrozole as first-line therapy in advanced ER+ post-menopausal breast cancer was initiated. The phase I portion has been completed and the recommended phase II dose (RP2D) was determined to be PD 0332991 125 mg once daily (QD) on Schedule 3/1 (3 weeks on treatment followed by 1 week off treatment) plus letrozole 2.5 mg QD. The combination was generally well tolerated, and encouraging antitumor activity was observed (Slamon et al. ASCO 2010. Abstract 3060). METHODS The phase II portion is a two-part study. In both parts, eligible patients are randomized to receive either letrozole 2.5 mg QD plus PD 0332991 125 mg QD on Schedule 3/1 or letrozole 2.5 mg QD alone. Part 1 enrolled post-menopausal women with ER+, HER2-negative breast cancer (N=60) without biomarker selection and Part 2 is now enrolling post-menopausal women with ER+, HER2-negative breast cancer with biomarker selection (CCND1 amplification and/or loss of p16; N=150). In Part 2, tissue samples are required at screening for fluorescence in situ hybridization (FISH) analysis for CCND1 and p16 copy number changes. Patients will continue with the assigned study treatment until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint is progression-free survival, and secondary endpoints include overall survival, response rate, safety, and biomarker correlative studies. Part 1 has completed accrual with 66 patients and Part 2 is now open for accrual.