Randomized phase II study of fulvestrant plus palbociclib or placebo in endocrine-sensitive, hormone receptor-positive/HER2-advanced breast cancer: GEICAM/2014-12 (FLIPPER).

BACKGROUND: The potential benefit of adding palbociclib to fulvestrant as first-line treatment in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative endocrine-sensitive advanced breast cancer (ABC) patients remains uncharacterized. PATIENTS AND METHODS: In this randomized (1:1), double-blind, phase II study, postmenopausal women with HR-positive, HER2-negative ABC with de novo metastatic disease or those who relapsed after >12 months of adjuvant endocrine therapy received palbociclib/fulvestrant or placebo/fulvestrant. Stratification was based on recurrent versus de novo metastatic disease and visceral involvement. The primary objective was one-year progression-free survival (PFS-1y) rate. The sample size was 190 patients. The two-sided alpha of 0.2, 80% of power to detect a difference between the arms, assuming PFS rates of 0.695 and 0.545 for palbociclib/fulvestrant and placebo/fulvestrant, respectively. RESULTS: In total, 189 patients were randomized to palbociclib/fulvestrant ([n = 94] or placebo/fulvestrant [n = 95]). 45.5% and 60.3% of patients had de novo metastatic disease and visceral involvement, respectively. PFS-1y rates were 83.5% and 71.9% in the palbociclib/fulvestrant and placebo/fulvestrant arms, (HR 0.55, 80% CI 0.36-0.83, P = 0.064). The median PFS were 31.8 and 22.0 months for the palbociclib/fulvestrant and placebo/fulvestrant arms (aHR 0.48, 80% CI 0.37-0.64, P = 0.001). The most frequent grade 3-4 adverse events were neutropenia (68.1% vs. 0%), leucopenia (26.6% vs. 0%), anemia (3.2% vs. 0%), and lymphopenia (14.9% vs. 2.1%) for the palbociclib/fulvestrant and placebo/fulvestrant, respectively. The most frequent non-hematologic grade 3-4 adverse event was fatigue (4.3% vs. 0%). CONCLUSIONS: Palbociclib/fulvestrant demonstrated better PFS-1y rates and median PFS than placebo/fulvestrant in HR-positive/HER2-negative endocrine-sensitive ABC patients.

Treatment and Outcome of Patients with Stage IS Testicular Cancer: A Retrospective Study from the Spanish Germ Cell Cancer Group.

PURPOSE: Stage IS testicular cancer is defined by the persistence of elevated serum tumor markers, including α-fetoprotein and/or ß-human chorionic gonadotropin, after orchiectomy without radiological evidence of metastatic disease. Current treatment recommendations include cisplatin based chemotherapy up front but the recommendations are based on limited single center series. MATERIALS AND METHODS: We retrospectively analyzed clinical and pathological characteristics, and long-term outcomes in 110 patients uniformly treated with primary chemotherapy between 1994 and 2016. The primary objective was to evaluate long-term disease-free survival. We also explored factors associated with the need for additional treatment. RESULTS: The elevated prechemotherapy tumor markers were α-fetoprotein in 48% of cases, ß-human chorionic gonadotropin in 14%, and α-fetoprotein and ß-human chorionic gonadotropin in 38%. Median α-fetoprotein and ß-human chorionic gonadotropin values were 71 ng/ml and 80 mIU/ml, respectively. The IGCCCG (International Germ Cell Cancer Collaborative Group) prognostic classification was good in 94% of cases. Mixed nonseminomatous germ cell tumor was found in 78% of cases. Of the patients 103 achieved a complete response to chemotherapy. In 6 patients radiological signs of progressive disease developed during chemotherapy, while 8 experienced relapse after an initial complete response. At a median followup of 108 months 108 patients were alive and disease-free. Five and 10-year disease-free survival rates were 87% and 85%, respectively. The predominance of embryonal carcinoma in the primary tumor was the only factor associated with the probability of needing additional therapy. CONCLUSIONS: Stage IS testicular cancer is more commonly associated with elevated α-fetoprotein, an IGCCCG good prognosis and mixed nonseminomatous germ cell tumor. Treatment with cisplatin based chemotherapy leads to cure in most cases. However, a proportion of patients require the integration of additional therapies, including more frequently when embryonal carcinoma is not predominant.

Bevacizumab for recurrent, persistent or advanced cervical cancer: reproducibility of GOG 240 study results in "real world" patients.

PURPOSE: Bevacizumab is the only therapeutic target approved for patients with persistent, recurrent or advanced cervical cancer from a phase III study that combined with chemotherapy; it proves a significant increase in overall survival. To retrospectively assess the efficacy and safety of bevacizumab as the first-line treatment in patients from usual clinical practice with recurrent/persistent or advanced cervical cancer. PATIENTS AND METHODS: Treatment consisted of cisplatin 50 mg/m2 or carboplatin AUC 5 plus paclitaxel 175 mg/m2 for 6-8 cycles and bevacizumab 15 mg/kg every 3 weeks up to progression or unacceptable toxicity. The endpoints were progression-free survival (PFS), overall survival (OS), response rates (RR) and toxicity. RESULTS: Twenty-seven patients were included from January 2014 to June 2017, with a median follow-up 10, 1 months. Eleven percent had recurrent/persistent disease and 89% had metastatic disease at diagnosis. The prior exposition to platinum was 70%. The median PFS and OS were 9, 6 and 21, 5 months, respectively. There was an increase of fistula formation (22%). All of them had pelvic and peritoneal disease at the beginning of treatment and previous treatment with chemoradiotherapy; non-incidence differences were found according to the type of platinum agent used. There were two treatment-related deaths, one from intestinal perforation and another from severe sepsis. CONCLUSION: Finally, although our study does have certain limitations, we believe that it can provide useful information and encouraging evidence that the routine use of bevacizumab as part of first-line treatment of patients with advanced cervical cancer may be associated with outcomes comparable with those obtained in GOG240 study.

Efficacy and safety of subcutaneous trastuzumab and intravenous trastuzumab as part of adjuvant therapy for HER2-positive early breast cancer: Final analysis of the randomised, two-cohort PrefHer study.

AIM: To assess efficacy (event-free survival, EFS) and safety in patients followed up for 3 years in the PrefHer study (NCT01401166). PATIENTS AND METHODS: Post surgery and post chemotherapy in the (neo)adjuvant setting, patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer were randomised to receive four cycles of the subcutaneous form of trastuzumab (Herceptin® SC [H SC] via single-use injection device [Cohort 1] or delivery via a hand-held syringe from an SC Vial [Cohort 2]; 600 mg fixed dose) followed by four of the intravenous form of trastuzumab (Herceptin® [H IV]; 8 mg/kg loading, 6 mg/kg maintenance doses) in the adjuvant setting or vice versa every 3 weeks. Patients could have received H before randomisation. H was then continued to complete a total of 18 cycles, including any cycles received before randomisation. RESULTS: A total of 488 patients were randomised across both cohorts. After median follow-up of 36.1 months, 3-year EFS across both groups in the evaluable intention-to-treat population (467 patients) was 90.6% overall, 89.9% in Cohort 1, and 91.1% in Cohort 2. No new safety signals were identified during long-term follow-up, with only one cardiac serious adverse event in the safety population (483 patients). CONCLUSIONS: Three-year EFS data following H SC and H IV treatment are consistent with those reported by previous trials for H in the adjuvant setting. The overall safety profile during adjuvant treatment was as expected.

Prognostic factors for relapse in stage I seminoma: a new nomogram derived from three consecutive, risk-adapted studies from the Spanish Germ Cell Cancer Group (SGCCG).

BACKGROUND: We aimed to analyze prognostic factors for relapse in stage I seminoma managed by either active surveillance or adjuvant chemotherapy, and to describe the long-term patterns of recurrence in both groups. PATIENTS AND METHODS: From 1994 to 2008, 744 patients were included in three consecutive, prospective risk-adapted studies by the Spanish Germ Cell Cancer Group. Low-risk patients were managed by surveillance and high-risk patients were given two courses of adjuvant carboplatin. Relapses were treated mainly with chemotherapy. Patient age, tumor size, histological variant, pT staging, rete testis invasion, and preoperative serum BHCG levels were assessed for prediction of disease-free survival (DFS). RESULTS: After a median follow-up of 80 months, 63 patients (11.1%) have relapsed: 51/396 (14.8%) on surveillance and 12/348 (3.2%) following adjuvant carboplatin. Actuarial overall 5-year DFS was 92.3% (88.3% for surveillance versus 96.8% for chemotherapy, P = 0.0001). Median time to relapse was 14 months. Most recurrences were located at retroperitoneum (86%), with a median tumor size of 26 mm. All patients were rendered disease-free with chemotherapy (92%), radiotherapy (5%), or surgery followed by chemotherapy (3%). A nomogram was developed from surveillance patients that includes two independent, predictive factors for relapse: rete testis invasion and tumor size (as a continuous variable). CONCLUSION: Long-term follow-up confirms the risk-adapted approach as an effective option for patients with stage I seminoma. The pattern of relapses after adjuvant chemotherapy is similar to that observed following surveillance. A new nomogram for prediction of DFS among patients on surveillance is proposed. Rete testis invasion and tumor size should be taken into account when considering the administration of adjuvant carboplatin. Prospective validation is warranted.

Tumor histological subtyping determined by hormone receptors and HER2 status defines different pathological complete response and outcome to dose-dense neoadjuvant chemotherapy in breast cancer patients.

PURPOSE: To assess the impact in pathological complete response (pCR) and outcome of two dose-dense neoadjuvant chemotherapy (DDNC) regimens among different histological subtypes determined by hormonal receptor (HR) and HER2 status in breast cancer patients. METHODS: A total of 127 breast cancer patients were treated with DDNC in two prospective studies. A: adriamycin 40 mg/m(2) on day (d) 1 plus paclitaxel 150 mg/m(2) and gemcitabine 2,000 mg/m(2) on d2 for six cycles (n = 54). B: epirubicin 90 mg/m(2), cyclophosphamide 600 mg/m(2) on d1 for three cycles, followed by paclitaxel 150 mg/m(2) and gemcitabine 2,500 mg/m(2) on d1 ± trastuzumab according to HER2 status (n = 73). Histological subtypes of breast cancer were 49 % HR+/HER2-, 17.5 % HR+/HER2+, 13.5 % HR-/HER2+ and 20 % HR-/HER2-. RESULTS: pCR (absence of invasive cells in breast and lymph node) was achieved in 35 patients (28 %). The pCR rate was significantly different between histological subtypes: HR+/HER2- (9 %), HR+/HER2+ (23 %), HR-/HER2+ (50 %), HR-/HER2- (56 %) (p < 0.001). The median follow-up was 81 months (r: 15-150 months). HR-/HER2- tumor subtype had a significantly worse DFS compared to HR+/HER2- (p = 0.02), RH+/HER2+ (p = 0.04) and HR-/HER2+ tumor subtypes (p = 0.02). HR-/HER2- tumor subtype had a significantly shorter OS compared to HR+/HER2- (p = 0.007), RH+/HER2+ (p = 0.05), and HR-/HER2+ (p = 0.03) tumor subtypes. However, no significant difference was observed in DFS and OS among HR-/HER2- tumors that achieved a pCR. CONCLUSIONS: HR-/HER2- and HR-/HER2+ subtypes had a high pCR rate to DDNC. HR-/HER2- tumors had a worse outcome compared to other tumor subtypes but no significant difference was observed among HR-/HER2- tumors that achieved a pCR.

A randomized phase II trial of platinum salts in basal-like breast cancer patients in the neoadjuvant setting. Results from the GEICAM/2006-03, multicenter study.

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.

Cross-sensitivity between taxanes in patients with breast cancer.

AIM This study was a retrospective analysis of our experience with severe cross-hypersensitivity reactions (HSR) to the taxanes paclitaxel (P) and docetaxel (D) in patients with breast cancer. PATIENTS AND METHODS We evaluated patients with breast cancer treated with P or D who experienced severe HSR to one of the two taxanes. Severe HSR was defined as any reaction severe enough to warrant discontinuation of the drug. Initial intravenous premedication for paclitaxel was dexamethasone (20 mg), ranitidine (50 mg) and dexchlorpheniramine (10 mg). For docetaxel, dexamethasone (4 mg) orally every 12 hours was administered the day before infusion and dexamethasone (20 mg) was administered intravenously prior to infusion. After severe HSR to the taxane and 30 minutes before infusion of another taxane, we administered dexamethasone (20 mg), ranitidine (50 mg) and dexchlorpheniramine (10 mg) iv as a premedication, and we also increased the time of the infusion. RESULTS Between March 2009 and April 2010, 23 patients experienced an initial severe HSR to taxane (12 P, 11 D). Substitution of another taxane was conducted in 17 patients in the two weeks following the initial HSR. Eight patients had an initial HSR with P, and three had a cross-HSR to D. Nine patients had an initial HSR to D, and four of these patients had a cross-HSR to P. Among the 17 patients who received both taxanes, 7 (41%) had a cross-HSR. All cross- HSRs were sufficiently severe (grade 3-4) to suspend taxane treatment permanently. In the remaining 6 patients, a desensitisation protocol to taxanes was performed by increasing the dose of the diluted drug (4 P, 2 D), which resulted in administration of the drug without complications in all cases. There were no treatment-related deaths. CONCLUSION Severe cross-HSR between P and D occurred in a significant proportion of our patients with breast cancer, so care must be taken when substituting taxanes (paclitaxel and docetaxel). A desensitisation protocol can be an effective alternative to decrease the risk of a new HSR.

Initialization of adjuvant hormonal treatment for breast cancer.

The introduction of aromatase inhibitors (AI) has resulted in practice change approaches in the treatment of early breast cancer. In this paper, we analyze the most relevant studies including the ATAC, BIG 1-98, TEAM, MA-17, NSABP B-33, and ABSCG-6 studies. Postmenopausal patients with hormone receptor-positive early breast cancer should be treated with AI for 5 years. For patients who have been initiated with tamoxifen (TAM), switching to an AI to complete 5 years of treatment is also recommended. The results of the extended adjuvant therapy studies recommend the use of an AI (anastrozole, letrozole, or exemestane) after the completion of standard TAM treatment. With regards to premenopausal women, TAM is the recommended adjuvant hormonal treatment for pre- and perimenopausal women. There is no indication for the use of AI in these subgroups of patients. Finally, determination of CYP 2D6 polymorphisms could be considered when choosing the best adjuvant hormonal treatment option.

Second complete remission induced by cyclophosphamide plus bevacizumab in two patients with heavily pre-treated ovarian cancer.

During the last decade we have been developing new therapeutic strategies for the treatment of ovarian cancer, based on the best knowledge of the molecular biology. New drugs like bevacizumab are showing antiangiogenic antitumour activity in ovarian cancer in preclinical models and in clinical trials. Bevacizumab is a monoclonal human antibody that has showed activity in both monotherapy and in combination with other therapies. We present the outcome of two patient cases with recurring heavily pre-treated ovarian cancer that were treated with cyclophosphamide and bevacizumab in combination and showed a complete remission of disease. After interruption of the treatment with bevacizumab, both patients had a disease relapse. Despite poor prognosis of the disease, in both cases a second complete and maintained remission was achieved, again with the same regimen.

Maintenance treatment in metastatic breast cancer.

Metastatic breast cancer (MBC) occurs in 20-30% of women with breast cancer and is an incurable disease. Treatment is palliative and directed to prolong survival, decrease symptoms and improve patients' quality of life. For patients with hormone receptor-negative disease or for hormone receptor-positive disease that has become resistant to endocrine therapy, or is progressing rapidly and life threatening, cytotoxic chemotherapy is indicated. However, the optimal duration of chemotherapy treatment for MBC is still a matter of debate. Studies using maintenance chemotherapy regimens standard in the 1990s showed a consistent benefit with a more prolonged time to progression, although an improvement in survival was only demonstrated in one study. Two recent trials with newer cytotoxic agents showed controversial results; whereas one study concluded that the policy of prolonging treatment in chemotherapy-sensitive patients, after aggressive, modern combination chemotherapy, cannot be recommended for women with MBC, the other study showed that maintenance therapy with pegylated liposomal doxorubicin significantly prolonged time to progression in MBC patients after first-line chemotherapy without significant clinical toxicity. Initial data regarding metronomic chemotherapy indicate that continuously low-dose cyclophosphamide and methotrexate is minimally toxic and effective in heavily pretreated breast cancer patients. In daily practice, maintenance chemotherapy is a reasonable strategy that prolongs time to progression in patients with MBC who did not show progression after first-line chemotherapy. However, this benefit should be considered together with toxicities of treatment and the patient's preference.

Prognostic value of hormonal receptors, p53, ki67 and HER2/neu expression in epithelial ovarian carcinoma.

OBJECTIVE: The role of molecular and biological factors in ovarian cancer is controversial. We investigated the levels of the estrogen (ER) and progesterone (PR) receptors, HER2/neu, p-53 and Ki 67 in patients with advanced ovarian cancer and correlated the results with the clinical course in order to define their predictive or prognostic significance. METHODS: Paraffin-embedded tumor tissues from 72 patients with ovarian cancer treated from 1999 to 2003 were analyzed. Overexpression of C-erb-B2 was defined as herceptest ++/+++ and positive fluorescence in situ hybridization (FISH) or herceptest +++/+++. Positivity for ER and PR was determined by > or =10% of the cellular membranes immunostained. Statistical analysis was performed to evaluate the prognostic impact of the molecular markers. RESULTS: 49 of the 72 patients were ER + (68%) and 36 PR + (50%). In 45 patients (62.5%) expression of p53 was > or =10%. Overexpression of C-erb-2 was found in 4 tumor samples (5%). A Ki67 labelled nuclear area >30% was found to be associated with a higher rate of complete response (chi(2); p=0.05). None of the biological markers were significantly associated with progression free survival (PFS). By multivariate analysis residual tumor after debulking surgery and ER status were associated with OS (p< or =0.05). CONCLUSIONS: Ki67 nuclear expression >30% is predictive of complete response in advanced ovarian cancer. HER2/neu overexpression is scarce in our study. Positive ER is an independent prognostic factor for OS. Further research with larger studies and hormonal treatment is guaranteed.