Prognostic Factors for Overall Survival in Patients with Hormone Receptor-Positive Advanced Breast Cancer: Analyses From PALOMA-3.

BACKGROUND: This analysis investigated whether baseline characteristics affect the survival benefit derived from palbociclib-fulvestrant and the optimal timing of cyclin-dependent kinase 4/6 inhibitor therapy for advanced breast cancer (ABC) in patients from PALOMA-3. PATIENTS AND METHODS: In total, 521 patients were randomized 2:1 to receive palbociclib (125 mg/day, 3/1 schedule)-fulvestrant (500 mg, intramuscular injection, on days 1 and 15 of cycle 1, and then day 1 of each subsequent cycle) or matching placebo-fulvestrant. Median overall survival (OS) and progression-free survival were estimated using the Kaplan-Meier method. RESULTS: Multivariable analysis identified endocrine sensitivity, nonvisceral disease, no prior chemotherapy for ABC, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 as significant prognostic factors for OS. Patients without chemotherapy for ABC had fewer prior lines of treatment in any setting and in the ABC setting versus patients with prior chemotherapy for ABC (two or fewer prior systemic therapies: 69% vs. 42%; no more than one prior line for ABC: 82% vs. 33%, respectively). Median OS was prolonged with palbociclib-fulvestrant in patients without prior chemotherapy for ABC (39.7 vs. 29.5 months; hazard ratio, 0.75; 95% confidence interval [CI]: 0.56-1.01) and was similar in patients with prior chemotherapy for ABC (25.6 vs. 26.2 months; hazard ratio, 0.91 [95% CI: 0.63-1.32]) versus placebo-fulvestrant. CONCLUSION: Prognostic factors for OS included endocrine sensitivity, nonvisceral disease, ECOG PS of 0, and no prior chemotherapy for ABC. Exploratory analyses suggest improved OS with palbociclib-fulvestrant versus placebo-fulvestrant in patients with no prior chemotherapy for ABC, prior endocrine sensitivity, and fewer prior regimens of systemic therapy. (Clinical trial identification number: NCT01942135). IMPLICATIONS FOR PRACTICE: Prognostic factors for overall survival in HR+/HER2- advanced breast cancer (ABC) include the absence of prior chemotherapy in the advanced setting, endocrine sensitivity, nonvisceral disease, and an ECOG performance status of 0. Improved overall survival benefit was observed with palbociclib-fulvestrant versus placebo-fulvestrant in patients (regardless of menopausal status or visceral involvement) with no prior chemotherapy for ABC, with prior endocrine sensitivity, and fewer prior regimens of systemic therapy. Progression-free survival was prolonged with palbociclib across subgroups (regardless of chemotherapy exposure in ABC). These exploratory findings suggest that patients may receive greater clinical benefit from palbociclib-fulvestrant if they receive the combination before chemotherapy in the advanced setting.

Relevance of tumour-infiltrating lymphocytes, PD-1 and PD-L1 in patients with high-risk, nodal-metastasised breast cancer of the German Adjuvant Intergroup Node-positive study.

BACKGROUND: Immune cell infiltration in breast cancer is important for the patient's prognosis and response to systemic therapies including immunotherapy. We sought to investigate the prevalence of tumour-infiltrating lymphocytes (TILs) and their association with immune checkpoints such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in high-risk, node-positive breast cancer of the adjuvant German Adjuvant Intergroup Node-positive (GAIN-1) trial. PATIENTS AND METHODS: We evaluated TILs by haematoxylin and eosin staining and PD-1 and PD-L1 (SP263 assay) expression by immunohistochemistry in 1318 formalin-fixed, paraffin-embedded breast carcinomas. The association of TILs with PD-1, PD-L1, molecular intrinsic subtypes, outcome and therapy regimens (dose-dense [dd] epirubicin, paclitaxel and cyclophosphamide [EPC] and dd epirubicin, cyclophosphamide, paclitaxel and capecitabine [EC-PwX]) was statistically tested. RESULTS: Overall TILs density was significantly associated with the expression of PD-1 and PD-L1 in immune cells (each p < 0.0001) and PD-L1 in tumour cells (p = 0.0051). TILs were more common in triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive tumours (each p < 0.0001). On multivariate Cox regression analyses, patients with breast cancer without TILs had an unfavourable disease-free survival (DFS) in the EPC arm compared with the EC-PwX arm (hazard ratio [HR] = 0.69 [0.44-1.06], p = 0.0915); but no differences were seen in tumours with TILs (HR = 1.24 [0.92-1.67], p = 0.1566, interaction p = 0.0336). PD-1-positive immune cells in TNBC were associated with a significantly better DFS (HR = 0.50 [0.25-0.99], p = 0.0457). PD-L1 expression had no impact on patient outcome. CONCLUSIONS: TILs predict the benefit of intensified ddEPC compared with ddEC-PwX therapy in node-positive, high-risk breast cancer. TILs, PD-1 and PD-L1 are linked to each other indicating tumour immunogenicity. Moreover, PD-1-positive immune cells have a positive prognostic impact in TNBC. CLINICAL TRIAL: NCT00196872.

Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer.

Morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer is gaining momentum as evidence strengthens the clinical relevance of this immunological biomarker. TILs in the post-neoadjuvant residual disease setting are acquiring increasing importance as a stratifying marker in clinical trials, considering the raising interest on immunotherapeutic strategies after neoadjuvant chemotherapy. TILs in ductal carcinoma in situ, with or without invasive carcinoma, represent an emerging area of clinical breast cancer research. The aim of this report is to update pathologists, clinicians and researchers on TIL assessment in both the post-neoadjuvant residual disease and the ductal carcinoma in situ settings. The International Immuno-Oncology Working Group proposes a method for assessing TILs in these settings, based on the previously published International Guidelines on TIL Assessment in Breast Cancer. In this regard, these recommendations represent a consensus guidance for pathologists, aimed to achieve the highest possible consistency among future studies.

Breast Cancer during Pregnancy: An Interdisciplinary Approach in Our Institution.

BACKGROUND: Breast cancer is the most common cancer diagnosed during pregnancy. CASE REPORT: We report on a case of a 26-year-old woman who was diagnosed with right-sided breast cancer in her 15th week of gestation. We discussed possible treatment scenarios and the patient opted for neoadjuvant therapy with taxanes and anthracyclines during pregnancy, followed by delivery and then followed by surgery, antibody therapy, and radiotherapy. The patient received neoadjuvant chemotherapy with paclitaxel 80 mg/m(2) weekly for 12 cycles, followed by 4 cycles of epirubicin and cyclophosphamide (90/600 mg/m(2)) every 3 weeks. Complete clinical response was seen after preoperative chemotherapy. After delivery of a healthy child at 40 weeks of gestation, she received breast-conserving surgery and axillary dissection. Anti-HER2 antibody treatment with trastuzumab was started concomitantly with adjuvant radiotherapy. Endocrine treatment with a gonadotropin-releasing hormone (GnRH) analog and tamoxifen for 5 years was planned to be started after radiotherapy. CONCLUSION: Treatment of breast cancer during pregnancy requires an interdisciplinary approach and careful consideration of the patient's stage of disease, the gestational age, and the preferences of the patient and her family.

Gefitinib in combination with tamoxifen in patients with ovarian cancer refractory or resistant to platinum-taxane based therapy--a phase II trial of the AGO Ovarian Cancer Study Group (AGO-OVAR 2.6).

BACKGROUND: Tamoxifen and gefitinib (IRESSA) combination therapy was studied in patients with ovarian cancer refractory or resistant to platinum- and taxane-based therapy. PATIENTS AND METHODS: In this phase II study, 56 patients with epithelial ovarian carcinoma or cancer of the fallopian tube or peritoneum received oral tamoxifen 40 mg/day and gefitinib 500 mg/day until progression or unacceptable toxicity. RESULTS: Seventeen patients (mean age: 59.6 years) had previously received first-line platinum/taxane treatment only, while 39 had received 2-8 (median 2) prior chemotherapy regimens. Gefitinib dose reduction to 250 mg/day was performed in 10 patients (14.9%), predominantly due to diarrhea (6 patients [10.7%]). Trial medication was discontinued in 6 patients (10.7%) due to adverse events (AEs). The most frequent drug-related AEs were diarrhea and acne-like skin rash. There were no tumor responses, but 16 patients had stable disease. Median time-to-progression was 58 days (95% CI, 55-71 days) and median survival was 253 days (95% CI, 137-355 days). CONCLUSION: Gefitinib plus tamoxifen did not appear to be efficacious in the treatment of patients with refractory/resistant ovarian cancer. The addition of tamoxifen did not worsen the known side effects of gefitinib, or induce additional side effects.