Impact of 2013 ASCO/CAP guidelines on HER2 determination of invasive breast cancer: A single institution experience using frontline dual-color FISH.

PURPOSE: The new ASCO/CAP guidelines published in 2013 (AC2013) significantly modified the scoring criteria for HER2-FISH, introducing the most controversial change to the HER2-equivocal category. We retrospectively evaluated the impact of AC2013 in a cohort of consecutive invasive breast cancers (IBCs) analyzed with frontline dual-color FISH. METHODS: 2788 consecutive IBCs were reclassified based on the AC2013 guidelines. Clinico-pathological features of equivocal IBCs were compared with HER2-negative and HER2-positive IBCs. FISH HER2-equivocal cases underwent reflex tests: HER2-IHC, RARA-FISH, and SMS-FISH. Overall and disease-free survivals were evaluated in AC2007 HER2-positive patients treated with trastuzumab and in patients that became eligible for target-therapy according to AC2013. RESULTS: Two-hundred HER2-negative cases (7.2%) were classified differently, following AC2013: 0.3% (8/2788) became HER2-positive and 6.9% (192/2788) HER2-equivocal. AC2013, compared with AC2007, significantly increased initial HER2-equivocal cases (6.9%vs1.6%, p < 0.001). AC2013 equivocal-IBCs affected older patients and showed pathological features between HER2-negative and HER2-positive IBCs. After reflex tests, 102 of the 190 equivocal cases (53.7%) were reclassified as HER2-positive, 51 (26.8%) as negative and 37 (19.5%) as equivocal. IHC tested negative in 44.7% of cases, whereas SMS-FISH showed the highest percentage of positive results (45.8%). Clinical outcomes showed no statistically significant differences. CONCLUSION: Overall, 80.5% of FISH-equivocal cases were solved with at least one reflex test and 3.6% of patients became AC2013 HER2-positive, therefore eligible for target-therapy, but showed clinical outcomes similar to HER2-positive patients treated with trastuzumab. Our data belittle the clinical impact of AC2013 HER2-equivocal reclassification; further prospective randomized clinical studies are necessary to support these findings.

Primary chemotherapy in operable breast carcinoma comparing CMF (cyclophosphamide, methotrexate, 5-fluorouracil) with an anthracycline-containing regimen: short-term responses translated into long-term outcomes.

BACKGROUND: The role of anthracyclines has been extensively studied in adjuvant chemotherapy, but much less in the primary chemotherapy of early breast carcinoma. This study, comparing CMF (cyclophosphamide, methotrexate, 5-fluorouracil) with the rotational anthracycline-containing regimen CMFEV (CMF plus epirubicin and vincristine) administered as primary chemotherapy, demonstrated a significant increase in clinical complete response in premenopausal women. We report the long-term results. PATIENTS AND METHODS: Two hundred and eleven patients with stage I or II palpable breast carcinoma and a tumour diameter of >2.5 cm were randomised to receive CMF or CMFEV for four cycles before surgery. After surgery, the patients in both arms received adjuvant CMF for three cycles. RESULTS: In the study population as a whole, there was a non-significant 20% reduction in mortality and relapse rates in the CMFEV arm. However, the effect of the experimental regimen was only found in premenopausal patients, especially in terms of relapse-free survival (P=0.07) and locoregional relapse-free survival (P=0.0009), thus mirroring the effect on response rates. After 10 years, the proportions of premenopausal patients free from locoregional relapse as a first event in the CMF and CMFEV groups were 68% and 97%, respectively. No relevant differences were found in postmenopausal patients. CONCLUSION: The overall results of this study showed that the greater activity of the experimental anthracycline-containing combination over CMF as primary chemotherapy in premenopausal patients translated into long-term effects in the same subgroup.

Gemcitabine, ifosfamide, cisplatin (GIP) for the treatment of advanced non-small cell lung cancer: a phase II study of the italian oncology group for clinical research (GOIRC).

The purpose of this study was to evaluate the activity and the toxicity of the combination of gemcitabine with ifosfamide and cisplatin (GIP) in chemonaive patients with advanced non small cell lung cancer (NSCLC). Eighty chemonaive patients with Stage IIIB-IV NSCLC were treated with the combination of gemcitabine 1 g/m(2) on Days 1 and 8, ifosfamide 2 g/m(2) on Day 1 and cisplatin 80 mg/m(2) on Day 2. Cycles were administered on an outpatient basis every 3 weeks. Hematologic toxicity was the main side effect; Grade III-IV thrombocytopenia was observed in 54 (67%) patients and Grade III-IV leucopenia in 44 (55%) patients, with 4 episodes of febrile neutropenia and 1 toxic death. Thirteen patients received platelet transfusions and 38 were transfused with packed red cells. All patients were evaluable for response. The overall response rate was 54% (95% confidence interval 43 to 65%) with 1 complete response. In patients with Stage IIIB and IV disease, response rates were 58% and 52%, respectively. Median time to progression was 40 weeks (range 0-114) and median overall survival was 12 months (16.6 months for stage IIIB and 10.4 months for stage IV). Median and minimum follow-up were 19 and 12 months, respectively. The GIP combination shows a response rate and overall survival of clinical interest. Hematologic toxicity was the main toxic effect, especially in patients with low performance status. This regimen will be tested in a Phase III randomized trial.

Three new active cisplatin-containing combinations in the neoadjuvant treatment of locally advanced and locally recurrent breast carcinoma: a randomized phase II trial.

We designed three new four-drug cisplatin-containing combinations and evaluated their activity in a randomized phase II study including patients with locally advanced (stage III) and locally recurrent breast carcinoma. All combinations included methotrexate (M) on day 1 and cisplatin (P) on day 2 (MVAC-like combinations) and differed from one another by the addition of Epirubicin (Epi), Vincristine (V), Etoposide (E), Mitomycin (Mi). Based on the administered agents, they were named MPEMi, MPEpiE, MPEpiV. The combinations were randomly assigned to 101 patients, 57 with locally advanced and 44 with locally recurrent breast carcinoma. Response was evaluated after 4 cycles. The complete response (CR) rates were 7% and 43% and the CR plus partial response (PR) rates were 84% and 89% in locally advanced and in locally recurrent disease, respectively. In locally advanced disease, a pathologic CR (pCR) was assessed in seven of 57 patients (12%). There were no significant differences among the three combinations. The toxicities were at times severe, but generally tolerable, as demonstrated by the high cumulative doses of the drugs received by the patients. In conclusion, these three innovative chemotherapy regimens induced high CR plus PR rates in the neoadjuvant treatment of stage III and of locally recurrent breast carcinoma, and a high rate of pCR in stage III disease. These regimens warrant testing in phase III trials.

Ifosfamide bolus followed by five days continuous infusion in extensively pretreated patients with advanced breast cancer: a phase II study.

PURPOSE: A phase II study with ifosfamide in pretreated patients with advanced breast cancer was performed to determine the objective response rate, the toxicity and the feasibility of the regimen. METHODS & STUDY DESIGN: Patients enrolled had advanced breast cancer pretreated with at least one previous regimen of chemotherapy for advanced disease. Treatment consisted of ifosfamide infused at a dose of 2 g/m2 iv in 4 hrs followed by ifosfamide, 8 g/m2 iv in 120 hrs in ambulatory treatment, using a portable external pump system. The total dose of ifosfamide was 10 g/m2; mesna (4 g/m2 iv) was administered mixed with ifosfamide in 120 hrs Cycles were repeated every 3 weeks. Three patients were pretreated with neoadjuvant and 15 with adjuvant chemotherapy. All patients were treated for advanced disease (median number of regimens, 1; range, 1-3): 21 with the cyclophosphamide-containing regimen and 15 with adryamicin. Sixteen patients received one or more lines of endocrine therapy. Fifteen patients had dominant site in viscera, 6 in bone, and only one in soft tissue; 17 patients had more than one site of disease. RESULTS: Twenty-two patients were enrolled and all were assessable for response and toxicity. A partial response was reached in 5 patients (23%; 95% confidence limits 5% to 60%). Hematologic toxicity was the dose-limiting side effect; grade 4 leukopenia occurred in 10 patients (46%). CONCLUSIONS: Considering the response rate obtained in our series of intensively pretreated patients, the results seem to indicate that the regimen is active and could be included among the possible options in the treatment of patients with refractory, poor-prognosis, advanced breast carcinoma.

Bolus versus 5-day continuous infusion of cisplatin with mitomycin and vindesine in the treatment of advanced non-small cell lung cancer (NSCLC): a phase III prospective randomised trial of the Italian Oncology Group for Clinical Research (GOIRC).

The aim of this randomised trial was to compare the efficacy of bolus versus continuous infusion cisplatin combined with mitomycin C and vindesine (MVP) for chemotherapy-naive patients with stage IIIB-IV non-small cell lung cancer (NSCLC). 97 patients (49 given bolus cisplatin-arm A and 48 given continuous infusion cisplatin--arm B) were evaluable for response. In arm A, 2 patients achieved a complete response (CR), 21 achieved a partial response (PR), whilst in arm B, 14 patients achieved a PR (29%) (P = 0.07). Median survival was 8 months in both arms. Myelosuppression was the most frequent and severe toxicity, with a higher incidence of grade 3-4 leucopenia in arm A when compared with arm B (44% versus 25%). In conclusion, there is no advantage for a cisplatin 5 day infusion in the MVP regimen.

Neoadjuvant chemotherapy with continuous infusion of cisplatin and fluorouracil in stage II-IV, M0 squamous cell carcinoma of the head and neck.

AIMS AND BACKGROUND: The aim of the study was to assess the activity and the toxicity of cisplatin (DDP) and fluorouracil (FU) administered by continuous infusion as neoadjuvant chemotherapy for patients with stage II-IV, M0 squamous cell carcinoma of the head and neck. METHODS: Thirty previously untreated patients were submitted to chemotherapy with DDP (20 mg/m2) and FU (1000 mg/m2), both in continuous infusion for 5 days, repeated every 21 days, for a maximum of 5 cycles. Following completion of chemotherapy, the patients underwent radiotherapy; in some patients surgery was performed immediately after chemotherapy. All patients were monitored for response, time to failure, survival, treatment-related events and toxicity. RESULTS: All patients were evaluated for response; after chemotherapy the complete response rate was 27% and the partial response rate 33%. Twenty-four patients underwent radiotherapy: the overall response rate was 83% (complete response 79%). After a median follow-up of 34 months, the median survival time was 22 months with a median time to failure of 15 months. Acute vascular accidents were the main and unexpected adverse events, with 2 deaths for pulmonary embolism and 1 for stroke. The response rate to the regimen does not seem to be better than that obtained with the standard combination of cisplatin bolus and fluorouracil continuous infusion. The disadvantage of the regimen is that it causes more discomfort for the patient in that it requires hospitalization. CONCLUSIONS: For this reason, we believe that there are no elements for recommending the schedule as neoadjuvant treatment of patients with squamous cell carcinoma of the head and neck or as an experimental arm in a randomized trial.

Immunocytochemical assay of estrogen and progesterone receptors in fine needle aspirates from breast cancer patients.

Estrogen receptors (ERs) and progesterone receptors (PRs) were determined by an immunocytochemical assay (ICA) on fine needle aspirates (FNAs) from patients with primary, recurrent and metastatic mammary carcinoma, and the results were compared to those with the biochemical dextran-coated charcoal (DCC) method performed on the surgical sample in order to compare the two methods. The aspirates were suspended in a buffered saline solution, cytocentrifuged onto glass slides and immunocytochemically stained according to the protocol of commercial kits employing monoclonal antibodies specific for ER and PR. Immunocytochemical staining of malignant cells was evaluated on the basis of the percentage of stained cells; 10% staining was taken as the cutoff value. Fine needle aspiration biopsies (FNABs) from 107 breast carcinomas were analyzed immunocytochemically for ER and 31 of them for PR, also. The overall concordance between ICA and DCC was 88% for ER and 87% for PR. The sensitivity, specificity, and positive and negative predictive value of ICA on FNAs as compared to conventional DCC were 87%, 90, 97% and 63%, respectively, for ER and 85%, 100%, 100% and 56% for PR. These findings suggest that estrogen immunocytochemical assays and progesterone immunocytochemical assays on FNAs in breast cancer patients are reliable techniques for evaluating receptor status and can be useful in assessing ER and PR whenever surgical biopsy is not indicated and when information about ER and PR status is required at the time of the clinical diagnosis.

Fine-needle aspiration technique for the concurrent immunocytochemical evaluation of multiple biologic parameters in primary breast carcinoma.

Fine-needle aspiration cytology has been already established as a reliable method for the diagnosis of breast cancer. Its application has been recently extended to immunocytochemical analysis of biological parameters. In the current study estrogen and progesterone receptors, Ki67 growth fraction, and p53 protein expression were immunocytochemically evaluated on the cellular material sampled by the same fine-needle aspirate used for the conventional cytologic diagnosis of malignancy. Fine-needle aspiration specimens from 100 patients with primary breast carcinoma were submitted to the immunocytochemical analysis. Twenty-eight percent were in premenopause; 23% had tumors with a diameter less than 2 cm, 59% from 2 to 5 cm, and 18% more than 5 cm; 60% had axillary nodal status negative, 34% positive, and 6% unknown. The concomitant immunocytochemical evaluation of all parameters was possible in 70% of the patients. A significant association was found between p53 overexpression and Ki67 values (p = 0.004), and between Ki67 values and progesterone receptor status (p = 0.003). No correlation was found between any parameter and clinical tumor size. Estrogen (p = 0.02) and progesterone (p = 0.04) receptor negativity and high Ki67 growth fraction (p = 0.005) were significantly associated with the clinical evidence of axillary node involvement. This study suggests that fine-needle aspiration cytology represents an effective practice for a simultaneous evaluation of multiple biologic indicators and could be useful as a preoperative procedure in patients who are candidates for neoadjuvant chemotherapy and/or endocrine therapy.