Caroline Cuvier

Single-Agent Gemcitabine Is Active in Previously Treated Metastatic Breast Cancer

Background: This phase II study was designed to assess the efficacy and safety of gemcitabine in patients with metastatic breast cancer (MBC) previously treated with an anthracycline- or anthracenedione-containing regimen as first-line therapy for metastatic disease. Patients and Methods: Forty-seven patients with MBC were enrolled in five French centers. Patients were eligible if they had received one prior chemotherapy regimen with an anthracycline or anthracenedione for metastatic disease, if they had responded to that prior regimen, and if they had relapsed at least 6 months after the first response. Fifteen patients received more than one prior anthracycline regimen; thus, gemcitabine was third-line therapy for 30% of patients. Gemcitabine 1,200 mg/m2 was administered as a 30-min intravenous infusion on days 1, 8, and 15 of a 28-day cycle for a maximum of eight cycles after the best response was obtained. Results: Objective responses were seen in 12 of 41 assessable patients (4 complete responses and 8 partial responses), for an objective response rate of 29% (95% confidence interval, 16–46%). The median response duration was 8.1 months (range: 2.5–27.4 months). Serious hematological toxicity was minimal, with grade 4 neutropenia in 2% of the patients (no neutropenic fever), grade 3 neutropenia in 28% of the patients, and grade 3 thrombocytopenia in 6% of the patients. Among the nonhematological toxicities, asthenia was the most common. Conclusions: Gemcitabine given at this dose and schedule is a well-tolerated treatment with definitive antitumor activity in pretreated MBC patients. This result warrants future exploration of the use of gemcitabine as a single agent and in combination in patients with MBC.

Combination of oxaliplatin plus irinotecan in patients with gastrointestinal tumors : Results of two independent phase I studies with pharmacokinetics

PURPOSE Two phase I studies of the oxaliplatin and irinotecan combination were performed in advanced gastrointestinal cancer patients to characterize the safety and pharmacokinetics of the regimen. PATIENTS AND METHODS Patients with a performance status (PS) of < or = 2 and normal hematologic, hepatic, and renal functions received oxaliplatin (2-hour intravenous infusion) followed 1 hour later by irinotecan administered over a 30-minute period, every 3 weeks. Dose levels that were explored ranged from 85 to 110 mg/m(2) for oxaliplatin and 150 to 250 mg/m(2) for irinotecan. Plasma pharmacokinetics of total and ultrafiltrable platinum, irinotecan, SN-38, and its glucuronide, SN-38G, were determined. RESULTS Thirty-nine patients with gastrointestinal carcinomas (24 with colorectal cancer [CRC], four with pancreas cancer, four with gastric cancer, three with hepatocarcinoma, and four with other) received 216 treatment cycles. Median age was 54 years (range, 21 to 72 years); 95% had PS of 0 to 1; all but six had failed fluorouracil (5-FU) chemotherapy. The maximum-tolerated dose was oxaliplatin 110 mg/m(2) plus irinotecan 200 mg/m(2) in one study and oxaliplatin 110 mg/m(2) plus irinotecan 250 mg/m(2) in the other study. Grade 3 to 4 diarrhea and febrile neutropenia were dose-limiting toxicities; other toxicities included emesis and dose-cumulative neuropathy. Recommended dose for phase II studies is oxaliplatin 85 mg/m(2) and irinotecan 200 mg/m(2). At this dose (12 patients, 65 cycles), grade 3 and 4 toxicities per patient included the following: emesis in 42% of patients, neutropenia in 33% (febrile episodes in 17%), peripheral neuropathy in 25%, delayed diarrhea in 17%, and thrombocytopenia in 8%. Two patients with Gilberts syndrome experienced severe irinotecan toxicity. No plasmatic pharmacokinetic interactions were detected. Seven partial responses were observed in 24 CRC patients. CONCLUSION This combination is feasible, with activity in 5-FU-resistant CRC patients. Phase I studies that explore the every-2-weeks schedule, in addition to phase II studies of this schedule (as well as in combination with 5-FU) as second-line therapy of metastatic CRC, are ongoing.

Effect of 18F-FDG PET/CT Imaging in Patients With Clinical Stage II and III Breast Cancer

PURPOSE To investigate the potential effect of using (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) in the initial assessment of patients with clinical Stage II or III breast cancer. METHODS AND MATERIALS During 14 consecutive months, 39 patients (40 tumors) who presented with Stage II or III breast cancer on the basis of a routine extension assessment were prospectively included in this study. PET/CT was performed in addition to the initial assessment. RESULTS In 3 cases, PET/CT showed extra-axillary lymph node involvement that had not been demonstrated with conventional techniques. Two of these patients had hypermetabolic lymph nodes in the subpectoral and infraclavicular regions, and the third had a hypermetabolic internal mammary node. PET/CT showed distant uptake in 4 women. Of these 4 women, 1 had pleural involvement and 3 had bone metastasis. Overall, of the 39 women, the PET/CT results modified the initial stage in 7 (18%). The modified staging altered the treatment plan for 5 patients (13%). It led to radiotherapy in 4 patients (bone metastasis, pleural lesion, subpectoral lymph nodes, and internal mammary nodes) and excision of, and radiotherapy to, the infraclavicular lymph nodes in 1 patient. CONCLUSIONS PET/CT can provide information on extra-axillary lymph node involvement and can uncover occult distant metastases in a significant percentage of patients. Therefore, initial PET/CT could enable better treatment planning for patients with Stage II and III breast cancer.

18F-FDG PET/CT in Staging Patients with Locally Advanced or Inflammatory Breast Cancer: Comparison to Conventional Staging

The prognosis of patients with locally advanced breast cancer (LABC) remains poor. We prospectively investigated the impact of 18F-FDG PET/CT at initial staging in this clinical setting and compared PET/CT performance with that of conventional distant work-up. Methods: During 60 mo, consecutive patients with LABC (clinical T4 or N2–N3 disease) underwent 18F-FDG PET/CT. The yield was assessed in the whole group and separately for noninflammatory and inflammatory cancer. The performance of PET/CT was compared with that of a conventional staging approach including bone scanning, chest radiography, or dedicated CT and abdominopelvic sonography or contrast-enhanced CT. Results: 117 patients with inflammatory (n = 35) or noninflammatory (n = 82) LABC were included. 18F-FDG PET/CT confirmed N3 nodal involvement in stage IIIC patients and revealed unsuspected N3 nodes (infraclavicular, supraclavicular, or internal mammary) in 32 additional patients. Distant metastases were visualized on PET/CT in 43 patients (46% of patients with inflammatory carcinoma and 33% of those with noninflammatory LABC). Overall, 18F-FDG PET/CT changed the clinical stage in 61 patients (52%). Unguided conventional imaging detected metastases in only 28 of the 43 patients classified M1 with PET/CT (65%). 18F-FDG PET/CT outperformed conventional imaging for bone metastases, distant lymph nodes, and liver metastases, whereas CT was more sensitive for lung metastases. The accuracy in diagnosing bone lesions was 89.7% for planar bone scanning versus 98.3% for 18F-FDG PET/CT. The accuracy in diagnosing lung metastases was 98.3% for dedicated CT versus 97.4% for 18F-FDG PET/CT. Conclusion: 18F-FDG PET/CT had the advantage of allowing chest, abdomen and bone to be examined in a single session. Almost all distant lesions detected by conventional imaging were depicted with PET/CT, which also showed additional lesions.

Molecular apocrine breast cancers are aggressive estrogen receptor negative tumors overexpressing either HER2 or GCDFP15

IntroductionMolecular apocrine (MA) tumors are estrogen receptor (ER) negative breast cancers characterized by androgen receptor (AR) expression. We analyzed a group of 58 transcriptionally defined MA tumors and proposed a new tool to identify these tumors.MethodsWe performed quantitative reverse transcription PCR (qRT-PCR) for ESR1, AR, FOXA1 and AR-related genes, and immunohistochemistry (IHC) for ER, PR, Human Epidermal Growth Factor Receptor 2 (HER2), CK5/6, CK17, EGFR, Ki67, AR, FOXA1 and GCDFP15 and we analyzed clinical features.ResultsMA tumors were all characterized by ESR1(-) AR(+) FOXA1(+) and AR-related genes positive mRNA profile. IHC staining on these tumors showed 93% ER(-), only 58% AR(+) and 90% FOXA1(+). 67% and 57% MA tumors were HER2(3+) and GCDFP15(+), respectively. Almost all MA tumors (94%) had the IHC signature HER2(3+) or GCDFP15(+) but none of the 13 control basal-like (BL) tumors did. Clinically, MA tumors were rather aggressive, with poor prognostic factors.ConclusionMA tumors could be better defined by their qRT-PCR-AR profile than by AR IHC. In addition, we found that HER2 or GCDFP15 protein overexpression is a sensitive and specific tool to differentiate MA from BL in the context of ER negative tumors. A composite molecular and IHC signature could, therefore, help to identify MA tumors in daily practice.

Estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast tumors: Early prediction of chemosensitivity with (18) F-fluorodeoxyglucose positron emission tomography/computed tomography during neoadjuvant chemotherapy.

The objective of this prospective study was to evaluate the ability of 18F‐fluorodeoxyglucose (18F‐FDG) positron emission tomography/computed tomography (PET/CT) to predict chemosensitivity in patients with estrogen receptor (ER)‐positive/human epidermal growth factor receptor 2 (HER2)‐negative breast cancer.

HER2-overexpressing breast cancer: FDG uptake after two cycles of chemotherapy predicts the outcome of neoadjuvant treatment.

Background:Pathologic complete response (pCR) to neoadjuvant treatment (NAT) is associated with improved survival of patients with HER2+ breast cancer. We investigated the ability of interim positron emission tomography (PET) regarding early prediction of pathology outcomes.Methods:During 61 months, consecutive patients with locally advanced or large HER2+ breast cancer patients without distant metastases were included. All patients received NAT with four cycles of epirubicin+cyclophosphamide, followed by four cycles of docetaxel+trastuzumab. 18F-fluorodeoxyglucose (18F-FDG)-PET/computed tomography (CT) was performed at baseline (PET1) and after two cycles of chemotherapy (PET2). Maximum standardised uptake values were measured in the primary tumour as well as in the axillary lymph nodes. The correlation between pathologic response and SUV parameters (SUVmax at PET1, PET2 and ΔSUVmax) was examined with the t-test. The predictive performance regarding the identification of non-responders was evaluated using receiver operating characteristics (ROC) analysis.Results:Thirty women were prospectively included and 60 PET/CT examination performed. At baseline, 22 patients had PET+ axilla and in nine of them 18F-FDG uptake was higher than in the primary tumour. At surgery, 14 patients (47%) showed residual tumour (non-pCR), whereas 16 (53%) reached pCR. Best prediction was obtained when considering the absolute residual SUVmax value at PET2 (AUC=0.91) vs 0.67 for SUVmax at PET1 and 0.86 for ΔSUVmax. The risk of non-pCR was 92.3% in patients with any site of residual uptake >3 at PET2, no matter whether in breast or axilla, vs 11.8% in patients with uptake ⩽3 (P=0.0001). The sensitivity, specificity, PPV, NPV and overall accuracy of this cutoff were, respectively: 85.7%, 93.8%, 92.3%, 88.2% and 90%.Conclusion:The level of residual 18F-FDG uptake after two cycles of chemotherapy predicts residual disease at completion of NAT with chemotherapy+trastuzumab with high accuracy. Because many innovative therapeutic strategies are now available (e.g., addition of a second HER2-directed therapy or an antiangiogenic), early prediction of poor response is critical.

Treating Breast Cancer During Pregnancy What Can be Taken Safely

SummaryThe occurrence of breast cancer during pregnancy is a rare clinical situation. However, if it is diagnosed, a multidisciplinary approach involving an obstetrician, a medical oncologist and a surgeon is needed. In this situation, breast cancer should be treated according to the same principles applied in nonpregnant patients. Termination of pregnancy does not improve survival. Decisions regarding abortion should be based on the desires of the patient and on therapeutic necessities.If required, surgery is always possible, but radiation therapy should be avoided because of the risk of fetal toxicity. Antineoplastic drug therapy, if indicated, is possible after the first trimester.

Long-term survival of advanced triple-negative breast cancers with a dose-intense cyclophosphamide/anthracycline neoadjuvant regimen.

Background:Triple-negative (TN) breast cancers exhibit major initial responses to neoadjuvant chemotherapy, but generally have a poor outcome. Because of the lack of validated drug targets, chemotherapy remains an important therapeutic tool in these cancers.Methods:We report the survival of two consecutive series of 267 locally advanced breast cancers (LABC) treated with two different neoadjuvant regimens, either a dose-dense and dose-intense cyclophosphamide–anthracycline (AC) association (historically called SIM) or a conventional sequential association of cyclophosphamide and anthracycline, followed by taxanes (EC-T). We compared pathological responses and survival rates of these two groups and studied their association with tumours features.Results:Although the two regimens showed equivalent pathological complete response (pCR) in the whole population (16 and 12%), the SIM regimen yielded a non-statistically higher pCR rate than EC-T (48% vs 24%, P=0.087) in TN tumours. In the SIM protocol, DFS was statistically higher for TN than for non-TN patients (P=0.019), although we showed that the TN status was associated with an increased initial risk of recurrence in both regimens. This effect gradually decreased and after 2 years, TN was associated with a significantly decreased likelihood of relapse in SIM-treated LABC (hazard ratio (HR)=0.25 (95% CI: 0.07–0.86), P=0.028).Conclusions:AC dose intensification treatment is associated with a very favourable long-term survival rate in TN breast cancers. These observations call for a prospective assessment of such dose-intense AC-based regimens in locally advanced TN tumours.

Anti-Müllerian hormone in breast cancer patients treated with chemotherapy: a retrospective evaluation of subsequent pregnancies.

Few studies have reported reproductive outcomes after breast cancer chemotherapy. The relationship between anti-Müllerian hormone (AMH) concentrations and the occurrence of subsequent pregnancies in women after chemotherapy for breast cancer was investigated. Women aged 18-43 years treated with chemotherapy for invasive breast cancer between May 2005 and January 2011 were retrospectively identified. Exclusion criteria were previous gonadotoxic treatment, oophorectomy or hysterectomy. Measurement of AMH took place before, during chemotherapy and at distant time points after the end of chemotherapy (4 months to 5.5 years). Seventeen out of 134 patients experienced 28 spontaneous pregnancies (median follow-up: 59 months). Neither baseline AMH (divided into quartiles) nor end-of-chemotherapy AMH (detectable versus undetectable) were significantly associated with the occurrence of pregnancy. Chemotherapy regimen with anthracyclines was associated with a greater probability of pregnancy compared with a taxane-containing regimen (hazard ratio 4.75; (95% CI 1.76 to 12.8); P = 0.002). Five-year disease-free survival and overall survival rates were 60% (95% CI: 51 to 70; relapse, n = 48) and 88% (95% CI 82 to 95; deaths, n = 21), respectively. AMH did not predict the occurrence of pregnancy. Additional studies assessing ovarian reserve and reproductive outcomes after breast cancer are required.