Prognostic impact of 18F-FDG PET/CT staging and of pathological response to neoadjuvant chemotherapy in triple-negative breast cancer.

PURPOSE: Mortality is high in patients with locally advanced triple-negative breast cancer (TNBC), especially in those with residual tumour after neoadjuvant chemotherapy (NAC). The aim of this study was to determine if pretreatment (18)F-FDG PET/CT staging and pathological findings after NAC could together allow stratification of patients into prognostic groups. METHODS: Initial staging with (18)F-FDG PET/CT was performed prospectively in 85 consecutive patients with stage II/III TNBC. Correlations between PET findings and disease-specific survival (DSS) were examined. In patients without distant metastases on PET staging, the impact of pathological response to NAC on DSS was examined. Patterns of recurrence were also analysed. RESULTS: (18)F-DG PET/CT revealed distant metastases in 11 of 85 patients (12.9 %). Among 74 M0 patients, 23 (31.1 %) showed a pathological complete response (pCR) at surgery, while 51 had residual invasive disease (no pCR). DSS differed considerably among the three groups of patients (log-rank P < .001): among patients with occult metastases on baseline PET/CT, 2-year DSS was 18.2 %, and among patients without initial metastases on PET/CT, 5-year DSS was 61.3 % in patients without pCR after NAC and 95.2 % in those with pCR. Of the 51 patients who did not achieve pCR, 21 relapsed (17 developed distant metastases). The sites of distant recurrence were: lung/pleura (nine patients), brain (eight patients), liver (six patients), distant lymph nodes (six patients) and bone (five patients). CONCLUSION: In patients with clinical stage II/III TNBC, (18)F-FDG PET/CT findings at initial staging and pathological response at the end of NAC allow three groups of patients with quite different prognoses to be defined. Extraskeletal recurrences predominated. Specific follow-up strategies in patients with TNBC who do not achieve pCR deserve investigation.

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.

Contraception after breast cancer: a retrospective review of the practice among French gynecologists in the 2000's.

PURPOSE OF INVESTIGATION: To describe the French practices regarding contraception after breast cancer in the 2000's. MATERIALS AND METHODS: A total of 2,500 forms were sent to gynecologists practicing in France. Inclusion criteria were premenopausal patients who had a history of breast cancer and who had been prescribed contraception after diagnosis. Between June 1, 2002 and January 1, 2003, 197 evaluable responses were retrieved. RESULTS: The median age of the sample was 38.5 years. The most commonly used form of contraception was an intrauterine device (n = 144, 73.1%). Hormonal contraception was prescribed for 42 patients (21.3%), and other methods were used in 29 patients (14.7%) (Condoms n = 14, tubal sterilization n = 7, and others n = 8). Recurrence occurred in 27 patients (13%); 2.9% in the progestin group, 16.3% in the IUD group, and 14.8% with the other methods). CONCLUSIONS: It is necessary to evaluate current contraception practices after breast cancer to evaluate the efficacy and safety of contraception in these patients.

Prognostic value of EndoPredict test in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary breast cancer screened for the randomized, double-blind, phase III UNIRAD trial.

BACKGROUND: The purpose of this study was to evaluate the prognostic value of the multigene EndoPredict test in prospectively collected data of patients screened for the randomized, double-blind, phase III UNIRAD trial, which evaluated the addition of everolimus to adjuvant endocrine therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. PATIENTS AND METHODS: Patients were classified into low or high risk according to the EPclin score, consisting of a 12-gene molecular score combined with tumor size and nodal status. Association of the EPclin score with disease-free survival (DFS) and distant metastasis-free survival (DMFS) was evaluated using Kaplan-Meier estimates. The independent prognostic added value of EPclin score was tested in a multivariate Cox model after adjusting on tumor characteristics. RESULTS: EndoPredict test results were available for 768 patients: 663 patients classified as EPclin high risk (EPCH) and 105 patients as EPclin low risk (EPCL). Median follow-up was 70 months (range 1-172 months). For the 429 EPCH randomized patients, there was no significant difference in DFS between treatment arms. The 60-month relapse rate for patients in the EPCL and EPCH groups was 0% and 7%, respectively. Hazard ratio (HR) supposing continuous EPclin score was 1.87 [95% confidence interval (CI) 1.4-2.5, P < 0.0001]. This prognostic effect remained significant when assessed in a Cox model adjusting on tumor size, number of positive nodes and tumor grade (HR 1.52, 95% CI 1.09-2.13, P = 0.0141). The 60-month DMFS for patients in the EPCL and EPCH groups was 100% and 94%, respectively (adjusted HR 8.10, 95% CI 1.1-59.1, P < 0.0001). CONCLUSIONS: The results confirm the value of EPclin score as an independent prognostic parameter in node-positive, hormone receptor-positive, HER2-negative early breast cancer patients receiving standard adjuvant treatment. EPclin score can be used to identify patients at higher risk of recurrence who may warrant additional systemic treatments.

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.

Sex moderates circadian chemotherapy effects on survival of patients with metastatic colorectal cancer: a meta-analysis.

BACKGROUND: Molecular circadian clocks can modify cancer chemotherapy effects, with a possible moderation according to sex differences. We investigated whether sex determine the optimal delivery schedule of chemotherapy for metastatic colorectal cancer. PATIENTS AND METHODS: A meta-analysis was performed using individual data from three international Phase III trials comparing 5-fluorouracil, leucovorin and oxaliplatin administered in chronomodulated (chronoFLO) or conventional (CONV) infusions. The data from 345 females and 497 males were updated at 9 years. The main end point was survival. RESULTS: Overall survival was improved in males on chronoFLO when compared with CONV (P = 0.009), with respective median values of 20.8 (95% CL, 18.7 to 22.9) and 17.5 months (16.1 to 18.8). Conversely, median survival was 16.6 months (13.9 to 19.3) on chronoFLO and 18.4 months (16.6 to 20.2) on CONV in females (P = 0.012). The sex versus schedule interaction was a strong predictive factor of optimal treatment schedule, with a hazard ratio of 1.59 (1.30 to 1.75) for overall survival (P = 0.002) in multivariate analysis. CONCLUSIONS: Males lived significantly longer on chronomodulated chemotherapy rather than on conventional chemotherapy. The current chronoFLO schedule deserves prospective assessment as a safe and more effective first-line treatment option than conventional delivery for male patients.

BI-RADS categorisation of 2,708 consecutive nonpalpable breast lesions in patients referred to a dedicated breast care unit.

OBJECTIVES: To determine the malignancy rate of nonpalpable breast lesions, categorised according to the Breast Imaging Reporting and Data System (BI-RADS) classification in the setting of a Breast Care Unit. METHODS: All nonpalpable breast lesions from consecutive patients referred to a dedicated Breast Care Unit were prospectively reviewed and classified into 5 BI-RADS assessment categories (0, 2, 3, 4, and 5). RESULTS: A total of 2708 lesions were diagnosed by mammography (71.6%), ultrasound (8.7%), mammography and ultrasound (19.5%), or MRI (0.2%). The distribution of the lesions by BI-RADS category was: 152 in category 0 (5.6%), 56 in category 2 (2.1%), 742 in category 3 (27.4%), 1523 in category 4 (56.2%) and 235 in category 5 (8.7%). Histology revealed 570 malignant lesions (32.9%), 152 high-risk lesions (8.8%), and 1010 benign lesions (58.3%). Malignancy was detected in 17 (2.3%) category 3 lesions, 364 (23.9%) category 4 lesions and 185 (78.7%) category 5 lesions. Median follow-up was 36.9 months. CONCLUSION: This pragmatic study reflects the assessment and management of breast impalpable abnormalities referred for care to a specialized Breast Unit. Multidisciplinary evaluation with BI-RADS classification accurately predicts malignancy, and reflects the quality of management. This assessment should be encouraged in community practice appraisal.

Immunohistochemical and molecular analyses of HER2 status in breast cancers are highly concordant and complementary approaches.

BACKGROUND: Immunohistochemistry (IHC) and fluorescent in situ hybridisation (FISH) are currently the most commonly used methods to assess HER2 status. PCR-based assays allow quantitative determination of HER2 amplification (Q-PCR) or overexpression (Q-RT-PCR), but are not routinely used. We evaluated the relevance of Q-RT-PCR for HER2 status determination. METHODS: We compared IHC and Q-RT-PCR in 466 breast tumours. In discordant or equivocal cases, five additional methods (IHC with two other antibodies, FISH, silver in situ hybridisation (SISH) and Q-PCR) were combined to determine HER2 status. Two cases with HER2 intra-tumour heterogeneity were further explored by allelic profiles analysis and HUMARA clonality determination after microdissection. RESULTS: We observed 97.3% concordance between Q-RT-PCR and non-equivocal IHC. Twelve out of 466 cases (3%) revealed discordances between the two methods. The power of Q-RT-PCR to predict HER2 status (defined by seven methods) was similar to that of IHC. Although rare, some discordances between techniques might be due to HER2 intra-tumour heterogeneity and we report two examples, one tumour containing two distinct clones, another tumour consisting of HER2 amplified and non-amplified subclones. CONCLUSION: Q-RT-PCR and IHC are highly concordant methods for HER2 status assessment, and Q-RT-PCR allows a highly reliable quantitative assessment and could be a useful adjunct to IHC.

Surgical resection versus systemic therapy for breast cancer liver metastases: Results of a European case matched comparison.

BACKGROUND: Resection of breast cancer liver metastases (BCLM) combined with systemic treatment is increasingly accepted but not offered as therapeutic option. New evidence of the additional value of surgery in these patients is scarce while prognoses without surgery remains poor. PATIENTS AND METHODS: For this case matched analysis, all nationally registered patients with BCLM confined to the liver in the Netherlands (systemic group; N = 523) were selected and compared with patients who received systemic treatment and underwent hepatectomy (resection group; N = 139) at a hepatobiliary centre in France. Matching was based on age, decade when diagnosed, interval to metastases, maximum metastases size, single or multiple tumours, chemotherapy, hormonal or targeted therapy after diagnosis. Based on published guidelines, palliative systemic treatment strategies are similar in both European countries. RESULTS: Between 1983 and 2013, 3894 patients were screened for inclusion. Overall median follow-up was 80 months (95% CI 70-90 months). The median, 3- and 5-year overall survival of the whole population was 19 months, 29% and 19%, respectively. The resection and systemic group had median survival of 73 vs. 13 months (P < 0.001), respectively. Three and 5-year survival was 18% and 10% for the systemic group and 75% and 54% for the resection group, respectively. After matching, the resection group had a median overall survival of 82 months with a 3- and 5-year overall survival of 81% and 69%, respectively, compared with a median overall survival of 31 months in the systemic group with a 3- and 5-year overall survival of 32% and 24%, respectively (HR 0.28, 95% CI 0.15-0.52; P < 0.001). CONCLUSIONS: For patients with BCLM, liver resection combined with systemic treatment results in improved overall survival compared to systemic treatment alone. Liver resection should be considered in selected cases.

[Invasive lobular carcinoma of the breast: specific diagnosis and evolution]. / Cancer lobulaire infiltrant du sein: particularités diagnostiques et évolutives.

Invasive lobular carcinoma accounts for 4 to 10% of breast cancers. The clinical and radiological diagnosis is difficult to make. Its progression is slower than that of ductal cancer, and the prognostic factors are more favourable. Its metastases are more frequently located in the digestive tract and the ovaries. It is more frequently bilateral. Its prognosis is not different from that of infiltrating ductal carcinomas. The choice of therapies depends on the individual characteristics of each patient and of the biological features of each tumour. However, lobular carcinomas seem to be less responsive to chemotherapy.

Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer.

PURPOSE: To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)-leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m(2)/d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m(2), as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans. RESULTS: Grade 3 to 4 toxicity from 5-FU-LV occurred in

Marked 24-h rest/activity rhythms are associated with better quality of life, better response, and longer survival in patients with metastatic colorectal cancer and good performance status.

The rest/activity circadian cycle has been used as a reference for chemotherapy administration at specific times to improve tolerability and efficacy. Because cancer processes may be associated with alterations of circadian rhythms, the rest/activity cycle was monitored noninvasively to assess its relationship with tumor response, survival, and quality of life in 200 patients with metastatic colorectal cancer. Patients wore an actigraph, a wristwatch that records the number of accelerations per minute, for 3 days before receiving chronomodulated chemotherapy. The circadian rhythms in activity were estimated by two robust parameters: the autocorrelation coefficient at 24 h (r24), and the dichotomy index (I

[Breast lobular carcinoma in situ: diagnosis and evolution]. / Cancer lobulaire in situ du sein. Particularités diagnostiques et évolutives.

The incidence of lobular cancers in situ is increasing, especially in post-menopausal women. Whereas this form of disease was regarded for a long time as nothing but a risk factor of the occurrence of later infiltrating carcinoma, it now tends to represent a precancerous state whose progression to subsequent infiltrating carcinoma does not inevitably occur. The clinical and radiological diagnosis remains difficult and the choice of therapies varies according to teams, ranging from mere surveillance to mastectomy.

Chronomodulation of chemotherapy against metastatic colorectal cancer. International Organization for Cancer Chronotherapy.

Toxic effects of 5-fluorouracil (5-FU) and oxaliplatin (L-OHP), two active drugs against metastatic colorectal cancer, varied by 50% or more according to circadian dosing time in mice or rats. Adaptation of chemotherapy delivery to circadian rhythms (chronotherapy) was assessed in fully ambulatory outpatients, using multichannel programmable pumps. These devices allowed us to reliably test the clinical relevance of such a chronotherapy principle. First, single agent 5-day chronomodulated schedules were devised and assessed in Phase I and II trials with 5-fluorouracil (5-FU, peak delivery at 4:00 h) or oxaliplatin (L-OHP, peak at 16:00 h). Both schedules were then combined, folinic acid (FA) being added, synchronous with 5-FU infusion. This three-drug chronomodulated regimen (chrono-FFL) produced a 58% response rate (95% C.I.: 48-68%) in 93 patients with metastatic colorectal cancer, 46 of whom had previously received chemotherapy. In the first European randomised trial in 92 previously untreated patients, chronomodulated three-drug delivery achieved 53% response, as compared to 32% in those patients receiving flat infusion (P = 0.038). These respective figures were confirmed in a subsequent multicentre randomised trial involving 186 additional patients. Since the most active schedule was also the least toxic one by 2- to 10-fold, chrono-FFL was further intensified in three consecutive Phase II trials involving a total of 200 additional patients. Results suggest that both response rate and quality were further improved with such treatment intensification. Thus, chrono-FFL more than doubled the activity of chemotherapy against metastatic colorectal cancer in a multicentre European setting.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of stage I testis seminoma by radiotherapy: long-term results--a 30-year experience.

PURPOSE: From 1956 to 1986, we have retrospectively studied 184 patients with a Stage I testis seminoma treated by orchidectomy and radiotherapy at the Institut Gustave Roussy. METHODS AND MATERIALS: The 184 patients received adjuvant radiotherapy to the para-aortic and ipsilateral iliac nodes. Of the 184 patients, 133 received additional mediastinal and supraclavicular irradiation, 47 received supraclavicular without mediastinum irradiation, 98 patients received additional radiotherapy given to inguino-scrotal area. The mean dose of irradiation is 21 Gy which is the lowest dose published. The actuarial survival rate is, respectively, 96%, 93%, 83% and 77% at 5, 10, 15, and 20 years. RESULTS: Four patients relapsed, and four died of progressive disease. Four patients presented cardiovascular disease, all of them had mediastinal irradiation, two were heavy smokers. Seventeen second malignancies were observed, six tumors in the contralateral testis. The actuarial risk of developing a second malignancy is 10% at 10 years, 21% at 20 years. The cure rate and relapse rate in our patients is the same as that obtained by higher dosage of irradiation. CONCLUSION: We conclude that low dose of prophylactic irradiation in lumbo aortic and ipsilateral iliac lymph nodes is active and safe in the treatment of Stage I testis seminoma.

A review of the antitumour activity of vinorelbine in breast cancer.

The use of vinorelbine 30 mg/m2/week as a single-agent treatment in advanced breast cancer has achieved response rates of > 20% as second-line treatment and 40 to 50% as first-line treatment. The major toxicity of the drug is reversible neutropenia; 35 to 50% of treated patients have grade IV neutropenia. The agent did not induce thrombocytopenia and proved mildly emetogenic and neurotoxic. Activity was confirmed in combination with fluorouracil or doxorubicin, when response rates ranging from 60 to 74% were achieved. Thus, vinorelbine appears to be a promising agent in the treatment of advanced breast cancer.

Chronotherapy of colorectal cancer metastases.

Chronotherapy has consisted in the adaptation of chemotherapeutic drug delivery to circadian (approximately 24-hour) rhythms. This can be achieved in fully ambulatory patients using multichannel programmable pumps. Up to approximately 1500 patients with metastatic colorectal cancer have been registered in one of 15 trials testing the relevance of this treatment method with 5-fluorouracil +/- leucovorin +/- oxaliplatin. Chronotherapy was shown as significantly less toxic and more effective than constant rate infusion in 2 consecutive multicenter trials. High efficacy and good tolerability permitted secondary surgical resection of previously inoperable metastases, with apparent survival improvement (3-year survival > or = 20%) and cures in some patients. This strategy is currently undergoing further testing within the European Organization for Research and Treatment of Cancer. Nevertheless, combining chronotherapy with surgery of colorectal cancer metastases can be readily offered to patients as a safer therapeutic option for optimizing outcome.

[Promising results of bimonthly chemotherapy with high dose cyclophosphamide and epirubicin in induction treatment of inflammatory cancer of the breast]. / Résultats prometteurs d'une chimiothérapie bimensuelle avec cyclophosphamide et épirubicine à forte dose dans le traitement d'induction du cancer du sein inflammatoire.

Forty-eight patients with inflammatory breast cancer were treated by an induction regimen with cyclophosphamide (1200 mg/m2), and epirubicin (75 mg/m2). Four to six courses were given every two weeks, whatever the absolute leukocyte counts, before mastectomy, loco-regional radiation, and conventional, or reinforced, for selected patients, chemotherapy. Main toxicity was leukopenia, with grade IV in 25% of cases. However, febrile neutropenia was rare, and relative dose intensity was 102% after four courses, and 97% after six courses. Complete disappearance of inflammatory signs was observed in 90% of patients. Three patients had a pathological complete response, and ten patients had negative axillary lymph nodes. Furthermore, 13 patients had a major pathological response. With a median follow-up of 42 months, progression-free survival and overall survival are 48% and 66%, respectively.

[Primary pseudo-ovarian peritoneal carcinosis. 4 cases]. / Carcinoses péritonéales primitives pseudo-ovariennes. Quatre observations.

Primary papillary carcinosis of the peritoneum is a rare disease seen in elderly women in whom no digestive or ovarian carcinoma could be detected. Its histological structure is identical with that of papillary carcinoma of the ovary. The 4 cases reported here were treated as advanced ovarian carcinomas, with multiple chemotherapy including doxorubicin and cis-platinum. Three patients were re-operated upon after 6 courses. Complete remission was obtained in all 4 cases, but the patients relapsed under maintenance therapy. The diagnosis must be suspected in elderly women presenting with unexplained carcinosis. This is particularly important since effective treatments can now be proposed, as for advanced ovarian carcinomas.