Yazid Belkacemi

Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial

BACKGROUNDnIf treatment of the axilla is indicated in patients with breast cancer who have a positive sentinel node, axillary lymph node dissection is the present standard. Although axillary lymph node dissection provides excellent regional control, it is associated with harmful side-effects. We aimed to assess whether axillary radiotherapy provides comparable regional control with fewer side-effects.nnnMETHODSnPatients with T1-2 primary breast cancer and no palpable lymphadenopathy were enrolled in the randomised, multicentre, open-label, phase 3 non-inferiority EORTC 10981-22023 AMAROS trial. Patients were randomly assigned (1:1) by a computer-generated allocation schedule to receive either axillary lymph node dissection or axillary radiotherapy in case of a positive sentinel node, stratified by institution. The primary endpoint was non-inferiority of 5-year axillary recurrence, considered to be not more than 4% for the axillary radiotherapy group compared with an expected 2% in the axillary lymph node dissection group. Analyses were by intention to treat and per protocol. The AMAROS trial is registered with ClinicalTrials.gov, number NCT00014612.nnnFINDINGSnBetween Feb 19, 2001, and April 29, 2010, 4823 patients were enrolled at 34 centres from nine European countries, of whom 4806 were eligible for randomisation. 2402 patients were randomly assigned to receive axillary lymph node dissection and 2404 to receive axillary radiotherapy. Of the 1425 patients with a positive sentinel node, 744 had been randomly assigned to axillary lymph node dissection and 681 to axillary radiotherapy; these patients constituted the intention-to-treat population. Median follow-up was 6·1 years (IQR 4·1-8·0) for the patients with positive sentinel lymph nodes. In the axillary lymph node dissection group, 220 (33%) of 672 patients who underwent axillary lymph node dissection had additional positive nodes. Axillary recurrence occurred in four of 744 patients in the axillary lymph node dissection group and seven of 681 in the axillary radiotherapy group. 5-year axillary recurrence was 0·43% (95% CI 0·00-0·92) after axillary lymph node dissection versus 1·19% (0·31-2·08) after axillary radiotherapy. The planned non-inferiority test was underpowered because of the low number of events. The one-sided 95% CI for the underpowered non-inferiority test on the hazard ratio was 0·00-5·27, with a non-inferiority margin of 2. Lymphoedema in the ipsilateral arm was noted significantly more often after axillary lymph node dissection than after axillary radiotherapy at 1 year, 3 years, and 5 years.nnnINTERPRETATIONnAxillary lymph node dissection and axillary radiotherapy after a positive sentinel node provide excellent and comparable axillary control for patients with T1-2 primary breast cancer and no palpable lymphadenopathy. Axillary radiotherapy results in significantly less morbidity.nnnFUNDINGnEORTC Charitable Trust.

HER2 status for prognosis and prediction of treatment efficacy in adenocarcinomas: A review

The past few years have seen flourish new biologic parameters for cancer prognosis that are revolutionizing therapeutic strategies. HER-2 is in this perspective a striking example, as it is now a key element for the care of 15-20% of breast cancer. HER-2 overexpression has first been reported as a prognostic factor before its consideration as a main parameter to predict treatment efficacy. However, although HER-2 status is now also used as a prognostic factor for many cancers, its ability to predict the action of trastuzumab in these new contexts is much lower than in breast cancer. In this literature review, we aimed to discuss HER-2 overexpression as a prognostic factor and as a predictive parameter of treatment response in selected solid tumors with a focus on adenocarcinomas.

The Henri Mondor Procedure of Morbidity and Mortality Review Meetings: Prospective Registration of Clinical, Dosimetric, and Individual Radiosensitivity Data of Patients With Severe Radiation Toxicity.

PURPOSEnAfter radiation therapy (RT), various radiation-induced toxicities can develop in about one-fourth of patients. An international interest in using morbidity and mortality rates to monitor the quality of care and integrate morbidity and mortality review (MMR) meetings into organizations governance processes has arisen. We report the first results of patients included in our MMR procedure that included biological assays for individual intrinsic radiosensitivity (IIRS).nnnMETHODS AND MATERIALSnTwenty-three patients were prospectively included in the MMR database. Twenty-two were evaluable for IIRS. Prostate (n=10) and breast (n=8) cancers were the most frequent disease types.xa0The total dose delivered, determined according to the type of disease, ranged from 30 to 74xa0Gy. Our MMR procedure requires strict criteria: patients with unresolved toxicity of grade 3 or higher with availability of clinical (photographic) data, IIRS results obtained from skin biopsy assays, treatment modalities, and follow-up data. The RT technique and dosimetry were reviewed.nnnRESULTSnOur prospective registration of toxicities showed mainly rectitis, occurring in 7 cases, and skin toxicities, occurring in 9. Of the 7 patients with rectitis, 5 received 66xa0Gy of post-prostatectomy RT with V50 (rectum volume receiving 50xa0Gy) ranging from 45% to 75% and a mean maximal dose of 66.5xa0Gy. For dermatitis and cystitis, the mean maximal doses were in the range of classical constraints without any overdosage or dose heterogeneity. No errors were found in the review of treatment planning and positioning. Conversely, all the patients were considered biologically as radiosensitive with genomic instability and ATM (ataxia telangiectasia mutated)-dependent DNA double-strand break repair impairments.nnnCONCLUSIONSnThe MMR review of files allowed clear answers for patients on the relationship between clinical events and their IIRS. Our procedure has allowed education of all our staff to monitor, identify, and document clinical, physical, and biological aspects of radiation-induced toxicities. Thus we recommend the introduction of the MMR procedure in RT departments.

Discrepancies between biomarkers of primary breast cancer and subsequent brain metastases: an international multicenter study

PurposeDiscordances between the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), expression between primary breast tumors and their subsequent brain metastases (BM) were investigated in breast cancer patients.MethodsWe collected retrospective data from 11 institutions in 8 countries in a predefined-standardized format. Receptor status (positive or negative) was determined according to institutional guidelines (immunohistochemically and/or fluorescence in situ hybridization). The study was subject to each institution’s ethical research committee.ResultsA total of 167 breast cancer patients with BM were included. 25 patients out of 129 with a complete receptor information from both primary tumor and BM (ER, PR, HER2) available, had a change in receptor status: 7 of 26 (27%) ER/PR-positive/HER2-negative primaries (3 gained HER2; 4 lost expression of ER/PR); 10 of 31 (32%) ER/PR-positive/HER2-positive primaries (4 lost ER/PR only; 3 lost HER2 only; 3 lost both ER/PR and HER2); one of 33 (3%) ER/PR-negative receptor/HER2-positive primaries (gained ER); and 7 of 39 (18%) triple-negative primaries (5 gained ER/PR and 2 gained HER2).ConclusionsThe majority of breast cancer patients with BM in this series had primary HER2-enriched tumors, followed by those with a triple-negative profile. One out of 5 patients had a receptor discrepancy between the primary tumor and subsequent BM. Therefore, we advise receptor status assessment of BM in all breast cancer patients with available histology as it may have significant implications for therapy.

Early onset breast cancer: differences in risk factors, tumor phenotype, and genotype between North African and South European women

PurposeThis report compares the risk factors, the tumor phenotypes, and the BRCA1/BRCA2 genotype of early onset breast cancer (EOBC) patients between Southern Europe and North Africa.MethodsFour hundred and fifty six women with invasive EOBC (≤40xa0years) were prospectively included from four centers in France (nxa0=xa0270) and four centers in North Africa (Algeria, Egypt, Morocco, Tunisia; nxa0=xa0186). Life style, tumor phenotype, familial history, BRCA1/BRCA2 genotype were compared between the two populations.ResultsWe found an older age at menarche, a higher number of childbearing, a more frequent breastfeeding, a higher body mass index, a lower use of oral contraceptives in North African women compared to French women. TNM stage at diagnosis was higher in North African women than in French women. North African women had a lower incidence of triple negative and proliferative (Ki 67 indexxa0>xa020%) tumors. There was a lower rate of BRCA1 mutation in North Africa (7 vs. 15%, Pxa0=xa00.02). Three putative BRCA1/2 founder mutations were identified in North Africa.ConclusionsIn EOBC, we foundxa0significant differences in risk factors, phenotype and a higher incidence of BRCA1 mutations in Southern Europe as compared to North Africa. The worst prognosis previously reported for EOBC in North Africa is more likely due to a higher stage at diagnosis than to a more aggressive phenotype, since triple negative tumors are more common in Southern Europe and advanced tumors in North Africa.

Incidence of Radiographically Occult Nodal Metastases in HPV+ Oropharyngeal Carcinoma: Implications for Reducing Elective Nodal Coverage

PURPOSEnInitial deescalation studies for human papilloma virus (HPV)-positive driven oropharyngeal squamous cell carcinomas (HPV+ OPSCC) altered radiation therapy dose or the systemic agent used. Newer trials examine the disease control achieved with a reduced elective nodal field. We examined patterns of nodal involvement in patients with HPV+ OPSCC with a focus on implications for radiation field design for treatment deescalation.nnnMETHODS AND MATERIALSnRecords of patients with HPV+ OPSCC with preoperative imaging (computed tomography or fludeoxyglucose positron emission tomography/computed tomography) who underwent neck dissection without neoadjuvant therapy from 2010 to 2017 were retrospectively reviewed. The number and location of clinically positive lymph nodes on preoperative imaging were compared with those documented on pathology. These data were then used to establish the probability of missing nodal disease in 3 modified radiation field designs.nnnRESULTSnOne hundred patients were included. The median time between imaging and surgery was 22 days. The most common clinical N stage was cN2a (35%), whereas the most common pathologic N stage was pN2b (45%). The median number of radiographically and pathologically involved nodes was 1 (range, 0-6) and 2 (range, 0-11), respectively. Forty-three percent of patients had more pathologically involved nodes than predicted on imaging, whereas 21% had pathologic involvement at an additional nodal level not predicted on imaging. Of the 21 patients with additional pathologically involved nodal levels, 14 had involvement of a directly adjacent station, 4 were patients with a cN0 hemineck with pathologically positive level II disease, and 3 had pathologic involvement of level 2 echelons removed from that predicted on imaging.nnnCONCLUSIONnOur study suggests that radiation fields encompassing only clinically involved nodes or levels has an unacceptably high likelihood of missing subclinical disease. Alternatively, treating the first uninvolved echelon nodes in addition would cover pathologic sites of disease in 97% of patients. This approach merits further study in prospective trials.

Single-Dose Daily Fractionation Is Not Inferior to Twice-a-Day Fractionated Total-Body Irradiation Before Allogeneic Stem Cell Transplantation for Acute Leukemia: A Useful Practice Simplification Resulting From the SARASIN Study

PURPOSEnTotal-body irradiation (TBI) is a major constituent of myeloablative conditioning regimens. The standard technique consists of 12xa0Gy in 6 fractions over a period of 3xa0days. The Standard-fractionation compAred to one-daily fRaction total body irrAdiation prior to tranSplant In LEUkemia patieNts (SARASIN) study aimed to compare standard fractionation with once-daily fractionation before transplant in leukemia.nnnMETHODS AND MATERIALSnWe retrospectively compared TBI regimens delivered in 2993 patients from the European Society for Blood and Marrow Transplantation database, who underwent transplantation between 2000 and 2014 for acute lymphoblastic leukemia (ALL, nxa0=xa01729) or acute myeloid leukemia (AML, nxa0=xa01264).xa0TBI was delivered as either 12xa0Gy in 6 fractions (group 1, considered the reference group; 1362 ALL and 857 AML patients), 9 to 12xa0Gy in 2 fractions (group 2, 173 ALL and 256 AML patients), or 12xa0Gy in 3 to 4 fractions (group 3, 194 ALL and 151 AML patients).nnnRESULTSnThe median follow-up was 60 and 84xa0months in ALL and AML patients, respectively. At 5xa0years, the leukemia-free survival rate, overall survival rate, relapse incidence, and nonrelapse mortality rate were 46.6%, 50.4%, 28.8%, and 24.6%, respectively, in ALL patients and 46.6%, 48.9%, 29.7%, and 23.6%, respectively, in AML patients. In multivariate analyses, the outcomes of groups 2 and 3 were not statistically different from those in group 1. The cumulative incidence of secondary malignancies (SMs) was significantly higher in group 2 (7.2%; Pxa0<xa010-6 for group 2 vs group 1). However, group 2 was not associated with an increase in SMs when we considered non-T-cell-depleted transplant patients.nnnCONCLUSIONSnWe showed that the 12-Gy fractionated TBI dose delivered either in 2 fractions or in 1 fraction per day over a period of 3 to 4xa0days resulted in nonsignificant differences in disease control and survival. However, 1-day fractionation may be associated with a higher risk of mucositis and hemorrhagic cystitis. The absence of a significant difference in the SM incidence in the non-T-cell-depleted group should be interpreted with caution in the context of a retrospective study design. Our findings are important to consider for radiation therapy department organization. In-depth analyses of other nonlethal toxicities and late effects are required.

Local and Regional Breast Cancer Recurrences: Salvage Therapy Options in the New Era of Molecular Subtypes

Isolated local or regional recurrence of breast cancer (BC) leads to an increased risk of metastases and decreased survival. Ipsilateral breast recurrence can occur at the initial tumor bed or in another quadrant of the breast. Depending on tumor patterns and molecular subtypes, the risk and time to onset of metastatic recurrence differs. HER2-positive and triple-negative (TNG) BC have a risk of locoregional relapse between six and eight times than luminal A. Thus, the management of local and locoregional relapses must take into account the prognostic factors for metastatic disease development. It is important to personalize the overall management, including or not systemic treatment according to the metastatic risk. All isolated recurrence cases should be treated with curative intent. Complete surgical resection is recommended whenever possible. Patients who did not receive postoperative irradiation during their initial management should receive full-dose radiotherapy to the chest wall and to the regional lymph nodes if appropriate. Overall, total mastectomy is the “gold standard” among patients who were previously treated by conservative surgery followed by radiation therapy. In terms of systemic therapy, the benefits of additional treatments are not conclusively proven in cases of isolated recurrence. The beneficial role of chemotherapy has been reported in at least one randomized trial, while endocrine therapy and anti-HER2 are common practice. This review will discuss salvage treatment options of local and locoregional recurrences in the new era of BC molecular subtypes.

Daily Practice Management of pT1a-b pN0 Breast Carcinoma: A Prospective French ODISSEE Cohort Study

Background Most breast cancer (BC) tumors ≤10 mm have an excellent prognosis. The subgroups with a higher risk for distant recurrence requiring adjuvant systemic therapy are not precisely defined in current international guidelines. Patients and Methods The OBSERVATOIRE DES PETITS CANCERS DU SEIN HER2 +/− (ODISSEE) study was a prospective, multicenter, cohort study that aimed to describe the daily adjuvant management and outcome of 616 patients with unifocal, invasive pT1a‐b pN0 nonmetastatic BC who underwent surgery. Results At the time of diagnosis, the median age of patients was 61 years. Tumor was detected on imaging or during a screening program in 397 patients (64.6%). Most patients (96%) underwent conservative surgery with sentinel node biopsy (89%), completed with axillary lymph node dissection in 15%. At inclusion, 82% of tumors were pT1b, 73% were pN0 (i−), 53% were Scarff–Bloom–Richardson Grade I, 91% were estrogen receptor (ER)‐positive, 5% overexpressed/amplified HER2, and 5% were triple negative (TNBC). Adjuvant treatments were radiotherapy (95%), hormone therapy (82%), chemotherapy (7%), and trastuzumab (3.5%). In patients with TNBC and HER2‐positive BC, chemotherapy and trastuzumab (if needed) were administered in 45% and 68%, respectively. After 5 years of follow‐up, 7 patients had contralateral BC, 7 had locoregional recurrence, and 1 had distant metastasis. At 5 years, overall survival, disease‐free survival, and recurrence‐free survival were: 98.4% (96.9%‐99.1%), 94.7% (92.4%‐96.3%), and 97.1% (95.2%‐98.2%), respectively. Conclusion This prospective cohort study showed that in France, the routine practice in pT1a‐b pN0 breast cancers follows international standard guidelines for practice including conservative surgery followed by radiotherapy and endocrine therapy for ER‐positive patients. Adjuvant chemotherapy with or without trastuzumab was used but their benefit in breast cancer of ≤10 mm remains controversial. Micro‐Abstract The subgroup of breast cancer tumors ≤10 mm requiring adjuvant systemic therapy is currently not well defined. A prospective cohort study was conducted in patients with unifocal, invasive pT1a‐b pN0 non‐metastatic breast cancer to describe the daily adjuvant management and outcome after surgery. In this study, most patients had conservative surgery followed by radiotherapy and hormone therapy; however the benefit of adjuvant chemotherapy with or without trastuzumab remains controversial.