Risk Of Locoregional Relapse Research Articles

Outcomes in Patients Treated With Mastectomy for Ductal Carcinoma In Situ

To examine, in a large, population-based cohort of women, the risk factors for recurrence after mastectomy for pure ductal carcinoma in situ (DCIS) and to identify which patients may benefit from postmastectomy radiation therapy. Data were analyzed for 637 subjects with pure DCIS, diagnosed between January 1990 and December 1999, treated initially with mastectomy. Locoregional relapse (LRR), breast cancer-specific survival, and overall survival were described using the Kaplan-Meier method. Reported risk factors for LRR (age, margins, size, Van Nuys Prognostic Index, grade, necrosis, and histologic subtype) were analyzed by univariate (log-rank) and multivariate (Cox modeling) methods. Median follow-up was 12.0 years. Characteristics of the cohort were median age 55 years, 8.6% aged ≤ 40 years, 30.5% tumors >4 cm, 42.5% grade 3 histology, 37.7% multifocal disease, and 4.9% positive margins. At 10 years, LRR was 1.0%, breast cancer-specific survival was 98.0%, and overall survival was 90.3%. All recurrences (n=12) involved ipsilateral chest wall disease, with the majority being invasive disease (11 of 12). None of the 12 patients with recurrence died of breast cancer; all were successfully salvaged (median follow-up of 4.4 years). Ten-year LRR was higher with age ≤ 40 years (7.5% vs 1.5%; P=.003). Mastectomy provides excellent locoregional control for DCIS. Routine use of postmastectomy radiation therapy is not justified. Young age (≤40 years) predicts slightly higher LRR, but possibly owing to the small number of cases with multiple risk factors for relapse, a subgroup with a high risk of LRR (ie, approximately 15%) was not identified.

P3-14-20: Concomitant Taxane-Anthracyclin Regimen for Neoadjuvant Chemotherapy of Primary Breast Cancer: Experience from a Cohort of 223 Patients Treated in a Single Institution.

Abstract Background: Neoadjuvant chemotherapy (NAC) may be an alternative to mastectomy for localized breast cancer ineligible for breast conservation. The optimal schedule (sequential versus concomitant) remains controversial. Based on encouraging results of a phase 2 study (Luporsi E. et al, ASCO 2000) a concomitant docetaxel (D) and epirubicin (E) neoadjuvant combination is applied in neoadjuvant setting in our institution since 2001 for HER2−negative patients (pts). The results of this combination are presented, with a particular focus on pathological complete response (pCR) and conservation rate. Methods: Between 2001 and 2010, 223 pts received NAC for a T2-T3 breast cancer initially ineligible for conservative surgery, but with hope of breast conservation in case of downstaging by pre-operative medical treatment. Six cycles of D (75mg/m2) and E (75mg/m2) were administered every 3 weeks before surgery, with prophylactic support of G-CSF in order to reduce the risk of febrile neutropenia and to maintain the dose-intensity of the NAC. All patients eligible for breast conservation after NAC underwent lumpectomy, the others were treated by mastectomy. In all cases, an axillary dissection was performed. After lumpectomy all patients received radiation therapy, after mastectomy RT was limited to high risk of loco-regional relapse. Patients with positive hormonal receptors (HR+) received hormonal therapy. Results were analyzed in term of breast conservation rate (BCR), pathologic response rate (pCR defined as no residual invasive tumour in breast and axilla, according to Sataloff's classification) and safety. Results: Mean age of patients was 49,6 years (range: 26–71). Median clinical tumor size was 40mm (range 20–110). Histological subtypes were:78,0 % ductal, 15,3 lobular, 1,8 % ductal/lobular and 4,9 % other types. SBR grading was: grade I: 14,3 %, grade II: 46,2 %, grade III: 33,2 % and 6,3 % unspecified. 77,3 % were HR+, 19,7 % of tumours were triple negative (HER2 unknown for 38 cases). A breast conservation was achievable for 73,5% of patients, the pCR rate was 20,6%. At a median follow up of 48 months, 31 pts relapsed: 9 pts (4%) experienced a local relapse, 5 regional and 28 distant recurrences occured. Additional data about safety and survival will be provided for the meeting. Conclusions: For HER2−negative tumours, 6 cycles of a concomitant taxane-anthracyclin pre-operative combination allowed a 20,6% pCR rate, slightly lower than obtained with 8 cycles of a sequential regimen in several published trials. However breast conservation rate was similar with a low risk of local recurrence. According to these results, concomitant cytotoxic combination is an acceptable option for neoadjuvant treatment of breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-20.

Prognosis in women with small (T1mic,T1a,T1b) node-negative operable breast cancer by immunohistochemically selected subtypes

Knowledge is limited about prognostic significance of breast cancer subtypes among women with small invasive node-negative breast tumours. We explored patterns of recurrence in 1691 women with pT1mic/T1a/T1b, pN0 and M0 breast cancer according to four immunohistochemically defined tumour subtypes: (i) Luminal A (ER-positive, PgR-positive, HER2-negative and Ki-67 < 14%); (ii) Luminal B (ER-positive and/or PgR-positive, HER2-positive and/or Ki-67 ≥ 14%); (iii) HER2-positive, both endocrine receptors absent; and (iv) Triple Negative. At multivariate analysis, women with the Triple Negative breast cancer subtype had an increased risk of loco-regional relapse (LRR) (Hazards Ratio (HR) 3.58; 95%CI: 1.40-9.13) and breast cancer related events (HR 2.18; 95%CI: 1.04-4.57). Overall, Luminal B subtype was not associated with a statistically significant increased risk of recurrence compared with Luminal A, while patients with Luminal B subtype tumours overexpressing HER2 had a 2 fold risk of reduced breast cancer related survival (BCS), but not an increased risk of LRR and distant metastases. Women with HER2 breast cancer subtype had a statistically significant increased risk of LRR (HR 4.53; 95%CI: 1.56-13.1), distant metastases and reduced BCS (HR 3.22; 95%CI: 1.44-7.18) and overall survival (HR 2.87; 95%CI: 1.05-7.89) when compared with the Luminal A subtype, at multivariate analysis. In conclusion, women with small size, node-negative, breast cancer are at higher risk of relapse if with HER2-positive endocrine receptor absent or Triple Negative disease.

Prognostic value of tissue polypeptide antigen in oral squamous cell carcinoma

Human oral cancer has a high risk of locoregional relapse which is difficult to diagnose early due to lack of prognostic markers. We and others have shown aberrant expression of cytokeratin (CK) 8 and 18 in human oral cancer. Aberrant supra-basal expression of CK19 has been shown earlier. In this study, our aim was to develop a non-invasive test for prognostication of human oral cancer. Immunoradiometric assay (IRMA) was used to measure the circulating levels of TPA in the sera of 80 oral cancer patients before surgery and seven days after surgery. Elevated serum TPA levels were noted in the post surgery samples of 28 out of the 50 patients for whom clinical follow-up was available, as compared to their pre-surgery samples. TPA levels in the pre-surgery serum samples of patients were significantly higher than levels in the sera of healthy controls (p=0.001). Elevated levels in patients correlated significantly with stage (p=0.02), development of recurrence (p<0.006), and impacted survival (p<0.033). IHC analysis showed statistically significant correlation between expression of CK8, 18 and 19 in surrounding uninvolved tissues of the tumour and post surgery elevated serum TPA levels (p<0.001). This suggests the possibility that CK fragments are released from the surrounding uninvolved tissues into the sera of patients after surgical removal of the tumour. Thus, our study indicates that TPA can be a useful tumour marker for the prediction of recurrence and poor prognosis in human oral cancer.

Radiothérapie postopératoire dans les sarcomes utérins : étude rétrospective multicentrique

Purpose Surgery is the treatment of choice for localized uterine sarcomas. We conducted a retrospective study to define prognostic factors. Patients and methods We studied 111 cases of patients treated by adjuvant radiotherapy for uterine sarcoma in seven French centers. The median decline was 31 months. We conducted a univariate analysis to identify factors correlated with local recurrence. The statistically significant factors were studied in multivariate analysis by Cox model. Results The median dose of external beam radiotherapy was 45 Gy. Forty-three percent of patients had vaginal vault brachytherapy and 21 % chemotherapy. Only 6.3 % of patients had complications of acute grade III and 8.1 % of long-term sequelae of radiotherapy. The survival rate at 5 years was 74.6 %. They noted 12.6 % of isolated locoregional recurrences, against 29.7 % for distant recurrences, 80 % were pulmonary. Factors correlated with the risk of locoregional relapse were menopausal status ( P = 0.045) and surgical margins suspicious or not healthy ( P = 0.0095). The chemotherapy did not improve overall survival or disease free survival but the numbers were low. Conclusion The postoperative radiotherapy provides good local control in this disease. Brachytherapy is sometimes done, but it does not improve local control. Chemotherapy is not a standard localized stage but the rate of metastatic recurrence calls for the development of strategies involving systemic treatment with radiotherapy.

DNA Repair Gene Expression and Risk of Locoregional Relapse in Breast Cancer Patients

Radiation therapy appears to kill cells mainly by inducing DNA double-strand breaks. We investigated whether the DNA repair gene expression status might influence the risk of locoregional recurrence (LRR) in breast cancer patients. We used a quantitative reverse transcriptase PCR-based approach to measure messenger RNA levels of 20 selected DNA repair genes in tumor samples from 97 breast cancer patients enrolled in a phase III trial (Centre René Huguenin cohort). Normalized mRNA levels were tested for an association with LRR-free survival (LRR-FS) and overall survival (OS). The findings were validated in comparison with those of an independent cohort (Netherlands Cancer Institute (NKI) cohort). Multivariate analysis encompassing known prognostic factors was used to assess the association between DNA repair gene expression and patient outcome. RAD51 was the only gene associated with LRR in both cohorts. With a median follow-up of 126 months in the CRH cohort, the 5-year LRR-FS and OS rates were 100% and 95% in the 61 patients with low RAD51 expression, compared with 70% and 69% in the 36 patients with high RAD51 expression, respectively (p < 0.001). RAD51 overexpression was associated with a higher risk of LRR (hazard ratio [HR], 12.83; 95% confidence interval [CI], 3.6-45.6) and death (HR, 4.10; 95% CI, 1.7-9.7). RAD51 overexpression was also significantly associated with shorter LRR-FS and OS in the NKI cohort. Overexpression of RAD51, a key component of the homologous DNA repair pathway, is associated with poor breast cancer outcome. This finding warrants prospective studies of RAD51 as a prognosticator and therapeutic target.

Radiothérapie du cancer du sein chez le sujet âgé

In Western countries, about 25% of breast cancers (BC) occur in women older than 70 years old. Local control is a crucial step to cure disease, because locoregional relapse (LRR) is a major risk factor of subsequent metastases. After mastectomy, radiotherapy (RT) confirmed a very high value (regardless of age) in several trials and meta-analyses, especially in case of high LRR risk factors (i.e. axillary nodal involvement). Globally, RT reduces LRR rates by 60–70% and also increases long-term survival rates by 8–9%. After breast conserving surgery, several trials and meta-analyses confirmed that RT decreases 10-year local recurrence rates from 20–25 to 5–8%. RT replacement by hormonal treatment leads to a significantly higher LRR rate. Hypofractionated RT schemes could usefully apply to elderly people, but partial breast irradiation techniques are still under investigation. Finally, all elderly fitted women should receive adjuvant RT according to general guidelines with optimal technique in order to avoid cardiotoxicity. Indeed, under-treatment has an unfavourable effect on long-term survival.

DNA repair gene expression profile and risk of locoregional relapse in locally advanced breast cancer patients

528 Background: The cytotoxicity of radiation therapy appears mainly mediated through the induction of DNA-double strand breaks. We explore whether DNA repair gene expression could be associated with the risk of locoregional recurrence (LRR) in locally advanced breast cancer patients. Methods: mRNA levels of 21 selected DNA repair genes were measured in tumors samples of 97 locally advanced breast cancer patients included in a phase III trial (CRH cohort), using quantitative reverse-transcriptase polymerase chain reaction. Normalized mRNA levels were evaluated for association with LRR-free survival (LRR-FS) and overall survival (OS). Results were validated in an independant cohort (Netherlands Cancer Institute: NKI cohort). Multivariate analysis, including known prognostic factors, was done to assess the association between gene expression profile of DNA repair genes and outcomes. Results: Overexpression of RAD51, PRKDC, and XRCC6 were associated with a higher risk of LRR in the CRH cohort. RAD51 was the only gene associated with LRR in the NKI cohort. With a median follow-up of 126 months (CRH cohort), the 5-year LRR-FS rates were 100% in patients (n = 61) with low RAD51, compared with 70% in patients (n = 36) with high RAD51 (p &lt; 0.0001). The 5-year OS rates were 95% in patients with low RAD51, compared with 69% in patients with high RAD51 (p = 0.00026). RAD51 overexpression was associated with a higher risk of LRR (multiadjusted hazards ratio [HR], 12.83, 95% CI: 3.6 - 45.6) and a higher risk of death (multiadjusted hazards ratio [HR], 4.10, 95% CI: 1.7 - 9.7). RAD51 was also significantly associated with shorter LRR-FS and OS in the NKI cohort. Conclusions: Our results suggest that overexpression of RAD51, a key component of the homologous recombination and the DNA DSBs repair, is associated with a higher risk of LRR and death, and may be a prognostic marker of LRR in locally advanced breast cancer patients. No significant financial relationships to disclose.

Neoadjuvante Radiochemotherapie des Rektumkarzinoms

Neoadjuvant radiochemotherapy has become established treatment for rectal cancer. It is indicated when primary R0 resection is not an option, in cases of higher risk of locoregional relapse following surgical treatment alone, and when initially impossible conservation of the anal sphincter becomes possible in conjunction with neoadjuvant radiochemotherapy. The indication for radiochemotherapy in the upper third of the rectum is still controversial. Reevaluation of the tumor situation following neoadjuvant treatment is necessary before decisions on operative strategy. Modern imaging techniques are limited in this respect, as they hardly allow differentiation between living tumor tissue and lesions. In case of doubt clarity is possible only through surgical exploration, taking R1 resection into account. Overall the recognition of lymph node metastasis is not a sufficient indicator of local relapse. The frequency of postoperative complications following neoadjuvant radiochemotherapy is independent of the operative method. The effect of neoadjuvant radiochemotherapy on long-term survival and formation of distant metastases is still not clarified. Current studies seek clarification through the use of new chemotherapies and modified treatment regimes. Further, the correct time interval between the end of neoadjuvant radiochemotherapy and the following surgical therapy has yet to be determined. This applies also to the management of patients following complete remission.

Different Natural Course of Disease in Patients With Melanoma

along with adjuvant systemic therapy treated all the nodal areas at risk, including the internal mammary node. However, the extent of the nodal fields is controversial. We await the outcome of the Selective Use of Post Mastectomy Radiotherapy trial with interest. Second, Russell et al cite a number of primarily adjuvant systemic therapy studies to suggest that the risk of local recurrence in the modern systemic therapy era may be less than has been previously reported. Many of these studies report only the first site of failure, not the total frequency of locoregional failure. Furthermore, some locoregional recurrences are subclinical and others are misclassified as systemic failures—internal mammary nodal recurrence classified as “sternal metastasis,” for instance. The bottom line, however, is the impact on survival, something easily and accurately measured. Third, nodal ratio is certainly an alternative and interesting way to define subgroups. All cut points are, to some degree, arbitrary. Although the risk of locoregional relapse will likely increase with the extent of nodal involvement (measured as either the number or fraction involved), so will the risk of systemic relapse. Thus, the impact of PMRT on survival is related to competing risks and may not exactly parallel the risk of locoregional relapse. Indeed, the magnitude of the benefit of PMRT on survival is similar in the patients with one to three versus four or more positive axillary nodes. Finally, in our editorial, we stated that “comprehensive PMRT is appropriate for the great majority of node-positive patients undergoing mastectomy,” but “some selection based on other clinical and biologic factors may be important and appropriate” as well. However,

A randomised controlled trial to evaluate both the role and optimal fractionation of radiotherapy in the conservative management of early breast cancer.

Abstract Abstract #5125 Background: Postoperative radiotherapy is routinely used in early breast cancer using 50Gy in 25 daily fractions (Long). Both the role of radiotherapy and shorter regimens require validation.&amp;#x2028; Methods: Patients with clinical stage 1 and 2 disease were randomised to receive immediate postoperative (RT) or delayed salvage treatment (No RT). Patients receiving RT were further randomised to Long or Short (40Gy in 15 daily fractions) regimens. The primary outcome measure was time to first relapse. Reported results are at median follow up of 16.9 years (IQR 15.4 - 18.8).&amp;#x2028; Results: 707 women were recruited between 1985 and 1992: median age 59 years (range 28-80), 72% post menopausal, median tumour size 2.0cms (range 0.12-8.0). 271 patients have relapsed: 110 RT, 161 No RT. Site of first relapse was reported as 158 (64%) locoregional and 87 (36%) distant. Immediate RT significantly reduced the risk of relapse by 42% (HR=0.58 (95%CI: 0.45, 0.73), chi2LR=20.40, p&amp;lt;0.001) consistent across all prognostic subgroups. Immediate RT reduced the risk of locoregional relapse by 65% (HR=0.35 (95%CI: 0.25, 0.47), (chi2LR=40.47, p&amp;lt;0.001). No difference in relapse site, or frequency was seen between the 2 fractions. No differences were seen in overall or breast cancer specific survival.&amp;#x2028; Discussion: With a median follow-up of 17 years, this study confirms the benefit for patients with early breast cancer receiving radiotherapy. We conclude that a radiotherapy schedule of 40 Gy in 15 daily fractions is a safe, efficient and effective regime at least as good as the international conventional regime of 50 Gy in 25 daily fractions. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5125.

Involved-Nodal Radiation Therapy As a Component of Combination Therapy for Limited-Stage Hodgkin's Lymphoma: A Question of Field Size

Combined-modality therapy is the standard of care for limited-stage Hodgkin's lymphoma (HL). Radiation therapy has evolved from extended-field radiation therapy (EFRT) to involved-field radiation therapy (IFRT), reducing toxicity while maintaining high cure rates. Recent publications recommend a further reduction to involved-nodal radiation therapy (INRT), however, this has not been clinically validated. We identified 325 patients with limited-stage HL, diagnosed between May 1, 1989 and April 1, 2005, and treated with chemotherapy and radiation therapy following era-specific guidelines: EFRT until 1996; IFRT from 1996 to 2001; INRT < or = 5 cm from 2001 to the present. INRT < or = 5 cm was defined as the prechemotherapy nodal volume with margins < or = 5 cm to account for physiological movement, set-up variation, and the limitations of conventional simulation and radiation therapy techniques. Exclusion criteria were age younger than 16, fluorine-18 fluorodeoxyglucose positron emission tomography, non-doxorubicin, bleomycin, vinblastine, and dacarbazine-like chemotherapy, and/or more than four chemotherapy cycles. At diagnosis, median age was 35 years; 52% male; stage IA 29%; stage IIA 71%. Ninety-five percent of patients received two chemotherapy cycles. The three radiation therapy groups were: EFRT, 39%; IFRT, 30%; and INRT < or = 5 cm, 31%. Median follow-up of living patients was 80 months. Median time to relapse was 37 months. Twelve relapses occurred: four after EFRT (3%); five after IFRT (5%); and three after INRT < or = 5 cm (3%; P = .9). No marginal recurrences occurred after INRT < or = 5 cm. Locoregional relapse (LRR) occurred in five patients: three after EFRT; two with IFRT; and none with INRT < or = 5 cm. At 5 years, progression-free survival (PFS) was 97%, and overall survival (OS) was 95%. At 10 years, PFS and OS were 95% and 90%, respectively. Reduction in field size appears to be safe, without an increased risk of LRR in patients receiving INRT < or = 5 cm.

Multicenter, prospective study of radiotherapy without surgery after AC followed by weekly paclitaxel for patients with inflammatory breast cancer: SBCCSG-04 study

10783 Background: Inflammatory breast cancer (IBC) is a rare and aggressive disease with a dismal outcome. It is still an open debate whether surgery is beneficial for patients with IBC. This study was conducted to evaluate treatment results when patients were treated by chemotherapy and radiotherapy (CRT) alone. Methods: 52 pts with nonmetastatic IBC were enrolled for a prospective registration trial from 9/01–11/04. A diagnosis required the presence of erythema, ridging, or peau d’orange, with or without dermal lymphatic invasion (DLI). All patients were invited to participate for an experimental protocol; 4 cycles of AC and 12 cycles of weekly paclitaxel (80 mg/m2) followed by radiotherapy. In patients who did not agree to the protocol, the decision about treatment was left to the patients/investigators. The primary endpoint was distant-disease-free survival, and the further endpoints were locoregional relapse (LR) and overall survival. Results: The mean follow-up was 25.7 months. 24 pts (46.2%) were planned for the protocol, but one pt (4%) was receipt surgery. Otherwise, 18 (64%) out of 28 pts have accepted mastectomy. The 2-year distant-disease-free, LR, and overall survival in patients treated with and without the protocol was 35.2 vs 61.0% (HR = 2.4, 1.1–5.3) and 55.2 vs 83.6% (HR = 2.9, 1.1–7.8), respectively. Surgery was not associated with the risk of LR (p = 0.48). There was marginally worse prognosis in patients with DLI. Conclusions: There was a limitation because this comparison had not been conducted a randomized fashion. However, CRT alone would be a feasible treatment schedule for a moderate percentage of patients with IBC. No significant financial relationships to disclose.

Cyclin E overexpression as an independent risk factor of visceral relapse in breast cancer

Aim: Prognostic value of the cyclin E overexpression in breast cancer has not been clearly established, especially in relation to the pattern of recurrence. We investigated the implication of cyclin E overexpression for the pattern of recurrence in Korean breast cancer patients. Methods: Using immunohistochemical methods, we retrospectively examined the cyclin E expression level in breast cancer specimens from 128 women who underwent curative breast surgery, and correlated the levels of expression with the pattern of relapse in patients. Results: Cox model-based multivariate analysis indicated that distant relapse could be predicted by the number of positive axillary lymph nodes, high cyclin E expression, and the younger age (<35 years) of the patient. We tested further the association of cyclin E overexpression with the specific types of recurrence; multivariate analyses indicated that adjusted relative risks of bone and visceral relapse as the first events among high cyclin E group were 2.46 (95% confidence interval (CI), 0.86–7.02) (P=0.092), and 3.98 (95% CI, 1.23–12.94) (P=0.022), respectively. On the other hand, cyclin E overexpression was not associated with the risk of locoregional relapse. Conclusion: Our data suggest that cyclin E overexpression in primary breast carcinoma tissue could independently predict the risk of distant relapse, especially of visceral relapse, as the first failure after curative breast surgery.

60. Factors detremining local control in patients (Pts) with locally advanced breast cancer (Labc) managed with radiotherapy (RT) as the primary locoregional treatment

Introduction RT plays an important role in the management of LABC, yet clinical outcomes still remain far from satisfactory. The aim of this study was to evaluate retrospectively factors determining local control in a large series of consecutive LABC pts managed with RT as the primary locoregional treatment. Material and methods The records of 261 primarily inoperable LABC pts treated between 1991 and 1997 at two institutions: Medical University of Gdansk, Poland and Velindre NHS Trust, Cardiff, UK were analysed. All pts received megavoltage RT to the breast with two tangential fields, and the adjacent lymph node areas were irradiated using customised fields. Due to a large scale of RT doses and fractionation schedules, normalised total dose (NTD) was calculated for all patients using a linear quadratic model. In 241 pts RT constituted the only local treatment and the remaining 20 pts were subsequently subjected to mastectomy. Most pts received chemotherapy and/or endocrine therapy prior or after RT. Results Within the median follow-up of 37 months, locoregional recurrence occurred in 95 of 251 evaluable pts (38%). Three-year and five-year locoregional-free survival rates were 59% and 48%, respectively. At multivariate analysis of variables predicting the risk of locoregional relapse, inflammatory carcinoma (p Conclusions Due to large heterogeneity of LABC pts, judicious tailoring of RT, particularly in terms of dose prescribing, is essential to increase the chance of locoregional cure.

2047 The influence of young age and positive family history on local recurrence after three treatment strategies for ductal carcinoma in situ

Purpose: Three recent studies have investigated the influence of a positive family history (+FH) of breast cancer on the prognosis of DCIS patients treated by conservafive surgery end radiation therapy (CS+RT), with two studies showing a higher risk of locoregional relapse (LRR) in these patients (pts) and another showing no significant difference. Since three treatment strategies have been used for DCIS at our institotion, we evaluated the influence of +FH and young age on outcome by treatment method.