Axillary Node-positive Patients Research Articles

Abstract P1-04-15: Clinical application of 21-gene breast-cancer assay (Oncotype DX) in early hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer with Lymph-Node-Positive Disease

Abstract The 21-gene breast-cancer assay (Oncotype DX) has become widely available since 2011 and it is incorporated in treatment guidelines for early hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer. The Rxponder trial shows the role of adjuvant chemotherapy in node positive patients with a RS score less than 25, but in patients under 50 years of age benefit from adjuvant chemotherapy treatment regardless of the Oncotype. We analyzed our results of the Oncotype Dx in 317 node positive hormone-receptor–positive, HER2-negative early breast cancer patients, performed as a clinical practice since 2015 to 2020. The aims to current study are to examine the clinical significance of the oncotype Dx results in this specific population. The median age was 59 years with 102 patients (32%) less than 50 years. Median Oncotype DX score was 18 ( 1–68), RS< 25 in 247 (78%) and RS>25 in 70 (22%) patients. Median initial tumor size was 20 mm and the expression of classical biological variables was: median estrogen and progesterone receptors by immunohistochemistry 276 and 139 respectively and median Ki67 index was 23%. 145 patients received chemotherapy treatment (45,7%), (RS < 25:32%, RS>25: 94%) with a 63% of the patients in the group less than 50 years of age in contrast to 36% in patients with more than 50 years. Patients with more than 50 years have less RS score (median 18 ) than patients less than 50 years (median 21 ). With a median of follow up of 45 month with achieved a total of 29 recurrence (9,1%), RS< 25: 8% and RS>25 13%. The estimated median disease free survival of patients with RS< 25 was 111 in contrast to 97 in patients with RS>25 (log rangk : p:0,035) and without differences according with age of the patients. In axillary node positive patients, Oncotype Dx could avoided chemotherapy in 55% of patients, with a index of recurrence of 9%. Patients with a RS score greater than 25 have a higher rate of recurrence (13%) despite the fact that the majority (94%) received treatment with chemotherapy. Improve adjuvant treatment is needed in patients with a score greater than 25. Citation Format: Ariadna Gasol Cudós, Serafin Morales Murillo, Noemí Tuset Der-Abrain, Ana Velasco Sánchez, Felip Vilardell Villellas, Douglas Sánchez Guzmán, Carles Canosa Morales, Jordi Melé Olivé, Laura Arbones Cid. Clinical application of 21-gene breast-cancer assay (Oncotype DX) in early hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer with Lymph-Node-Positive Disease [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-04-15.

Oncological safety of selective axillary dissection after axillary reverse mapping in node-positive breast cancer

IntroductionAlthough the need for axillary lymph node dissection (AD) is decreasing in breast cancer patients, it remains necessary in some cases. Axillary reverse mapping (ARM) enables the detection of upper extremity lymphatic drainage that may be spared during selective axillary dissection (SAD) so as to reduce the risk of lymphedema.The ability of the ARM-SAD procedure to reduce the incidence of lymphedema is being tested in an ongoing randomized trial. Crossover between arm drainage and breast drainage is well documented in the axilla, however, and whether the procedure is oncologically safe remains controversial. We aim to assess the axillary failure rate when a few nodes draining the upper arm are being spared by the ARM-SAD. MethodsWe report oncological outcomes, and axillary failure in particular, in the first 100 consecutive axillary node-positive patients treated with ARM-SAD as part of a pilot study and a randomized trial. ResultsA median of 18 (IQR 14–22) axillary nodes were excised per patient. During the follow-up (median 51 months, IQR 34–91), 11 patients experienced a treatment failure, but only one - treated with neoadjuvant chemotherapy - developed overt axillary disease as a first (and isolated) event. The crude rate of axillary failure was 1.36% (95% CI: 0.19–9.63) with an estimated 5-year crude cumulative incidence of 1.85% (95% CI: 0–5.47%). ConclusionsThe axillary failure rate was low in our patients and did not exceed rates reported in the literature after standard AD, thus indicating that the ARM-SAD procedure is oncologically safe.

The Adventure of Axillary Treatment in Early Stage Breast Cancer.

Axillary lymph node dissection (ALND) which was an essential part of breast cancer treatment and the gold standard in evaluation of the status of axillary lymph node had notorious with increased arm morbidity and reduction of quality of life. Sentinel lymph node biopsy (SLNB) accurately stages the axilla in early breast cancer and ALND is omitted in SLNB negative patients. In patients with positive SLNB the omission of ALND with or without replacement of axillary radiotherapy has also been recommended by guidelines. The neoadjuvant chemotherapy (NAC) which has been increasingly used for large breast cancers to downstage the tumours for allowing breast conserving surgery and decreasing mastectomy rate has also been used in axillary node positive patients to reduce the need for ALND. The issues surrounding the treatment of axilla in patients treated with NAC; application and false negative rate of SLNB, number of identified sentinel lymph nodes, and axillary radiotherapy instead of ALND are currently the discussed and practiced hot topics. The quests for decreasing arm morbidity without compromising outcome in breast cancer treatment which have begun with the invention of SLNB continue for axilla conserving surgery. This article reviews the adventure of axillary treatment in breast cancer patients treated with or without NAC.

Prognostic factors of axillary lymph node-positive patients in clinical stage II and III breast cancer after neoadjuvant chemotherapy

Background: Surgery following neoadjuvant chemotherapy (NAC) is increasingly utilized for breast cancer treatment with respect to downstage and recurrent risk reduction. However, there are some uncertainties about the solutions of adjuvant radiotherapy (design of RT field and indication in low-risk patients) in patients after NAC, especially in clinically node-positive patients. The objective of this study is to identify the risk factors of loco-regional recurrence (LRR), relapse and overall survival (OS) regarding tumor response post-NAC in this institution. Methods: From 2007 to 2015, 90 patients with newly diagnosed clinical stage II (n=44) or III (n=46) breast cancer and pathological positive lymph nodes who received chemotherapy followed by breast conserving surgery or mastectomy, adjuvant radiotherapy, and some with adjuvant systemic therapy were identified. All of them received anthracycline-based or taxane-based chemotherapy, external beam radiotherapy and systemic treatment including target or hormone therapy if indicated. Methods: The patient characteristics included clinical T/N stage, pathologic T/N stage, response after NAC, tumor grade, surgical margin, the presence or absence of lymphovascular invasion and extracapsular extension, the total number of lymph nodes dissection, the positive lymph nodes ratio (pLNR), tumor biomarker status [estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER-2)], and adjuvant chemotherapy/target therapy or not. Univariate and multivariate analyses for risks of loco-regional recurrence (LRR), relapse (any local, regional or distant recurrence), and overall survival (OS) and the survival curves of LRR and relapse were performed. Results: After a median follow-up duration of 62 months (7–125 months), the multivariate analysis for risks of LRR showed that the status of clinical lymph nodes (cN2: HR =6.07, P=0.046; cN3: HR =30.22, P=0.001), response subgroups (stable disease: HR =3.01, P=0.047; progressive disease: HR =10.76, P<0.001), and pLNR (67–100%: HR =4.32, P=0.025) have statistical significance. The multivariate analysis for risks of relapse also showed that the status of clinical lymph nodes (cN1 micro/N1: HR =3.97, P=0.037; cN2: HR =4.06, P=0.053; cN3: HR =10.39, P=0.005), response subgroups (progressive disease: HR =3.73, P=0.008) and pLNR (67–100%: HR =3.02, P=0.032) have statistical significance. The multivariate analysis of OS only showed the tumor biomarker status of triple-negative breast cancer (TNBC) (HR =3.04, P=0.048) has statistical significance. Conclusions: In this study, we recorded poor therapeutic response, advanced clinically positive lymph nodes, and higher proportional positivity of dissected lymph nodes showing poor outcome regarding the loco-regional control and relapse-free survival among patients with positive axillary lymph nodes after NAC.

Predictive factors of pathologic complete response in HER2-positive and axillary lymph node positive breast cancer after neoadjuvant paclitaxel, carboplatin plus with trastuzumab.

ObjectiveThis study was performed to investigate the proportion as well as the predictive factors of pathologic complete response in HER2-positive and axillary lymph node positive breast cancer after neoadjuvant paclitaxel, carboplatin plus with trastuzumab (PCH).ResultsThe pCR rate in the breast, axilla and both was 44.3% (39/88), 47.7% (42/88) and 34.1% (30/88), respectively. Patients with and without pCR were similar in term of age, BMI, menstrual status, family history, treatment cycles and tumor characteristics (laterality and size of tumor). Multivariate logistic regression demonstrated that pCR was significantly associated with HR negativity (HR = 5.587, 95% CI 2.25−3.889, p < 0.001), high Ki67 index (HR = 4.130, 95% CI 1.607−10.610, p = 0.003). Further investigation found that patients with HR-negative/high Ki67 index had higher pCR rate, compared to other patients (HR = 7.583, 95% CI 2.503−22.974, p < 0.001).Materials and Methods88 consecutive Chinese HER2-positive/axillary lymph node-positive breast cancer patients with neodjuvant therapy regimen containing paclitaxel, carboplatin and trastuzumab were divided into two groups: pathological complete response (pCR) or non-pCR group. Clinico-pathological characteristics were compared and analyzed, and univariate and multivariate analyses were performed to detect the predictive factors of pCR.ConclusionsPreoperative PCH regimen was an effective neoadjuvant therapy in HER2 positive and axillary lymph node positive patients, and patients coexisting with HR-negative and high Ki67 index may benefit more from this regimen.

Correlation between estrogen receptor, progesterone receptor, HER-2/neu status and other prognostic factors in carcinoma breast in Indian population

Background: Incidence of breast carcinoma (BC) is increasing all over the world. Contrary to the West where it is more common in the elderly; in India it is more common among the younger women. India accounts for nearly six percent of deaths, due to breast cancers in the world and also that one out of every 22 women in India is diagnosed with breast cancer every year. But no information is available on its biological characteristics in the Indian population. Our aim was to evaluate the estrogen receptor, progesterone receptor and HER-2/neu receptor in single institute patients and to compare the expression of these factors with other prognostic parameters such as menopausal state, size of tumor, grade, histological type, mitotic index, lymphovascular invasion and nodal metastases. Methods: This is a prospective study conducted in the Department of General Surgery at Sri Ramachandra Medical University Hospital, Chennai, India. A batch of 60 confirmed patients of BC, diagnosed in between 2012 to 2014, were included in this study. ER, PR and HER-2/neu status were studied by immune-histochemistry and were correlated with other prognostic factors. Results: ER negative and PR negative cases were comparatively high (61.7% and 70%) than the positive cases. 66.7% of the cases were post-menopausal group, 68.3% of cases were T2 tumor and 81.7% cases were ductal carcinoma. There was a significant correlation identified between ER, PR with tumor grade and Mitotic Index of the tumor. HER-2/neu positive cases tended to have significant higher axillary metastasis. There was no significant correlation between ER, PR and HER-2/neu with menopausal state, size, histological type and lymphovascular invasion. Conclusions: The ER, PR and Her2/neu expression in BC in our patients is comparable with the available international data. ER and PR negative expressions are strongly associated with some known bad pathological factors like high grade tumor and high Mitotic Index. HER-2/neu expression was high in advanced diseases like axillary node positive patients.

The role of ultrasound-guided lymph node biopsy in axillary staging of invasive breast cancer in the post-ACOSOG Z0011 trial era.

Axillary status in invasive breast cancer, established by sentinel lymph node biopsy (SLNB) or ultrasound-guided lymph node biopsy, is an important prognostic indicator. The ACOSOG Z0011 trial showed that axillary dissection may be redundant in selected sentinel node-positive patients, raising questions on the applicability of these conclusions on ultrasound positive patients. The purpose of this study was to evaluate potential differences in patient and tumor characteristics and survival between axillary node positive patients after ultrasound (US group) or sentinel lymph node procedure (SN group). Patients diagnosed with invasive breast cancer at the Máxima Medical Center between January 2006 and December 2011 were studied. In total, 302 node-positive cases were included: 139 and 163 cases in the US and SN groups, respectively. Patients in the US group were older at diagnosis (p<0.001), more often had palpable nodes (p<0.001), mastectomy (p<0.001), larger tumors (p<0.001), higher tumor grade (p=0.001), lymphovascular invasion (p=0.035), a positive Her2Neu (p=0.006), and a negative hormonal receptor status (p=0.003). Also, they were more likely to have more lymph nodes with macrometastases (p<0.001), extranodal extension (p<0.001), and involvement of level-III-lymph node (p<0.001). Finally, they showed a worse disease-free survival [hazard ratio (HR)=2.71; 95% confidence interval (CI)=1.49-4.92] and overall survival (HR=2.67; 95% CI=1.48-4.84) than the SN group. These results suggest that ultrasound-positive patients have less favorable disease characteristics and a worse prognosis than SN-positive patients. Therefore, we conclude that omitting an ALND is as yet only applicable, as concluded in the Z0011, in patients with a positive SLNB.

The effects of ECE on the benefits of PMRT for breast cancer patients with positive axillary nodes

BackgroundThe purpose of the present study was to retrospectively evaluate the effects of extracapsular extension (ECE) on the benefits of post-mastectomy radiation therapy (PMRT) for groups of patients with varying numbers of positive axillary nodes (1–3, 4–9 and ≥10 positive axillary nodes). Methods: A total of 1220 axillary node-positive patients who had received mastectomy were involved in this study. Patients were grouped as ‘Radio + /ECE + ’, ‘Radio–/ECE + ’, ‘Radio + /ECE–’ or ‘Radio–/ECE–’ according to status of ECE and whether receiving PMRT or not, and were evaluated in terms of local region relapse (LRR) rate. The 5-year and 10-year Kaplan-Meier disease-free survival and overall survival (OS) rates were analyzed. Results: ECE-positive differed from ECE-negative groups with statistical significance for all comparisons in favor of the ECE-negative group: 5-year locoregional failure-free survival (LRFFS) (82.69% vs 91.83%, P < 0.001), 10-year LRFFS (75.39% vs 90.02%, P < 0.001); 5-year OS (52.12% vs 74.46%, P < 0.001), 10-year OS (35.17% vs 67.63%, P < 0.001). There were no significant effects of ECE on the benefits of PMRT for patients with 1–3 (P = 0.5720), ≥10(P = 0.0614) positive axillary nodes. However, for the group of patients with 4–9 positive axillary nodes, ECE status had a significant effect on the benefits of PMRT with respect to 5-year and 10-year LRFFS (P < 0.05). Conclusion: In our study, regardless of the ECE status, PMRT didn't significantly improve the LRFFS for patients with 1–3 or ≥10 positive axillary nodes. However, for patients with 4–9 positive axillary nodes, ECE could be an important criterion to consider when deciding whether to receive PMRT.

Clinical observation of early breast cancer after breastconserving surgery and radiotherapy

Objective To observe the oncololigcal and cosmetic outcomes and complication of breastconserving surgery and radiotherapy for early breast cancer. Methods A total of 78 early breast cancer patients, who were treated in the First People's Hospital of Pingdingshan between January 2001 and September 2008, were identified and followed. Among them, 36 were in stage Ⅰ and 42 in stage Ⅱ. Tangential irradiation was used with a dose of 50 Gy. Tumor bed received a boost dose of 10 Gy electron beam. For axillary lymph node-positive patients, ipsilateral supraclavicular field was hybrid irradiated with 50 Gy X and electron beam.Results The total follow-up ranged from 6 to 98 months. Local recurrence was observed among 4.9% of the patients. The 3-year and 5-year overall survival rate were 96.6% and 92.7% ,respectively. The breast cosmetic satisfaction rate was 94.9%. The main complications reported were acute skin reaction and upper limb edema.Conclusion Breast-conserving surgery and post-operative radiotherapy in early breast cancer patients can lead to satisfactory survival rates and cosmetic effects and hence improved life quality. Key words: Breast neoplasms; Breast conserving therapy; Radiotherapy

Comparison of Treatment Outcome Between Breast-Conservation Surgery With Radiation and Total Mastectomy Without Radiation in Patients With One to Three Positive Axillary Lymph Nodes

To test the difference in treatment outcome between breast-conservation surgery with radiation and total mastectomy without radiation, to evaluate the benefits of adjuvant radiotherapy in patients with one to three positive axillary lymph nodes. Using the Severance Hospital Breast Cancer Registry, we divided the study population of T1, T2 and one to three axillary node-positive patients into two groups: breast-conservation surgery with radiation (BCS/RT) and total mastectomy without radiation (TM/no-RT). Data related to locoregional recurrence, distant recurrence, and death were collected, and survival rates were calculated. The study population consisted of 125 patients treated with BCS/RT and 365 patients treated with TM/no-RT. With a median follow-up of 68.4 months, the 10-year locoregional recurrence-free survival rate with BCS/RT and TM/no-RT was 90.5% and 79.2%, respectively (p = 0.056). The 10-year distant recurrence-free survival rate was 78.8% for patients treated with BCS/RT vs. 68.0% for those treated with TM/no-RT (p = 0.012). The 10-years overall survival rate for patients treated with BCT/RT and TM/no-RT was 87.5% and 73.9%, respectively (p = 0.035). After multivariate analysis, patients treated with BCT/RT had better distant recurrence-free survival (hazard ratio [HR], 0.527; 95% confidence interval [CI], 0.297-0.934; p = 0.028), with improving locoregional recurrence-free survival (HR, 0.491; 95% CI, 0.231-1.041; p = 0.064) and overall survival trend (HR, 0.544; 95% CI, 0.277-1.067; p = 0.076). This study provides additional evidence that adjuvant radiation substantially reduces local recurrence, distant recurrence, and mortality for patients with one to three involved nodes.

Medial Tumor Localization in Breast Cancer – an Unappreciated Risk Factor?

To demonstrate the unfavorable results in survival rates in patients with medial breast cancer compared to patients with laterally located tumors of the mammary gland. Between 1984 and 1995, 1,089 patients presenting with a total of 1,100 pT1-2 invasive carcinomas of the breast were treated at the authors' institution. 707 presented with tumors in the lateral quadrants, 294 with tumors in the medial quadrants, and 99 with tumors in the central quadrant. Treatment protocols involved breast-conserving surgery and whole-breast radiotherapy in all women, followed by a tumor bed boost dose according to risk factors for local recurrence. All axillary node-positive patients underwent systemic therapy (six cycles of classic CMF and/or 2-5 years of tamoxifen 20 mg/day). Rates of actuarial survival and local control were calculated by the Kaplan-Meier method and differences in survival curves were compared by use of the log-rank test. The mean follow-up of survivors was 97 months (range 36-192 months). Comparing patients with medial and lateral tumors, the actuarial survival data were significantly better for patients with lateral tumors. At 10 years, overall survival for patients with medial tumors was 71%, for patients with lateral tumors 81.8% (p < 0.025), disease-specific survival for patients with medial tumors 79.9%, for patients with lateral tumors 89.1% (p < 0.025). There was no significant difference in local tumor control according to tumor location. Medial tumor location is associated with a lower survival rate, but not with inferior local tumor control. Failure to identify nodal metastases confined to the internal mammary chain may lead to undertreatment with systemic/local agents and compromised survival.

Local Relapse after Breast-Conserving Surgery and Radiotherapy

This retrospective analysis of 1,610 women treated for breast cancer and 88 patients with local relapse aims to show the poor survival parameters after local failure and to evaluate risk factors and compare them with other studies and analyses published. Between 1984 and 1997, 1,610 patients presenting with a total of 1,635 pT1-2 invasive and noninvasive carcinomas of the breast were treated at the authors' institution. The mean age was 57.1 years (range 25-85 years). Treatment protocols involved breast-conserving surgery with or without systemic therapy and whole-breast radiotherapy in all women, followed by a boost dose to the tumor bed according to risk factors for local recurrence. All axillary node-positive patients underwent systemic therapy (six cycles of classic CMF or tamoxifen 20 mg/day for 2-5 years). The time of diagnosis of local relapse was defined as time 0 for the survival curves after local failure. The association of clinicopathologic factors was studied using uni- and multivariate analyses. Survival and local control were calculated by the Kaplan-Meier actuarial method and significance by the log-rank test. After a mean follow-up of 104 months, 88 local failures were recorded (5.4%). Calculated from the time of diagnosis of local relapse, 5-year overall survival (OS) was 62.8%, metastasis-free survival 60.6%, and disease-specific survival 64.2%. In patients with failure during the first 5 years after treatment, the survival parameters were worse (OS 50.6%) compared to those who relapsed after 5 years (OS 78.8%; p < 0.028). Significances were also found for initial T- and N-stage and type of failure (solid tumor vs. diffuse spread). This analysis again shows that the survival parameters are worsening after local relapse, especially in case of early occurrence. In breast cancer treatment, therefore, the goal remains to avoid local failure.

The impact of IMC nodal drainage on primary breast cancer outcome

534 Background: Involvement of the internal mammary node chain (IMC) portends a poor prognosis in primary breast cancer. Theoretically, internal mammary node involvement cannot be present in the absence of primary tumor lymphatic drainage to these nodes. We examined whether the presence of IMC drainage negatively impacted regional and systemic recurrence and overall survival (OS). Methods: We performed a retrospective review of a prospective surgical database of patients with invasive breast cancer (Stage I-III) who underwent preoperative lymphoscintigraphy (LSG) with peritumoral injection and subsequent intraoperative lymphatic mapping from 1996-2002. The study was limited to 1,854 patients who demonstrated drainage on LSG and did not undergo IMC nodal biopsy. Medical records were reviewed for demographics, clinicopathologic data, and medical and surgical treatment data. Outcomes were evaluated including regional and systemic recurrence and overall survival (OS). Patients with any IMC drainage (IM+, alone or with axillary drainage) were compared to those without IMC drainage (IM-) as identified on LSG. Median follow-up was 57.9 months. Results: Three hundred forty-four (18.5%) patients showed IM drainage. Patients with IM drainage were younger and less likely to have upper outer quadrant tumors than those with non-IM drainage (p< 0.0001 for both). Tumor size and axillary sentinel node status were not significantly different between both groups (p=0.08 and p=0.39, respectively). There was no difference in IM irradiation rates of patients who were IM+ versus patients who were IM-. The 5-year systemic recurrence rate was 3.8% for IM+ patients and 2.1% for IM- patients (p=0.07). The 5-year regional recurrence rate was 0.9% for IM+ patients and 0.5% for IM- patients (p=0.46). Only one patient recurred in the IM nodal chain. There was no statistically significant difference in the 5-year OS rates of IM+ versus IM- patients in the entire study cohort as well as in the axillary node positive patients. Conclusions: A finding of IM drainage on LSG was not a significant predictor of OS during this study period. This finding needs to be confirmed at longer follow-up. Further studies are needed to determine the role of the IM sentinel node biopsy. No significant financial relationships to disclose.

Implication of Xenobiotic Metabolizing Enzyme gene (CYP2E1, CYP2C19, CYP2D6, mEH and NAT2) Polymorphisms in Breast Carcinoma

BackgroundXenobiotic Metabolizing Enzymes (XMEs) contribute to the detoxification of numerous cancer therapy-induced products. This study investigated the susceptibility and prognostic implications of the CYP2E1, CYP2C19, CYP2D6, mEH and NAT2 gene polymorphisms in breast carcinoma patients.MethodsThe authors used polymerase chain reaction and restriction enzyme digestion to characterize the variation of the CYP2E1, CYP2C19, CYP2D6, mEH and NAT2 gene in a total of 560 unrelated subjects (246 controls and 314 patients).ResultsThe mEH (C/C) mutant and the NAT2 slow acetylator genotypes were significantly associated with breast carcinoma risk (p = 0.02; p = 0.01, respectively). For NAT2 the association was more pronounced among postmenopausal patients (p = 0.006). A significant association was found between CYP2D6 (G/G) wild type and breast carcinoma risk only in postmenopausal patients (p = 0.04). Association studies of genetic markers with the rates of breast carcinoma specific overall survival (OVS) and the disease-free survival (DFS) revealed among all breast carcinoma patients no association to DFS but significant differences in OVS only with the mEH gene polymorphisms (p = 0.02). In addition, the mEH wild genotype showed a significant association with decreased OVS in patients with axillary lymph node-negative patients (p = 0.03) and with decreasesd DFS in patients with axillary lymph node-positive patients (p = 0.001). However, the NAT2 intermediate acetylator genotype was associated with decreased DFS in axillary lymph node-negative patients.ConclusionThe present study may prove that polymorphisms of some XME genes may predict the onset of breast carcinoma as well as survival after treatment.

Correlation of Her-2 overexpression with endocrine status and response to tamoxifen treatment in patients with breast cancer

To investigate the correlation of Her-2 overexpression with endocrine status and response to tamoxifen treatment in patients with breast cancer. Immunohistochemistry was used to measure the expression of estrogen receptor (ER), progesterone receptor (PR), Her-2, p53, proliferating cell nuclear antigen (PCNA) in 4773 consecutive in-hospitalized patients with primary breast cancer confirmed by pathological examination of the resected specimens, all females, aged 50 (15 - 92), and were followed up for 42 months on average. 1090 if then received tamoxifen (TAM), an anti-estrogen agent, post-operationally. The correlation of Her-2 overexpression with other factors was analyzed. (1) The Her-2 overexpression rate was 26.6%. Her-2 overexpression was significantly negatively correlated with expressions of ER and PR (both P < 0.01). (2) The general 3-year disease-free survival (DFS) rate of those treated with TAM was 92.7%; and the 3-year GFS rate of the subgroup of the TAM-treated patients with Her-1 overexpression was 91.2%, significantly lower than that of those without Her-2 overexpression (93.4%, P = 0.004). (3) The 3-year DFS rate premenopausal patients with Her-2 overexpression was 91.8%, not significantly different from that of those without Her-2 overexpression (92.6%, P > 0.05), however, the 3-year DFS rate of the postmenopausal patients with Her-2 overexpression was 90.4%, significantly lower than that of those without Her-2 overexpression (92.6%, P = 0.010). (4) The 3-year DFS rate of the axillary lymph node-positive patients with Her-2 overexpression was 89.1%, significantly lower than that without Her-2 overexpression (92.3%, P = 0.037). (5) In the premenopausal patients there was no significant difference in the 3-year DFS rate between the lymph node-negative patients with and without Her-2 overexpression (P > 0.05). However, in the postmenopausal lymph node positive patients the 3-year DFS rate of those with Her-2 overexpression was 88.7%, significantly lower than that of those without Her-2 overexpression (92.2%, P = 0.0069). ER and PR are independent factors of Her-2 expression. Her-2 overexpression signifies resistance to TAM treatment. The response to TAM is not influenced by the Her-2 expression and axillary lymph node metastasis status in the premenopausal patients, and is not influenced by the Her-2 expression level in the postmenopausal patients.

Sentinel node identification rate, but not accuracy, is significantly decreased after pre-operative chemotherapy in axillary node-positive breast cancer patients

The aim was to prove the low identification rate of sentinel lymph node biopsy (SNB) and to determine the feasibility of replacing axillary lymph node dissection (AND) in axillary lymph node positive patients after chemotherapy. From October 2001 to July 2005, 875 consecutive patients with primary operable breast cancer underwent SNB and AND. Among them, 238 received pre-operative chemotherapy. We compared the identification rate, false negative rate (FNR), negative predictive value (NPV), and accuracy of SNB in clinically node-positive patients with or without chemotherapy. The identification rate was significantly lower in patients received chemotherapy (77.6%) than in those not received it (97.0%) (P<0.001). In those received the therapy, the FNR was 5.6%, the NPV was 86.8%, and the accuracy was 95.9%. In those not received therapy, the FNR was 7.4% and the accuracy was 92.6% (differences not statistically significant). The identification rate in confirmed axillary lymph node-positive patients was significantly lower in patients received pre-operative chemotherapy, but accuracy did not differ significantly between the two groups. Thus, for patients who achieve complete axillary clearance by chemotherapy, SNB could replace AND.

Breast cancer recurrence dynamics following adjuvant CMF is consistent with tumor dormancy and mastectomy-driven acceleration of the metastatic process

The aim of this study was to better understand human breast cancer biology by studying how the timing of metastasis following primary resection is affected by adjuvant CMF (cyclophoshamide, methotrexate, 5-fluorouracil) chemotherapy. Discrete hazards of recurrence and recurrence risk reductions for treated patients relative to controls were analyzed for all patients enrolled in two separate randomized clinical trials [study 1 (386 women): no further treatment versus 12 cycles of CMF; study 2 (459 women): six versus 12 cycles of CMF] and a historical group (396 women: surgery alone) of axillary node-positive patients undergoing mastectomy. (i) Nearly all CMF benefit occurs during the first 4 years following resection/chemotherapy. (ii) The CMF recurrence rate reduction is largely restricted to two specific spans. These temporally separate recurrence clusters occur during the first and third year of follow-up, while the second-year recurrences are weakly affected. (iii) Prolonging adjuvant treatment from 6 to 12 months partially alters this recurrence timing, without appreciably affecting the overall recurrence rate. (iv) These effects upon the dynamics of post-resection occurrence are menopausal status-independent. At least two different therapeutically vulnerable proliferative events, resulting in clinical appearance of two metastasis temporally distinct clusters of post-resection cancer recurrence, apparently occur during the administration of adjuvant chemotherapy. Metastases that transpire outside of these temporal windows are refractory to adjuvant therapy. The dynamics of both post-treatment recurrence risk and CMF effectiveness are similar for both pre- and postmenopausal women, suggesting that post-resection mechanisms by which chemotherapy prevents metastases are similar, but of different magnitude in pre- and postmenopausal women. These findings are consistent with a metastasis model that includes tumor dormancy in specific micrometastatic phases (single cells and avascular foci) and with the acceleration of the metastatic process by the surgical resection of the primary breast cancer.

Low Levels of Estrogen Receptor β Protein Predict Resistance to Tamoxifen Therapy in Breast Cancer

Breast cancer is a hormone-dependent cancer, and the presence of estrogen receptor alpha (ER-alpha) in tumors is used clinically to predict the likelihood of response to hormonal therapies. The clinical value of the second recently identified ER isoform, called ER-beta, is less clear, and there is currently conflicting data concerning its potential role as a prognostic or predictive factor. To assess whether ER-beta expression is associated with clinical outcome, protein levels were measured by immunoblot analysis of a retrospective bank of tumor cell lysates from 305 axillary node-positive patients. A total of 119 received no adjuvant therapy, and 186 were treated with tamoxifen only. The median follow-up time was 65 months. Univariate and multivariate Cox regression modeling was done to assess the prognostic and predictive significance of ER-beta expression. Expression of ER-beta protein did not correlate significantly with any other clinical variables, including ER and progesterone levels (as measured ligand binding assay), tumor size, age, or axillary nodal status. In the untreated population, those patients whose tumors who expressed both receptor isoforms exhibited the most favorable outcome as compared with those patients who had lost ER-alpha expression. However, there was no association between ER-beta levels alone and either disease-free or overall survival in the untreated patient population. In contrast, in both univariate and multivariate analyses, high levels of ER-beta predicted an improved disease-free and overall survival in patients treated with adjuvant tamoxifen therapy. These findings provide evidence that ER-beta may be an independent predictor of response to tamoxifen in breast cancer. Furthermore, these results suggest that ER-beta may influence tumor progression in ways different from those mediated by the ER-alpha isoform.

The timing of breast cancer recurrence after mastectomy and adjuvant CMF chemotherapy supports a dormancy-based model for metastatic development

9573 Background: Adjuvant chemotherapy may be regarded as a probe revealing features of the metastasis development, by changes induced in the recurrence timing. Methods: Two randomized clinical trials and a historical group of axillary node positive patients undergoing mastectomy, all treated at the Ist. Naz. Tumori of Milan, were analyzed. Study 1 involved 386 women (no further treatment vs. 12 cycles of CMF), Study 2 involved 459 women (6 vs. 12 cycles of CMF) and the historical group involved 575 patients (mastectomy alone). Discrete hazards of early recurrence (over 4 years), and recurrence risk reductions for treated patients relative to controls were estimated. Results: 1) recurrence rate reduction by CMF is mainly restricted to specific, temporally separate recurrence clusters at the first and third year, while the second-year recurrences are weakly affected; 2) prolonging adjuvant treatment from 6 to 12 months partially changes the recurrence timing, without affecting the overall treatment effectiveness; 3) findings are menopausal status independent. Conclusions: At least two different proliferative events, resulting in clinical appearance of the two metastasis clusters, should be assumed as occurring during treatment administration, when some other metastases are in a rather refractory status. The time distributions of both post treatment recurrence risk and CMF effectiveness are similar for both menopausal statuses, suggesting that the metastatic mechanisms may be substantially the same, although differently modulated. Cytotoxic chemotherapy changes differing recurrence dynamics of pre and post menopausal women to a common later recurrence pattern. These findings give further support to a metastasis development model based on tumour dormancy in specific micro-metastatic phases (single cells and avascular foci) and on acceleration of the metastatic process due to surgery. No significant financial relationships to disclose.

Dye-guided sentinel node biopsy revisited; validation and observational study from a single institute.

The aims of this study were to evaluate the feasibility and accuracy of indigocarmine dye-guided sentinel node biopsy and to apply this method to avoid further axillary node dissection in sentinel node negative cases. Sixty consecutive clinically node-negative breast cancer patients underwent sentinel node biopsy using 0.5% indigocarmine followed by standard axillary node dissection. Sentinel node biopsy was then applied to 42 clinically node-negative patients to avoid axillary node dissection with intraoperative diagnosis made by frozen section. Validation study: Sentinel nodes were successfully detected in all 60 patients. The mean number of harvested nodes was 1.7 (range 1-3). Sentinel nodes were positive in all 20 axillary node-positive patients, and therefore the false negative rate was 0% (0/20). Only sentinel nodes contained metastases in 55% (11/20) of node positive patients. Observational study: Sentinel nodes were successfully detected in all 42 patients. The mean number of harvested nodes was 1.6 (range 1-3). Sentinel nodes were positive in 12 patients by final histology, and there was one false negative case by frozen section (8%, 1/12). Only sentinel nodes contained metastases in 55% (6/11) of node positive patients. The detection rate, mean number of harvested sentinel nodes and proportion of node positive patients were similar between the validation and observational studies. Indigocarmine dye-guided sentinel node biopsy was feasible and accurate. This method can be applied to observational studies after successful validation.