Neoadjuvant Chemoendocrine Therapy Research Articles

Abstract OT1-08-01: Concurrent versus sequential chemo-endocrine therapy in er positive and her2 negative non-metastatic breast cancer- an open-label, phase III, randomized controlled trial

Abstract Background-Traditionally, endocrine therapy follows chemotherapy for hormone receptor (HR) positive breast cancer (BC) in the adjuvant setting. Concurrent chemo-hormonal therapy fell into disrepute due to previous studies showing a probable, small detriment in survival. (Albain et al, Lancet, 2009; Bedognetti et al, JNCI, 2009; Pico et al, Ann Oncol, 2004) However, the early studies are fraught with biases. The biological rationale was that endocrine therapy is cytostatic, pushing cancer cells into G0 phase which was feared to reduce the efficacy of chemotherapy which is known to act best on rapidly dividing cells. Thus, the two mechanisms of actions were thought to be antagonistic. However, this fear may be irrational and evidence at molecular level is contradictory. The current sequential strategy delays the start of an equally effective treatment modality in HR+ BC patients. Recent studies have shown that concurrent chemo-endocrine therapy is safe in metastatic HR+ setting. (Sledge et al, J Clin Oncol, 2000) One also needs to rethink neoadjuvant strategies in these patients to improve the current dismal pathological complete response (pCR) rates in this subset. (Cortazar et al, Lancet, 2014) Concurrent treatment seems to have improved pCR rate. (Sagiu K et al, Acta Med Okayama, 2015) Here, we describe a phase III, randomized study aimed to evaluate the efficacy of concurrent chemo-endocrine therapy in the adjuvant and neoadjuvant setting. (CTRI/2018/09/015643) Aims and Objectives- The primary objective is to assess the improvement in disease-free survival by administering concurrent versus sequential, (neo) adjuvant chemo-endocrine therapy in HR+, HER2 negative, non-metastatic BC. The secondary objectives are to assess improvement in overall survival, pCR rates, breast conservation rates. Biomarkers of response to treatment and tumour dormancy in HR+ BC will be studied in a subset of patients.Patients and methods-This is a prospective, open label study where non-metastatic, biopsy proven, HR+, HER2- BC patients who warrant chemotherapy in the adjuvant or neoadjuvant setting are considered. The study started accrual in December 2018 and 285 patients are randomized till date. Pregnant or lactating women and those with inflammatory breast carcinoma are excluded. After obtaining informed consent, patients are randomized to receive concurrent versus sequential chemo-endocrine treatment. Patients will receive all chemo and endocrine therapy as per the institutional standard protocols otherwise. Stratification criteria are neoadjuvant vs adjuvant therapy, pre vs postmenopausal status, node positive vs node negative status, 1st gen (anthracyclines alone) versus 2nd gen (including taxanes) chemotherapy. A two-sided log-rank test with an overall sample size of 2316 (2432 with a 5% dropout rate) (1158 in control and 1158 in treatment group) achieves 80% power at a 0.05 significance level to detect a hazard ratio of 0.80 when the proportion surviving in the control group is 0.70. An interim with respect to safety is planned in the protocol. Expected results and conclusion-Ours is a large, prospective trial evaluating the efficacy of concurrent chemo-endocrine therapy in HR+ BC patients. This has the potential to improve pCR rates in the neoadjuvant setting and change the standard of care in the management of HR+ BC patients. The biomarker analysis will help us further understand the biology of HR+ BC and shed light upon tumour dormancy signatures. Citation Format: Shalaka Joshi, Sridevi Murali-Nanavati, Vaibhav Vanmali, Rohini Hawaldar, Mujahid Gafur Shaikh, Mohammad Sadique Ansari, Sushmita Rath, Jaya Ghosh, Seema Gulia, Jyoti Bajpayi, Nita Nair, Vani Parmar, Purvi Thakkar, Garvit Chitkara, Tanuja Shet, Sangeeta Desai, Ayushi Sahay, Sudeep Gupta, Rajendra Badwe. Concurrent versus sequential chemo-endocrine therapy in er positive and her2 negative non-metastatic breast cancer- an open-label, phase III, randomized controlled trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-08-01.

The tumour response of postmenopausal hormone receptor-positive breast cancers undergoing different types of neoadjuvant therapy: a meta-analysis

BackgroundTo investigate the efficacy of neoadjuvant chemotherapy (NCT), neoadjuvant endocrine therapy (NET) and neoadjuvant chemoendocrine therapy (NCET) on the tumour response, including pathological complete response (pCR) rate and overall response rate (ORR), in postmenopausal women with hormone receptor (HR)-positive breast cancer.MethodsBased on a PRISMA-IPD statement, the PubMed, Embase and Cochrane Library databases were used to identify eligible trials published from inception to 7 May 2019. Pooled odds ratio (OR) with 95% confidential interval (CI) was calculated to assess the pCR rate and ORR of tumours among those three treatments via fixed- or random-effect Mantel-Haenszel models in terms of a Heterogeneity Chi2 test with a significant level of p < 0.1. All statistical tests were performed by the software of StataSE, version 12.0.ResultsThe analysed data consisted of 10 eligible clinical trials with 971 unique HR-positive breast cancer patients. The pooled results indicated that the pCR rate of those patients undergoing NET was significantly lower than those undergoing NCT (pooled OR, 0.48; 95% CI, 0.26–0.90), whereas the difference of ORR between both therapies was not statistically significant (pooled OR, 1.05; 95% CI, 0.73–1.52). The combined paradigm of NCET compared with the monotherapy of NET or NCT did not present a significantly improved pCR rate or ORR (pooled OR, 2.61; 95% CI, 0.94–7.25; and 2.25; 95% CI, 0.39–13.05; respectively).ConclusionPostmenopausal HR-positive breast cancer patients after NCT may have better tumour response than those after NET, while those undergoing NCET may not manifest the apparently improved clinical efficacies compared to those receiving monotherapy.

COX Inhibition and Biomarkers During Neoadjuvant Chemoendocrine Therapy for ER+, HER2- Stage I-III Breast Cancer

COX Inhibition and Biomarkers During Neoadjuvant Chemoendocrine Therapy for ER+, HER2- Stage I-III Breast Cancer

Utility of Ki67 labeling index, cyclin D1 expression, and ER-activity level in postmenopausal ER-positive and HER2-negative breast cancer with neoadjuvant chemo-endocrine therapy.

In this study, we investigated the relationships of pathological response after neoadjuvant chemo-endocrine therapy with alterations in the Ki67 labeling index (LI), expression of cyclin D1 (CCND1) and progesterone receptor (PgR), and estrogen receptor (ER) activity in breast cancer. A total of 43 Japanese post-menopausal ER-positive and human epidermal growth factor receptor 2-negative invasive breast cancer patients with tumors >2 cm or positive lymph nodes were enrolled. Exemestane alone was administered for 2 months. Neoadjuvant chemo-endocrine therapy included four cycles of doxorubicin plus paclitaxel followed by weekly paclitaxel. The immunohistochemical expression of Ki67 LI, CCND1, and PgR, and ER activity were evaluated using core needle biopsy samples at the pretreatment and post-exemestane alone stages. ER activity was evaluated through transfection of an adenovirus vector carrying an estrogen-response element-green fluorescent protein gene. In current study, marked pathological responses (including 4.7% with pathological complete response) were obtained in 34.9% of patients. Ki67 LI and PgR expression were significantly decreased after treatment. High Ki67 LI at pretreatment was a significant predictive factor of marked pathological response. At the stage of post-exemestane alone, Ki67 LI was not significantly associated with pathological response; however, high CCND1 expression was significantly correlated with high Ki67 LI. Moreover, low-level ER activity at the post-exemestane alone stage was significantly associated with marked pathological response. In conclusions, pretreatment Ki67 LI was a predictor of response to neoadjuvant chemo-endocrine therapy. CCND1 expression and ER activity at the post-endocrine therapy alone stage may be useful in determining further treatments.

Concurrent neoadjuvant chemotherapy and estrogen deprivation in patients with estrogen receptor–positive, human epidermal growth factor receptor 2–negative breast cancer (CBCSG‐036): A randomized, controlled, multicenter trial

The current randomized, controlled, multicenter clinical trial was conducted to investigate the efficacy of concurrent neoadjuvant chemotherapy (NCT) and estrogen deprivation in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Eligible patients with AJCC stage IIB to stage IIIC, ER-positive, HER2-negative breast cancer were enrolled and randomly assigned to receive NCT with or without estrogen deprivation. The primary endpoint was the objective response rate (ORR). A total of 249 patients were assigned to either neoadjuvant chemoendocrine therapy (NCET) (125 patients) or the NCT group (124 patients). In the intention-to-treat analysis, the ORR was found to be significantly higher in the NCET group compared with the NCT group (84.8% vs 72.6%; odds ratio, 2.11 [95% CI, 1.13-3.95; P=.02). The efficacy of NCET was more prominent in tumors with a higher Ki-67 index (>20%), with an ORR of 91.2% reported in the NCET group versus 68.7% in the NCT group (P=.001). The pathologic complete response and pathological response rates did not differ significantly between the 2 groups. Although there was no significant difference with regard to progression-free survival (PFS) between the 2 groups (P=.188), patients with a higher baseline Ki-67 index appeared to derive a greater PFS benefit from NCET (2-year PFS rate of 91.5% in the NCET group vs 76.5% in the NCT group; P=.058). Adding endocrine agents to NCT did not result in significant differences in adverse events (grade 3 or 4; graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) between the 2 groups. The addition of estrogen deprivation to NCT appears to improve the clinical response in patients with ER-positive, HER2-negative breast cancer, especially for those individuals with a higher Ki-67 index. Patients with a higher Ki-67 index might derive more PFS benefit from concurrent neoadjuvant treatment.

Abstract P4-14-07: Neoadjuvant exemestane or exemestane plus docetaxel and cyclophosphamide tailored by clinicopathological response to 8–12 weeks' exemestane exposure for ER+/HER2– postmenopausal breast cancer patients

Abstract Aim To investigate the efficacy and safety of initial neoadjuvant endocrine therapy with exemestane (EXE) alone followed by tailored treatment: continued EXE monotherapy for responders or EXE plus docetaxel–cyclophosphamide (TC) combination therapy for non-responders. Methods This open-label phase II study enrolled postmenopausal patients with primary invasive estrogen receptor (ER)-positive, HER2-negative, stage I–IIIA (T1c–T3 N0–2 M0) breast cancer and Ki67 index ≤30%. Patients first received EXE 25 mg/day for 12 weeks. Based on clinical response and change in Ki67 index, responders were defined as patients who achieved complete response (CR), partial response (PR) with Ki67 index ≤5% after treatment, or stable disease (SD) with Ki67 index ≤5% both before and after treatment. Non-responders were defined as patients with PR and Ki67 index &amp;gt;5% after treatment, or SD and Ki67 index &amp;gt;5% before or after treatment. For the subsequent 12 weeks, responders continued EXE monotherapy (continued EXE group) and non-responders received EXE plus 4 cycles of TC (docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks) (EXE+TC group). Primary endpoint was clinical response (CR and PR) at week 24. Results A total of 58 patients (median age 60 years, range 53–67 years) were enrolled between December 2010 and May 2016. Five patients discontinued treatment in the initial 12-week EXE monotherapy period; therefore 53 received the subsequent treatment. After 8–12 weeks of initial EXE monotherapy, 15 patients were classified as responders (8 with PR and Ki67 index ≤5% after treatment, 7 with SD and Ki67 index ≤5% before and after treatment) and 38 as non-responders (5 with PR and Ki67 index &amp;gt;5% after treatment, 33 with SD and Ki67 index &amp;gt;5% before or after treatment). Clinical response rates at weeks 12 and 24 were 71% (10/14, 95%CI 41.9–91.6%) and 57% (8/14, 95%CI 28.9–82.3%), respectively, in the continued EXE group, and 16% (4/25, 95%CI 4.5–36.1%) and 56% (14/25, 95%CI 34.9–75.6%), respectively, in the EXE+TC group. At week 24, no significant difference was found in median Ki67 index between the continued EXE and EXE+TC groups (1.4% and 2.0%, respectively). The proportion of patients with preoperative endocrine prognostic index (PEPI) 0 was higher in the continued EXE than in the EXE+TC group (60% vs 29%), but not significantly so (P=0.058, Fisher's exact test). The breast-conserving surgery rate was 93% and 56% (continued EXE and EXE+TC groups, respectively). Adverse events (AEs) ≥grade 3 were reported in 40% (21/53) of patients (continued EXE group 8%, 1/15; EXE+TC group 53%, 20/38). The most common AEs were leukopenia (37%, 14/38), neutropenia (32%, 12/38), and febrile neutropenia (16%, 6/38) during chemotherapy (EXE+TC group). Conclusion Tailored treatment maintained the favorable clinical response to EXE alone in responders and improved subsequent clinical response in non-responders. EXE+TC was associated with higher incidence of hematological AEs, but these were manageable. The results show the effectiveness of tailored neoadjuvant endocrine and chemoendocrine therapy in postmenopausal ER-positive breast cancer patients. (JBCRG-11TC; UMIN000004752) Citation Format: Yasojima H, Sato N, Masuda N, Morimoto T, Ueno T, Kanbayashi C, Kaneko K, Saji S, Sasano H, Morita S, Ohno S, Toi M. Neoadjuvant exemestane or exemestane plus docetaxel and cyclophosphamide tailored by clinicopathological response to 8–12 weeks' exemestane exposure for ER+/HER2– postmenopausal breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-07.

Abstract P3-13-06: Tailored neoadjuvant endocrine and chemo-endocrine therapy for postmenopausal patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative primary breast cancer

Abstract Aims We investigated the efficacy and safety of initial neoadjuvant endocrine therapy with exemestane (EXE) alone followed by subsequent tailored treatment with EXE alone for responders or EXE plus oral metronomic cyclophosphamide (CPA) for non-responders. Methods In this multicenter open-label phase II study, we enrolled postmenopausal patients with primary invasive estrogen receptor (ER)-positive, HER2-negative, stage I–IIIA (T1c–T3 N0–2 M0) breast cancer and Ki67 index ≤ 30%. Patients first received EXE 25mg/day for 12 weeks. Based on clinical response and change in Ki67 index in response to the initial therapy, patients who achieved complete response (CR), partial response (PR) with Ki67 index ≤5% after treatment, or stable disease (SD) with Ki67 index ≤5% both before and after treatment were defined as responders. Non-responders were defined as patients with PR and Ki67 index &amp;gt;5% after treatment, or SD and Ki67 index &amp;gt;5% before or after treatment. For the subsequent 24 weeks, responders continued the EXE monotherapy (continued EXE group), whereas non-responders switched to combination therapy with EXE plus CPA 50mg/day (EXE+CPA group). The primary endpoint was clinical response (CR and PR) at weeks 24 and 36. Results A total of 59 patients (median age 69 years, range 53–86 years) were enrolled between January 2011 and July 2015. After exclusion of 3 (2 with progressive disease, 1 with an adverse event, AE) who discontinued treatment in the initial 12-week EXE monotherapy period, 56 remained enrolled to receive subsequent treatment. After 8–12 weeks of the initial EXE monotherapy, 14 patients were classified as responders (9 with PR and Ki67 index ≤5% after treatment; 5 with SD and Ki67 index ≤5% before and after treatment), whereas 42 were classified as non-responders (3 with PR and Ki67 index &amp;gt;5% after treatment; 39 with SD and Ki67 index &amp;gt;5% before or after treatment). Clinical response rates at weeks 24 and 36 were 85% (12/14, 95%CI 57.2–98.2%) and 76% (10/13, 95%CI 46.2–95.0%), respectively, in the continued EXE group, and 56% (23/41, 95%CI 39.7–71.5%) and 76% (30/39, 95%CI 60.7–88.9%), respectively, in the EXE+CPA group. At week 36, no significant difference was found in median Ki67 index between the continued EXE and EXE+CPA groups (3.5% and 4.0%, respectively). The proportion of patients with preoperative endocrine prognostic index (PEPI) 0 was also similar between the continued EXE and EXE+CPA groups (21.4% and 23.8%, respectively). The breast-conserving surgery rate was 71.4% and 69.0%, respectively. Grade 3 AEs were elevated liver enzymes (1 patient) in the continued EXE group, and gastritis, hypertriglyceridemia, and bone mineral density loss (1 patient each) in the EXE+CPA group. Conclusion Switching from EXE monotherapy to EXE+CPA combination therapy based on clinical response and biological response (change in Ki67 index) to initial therapy improved subsequent clinical response in non-responders. Favorable clinical response to EXE alone was maintained in responders. Tailored neoadjuvant endocrine and chemo-endocrine therapy was shown to be effective in postmenopausal ER-positive breast cancer patients. (JBCRG-11CPA; UMIN000004751) Citation Format: Masuda N, Sato N, Morimoto T, Ueno T, Kanbayashi C, Kaneko K, Yasojima H, Saji S, Sasano H, Morita S, Ohno S, Toi M. Tailored neoadjuvant endocrine and chemo-endocrine therapy for postmenopausal patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative primary breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-13-06.

Abstract P3-01-05: The use of Tc-99 tilmanocept in sentinel lymph node biopsy after neoadjuvant chemotherapy in clinically node-negative patients with breast cancer

Abstract Background: Neoadjuvant chemotherapy (NAT) has been shown to induce fibrosis and inflammation that alters lymphatic drainage of axillary lymph nodes in breast cancer. Technetium- 99 Tilmanocept (TcTM), a CD206-macrophage receptor targeted radiopharmaceutical, is a small agent with recent FDA-approval for lymphatic mapping. No prior studies have investigated the use of TcTM in the neoadjuvant setting. The aim of this study was to compare the identification rate, node-positivity rate, and number of total nodes evaluated in sentinel lymph node (SLN) biopsy with TcTM and vital blue dye (VBD) in clinically node-negative patients receiving NAT vs. initial surgery. Methods: A retrospective review was conducted on patients undergoing SLN biopsy with TcTM and VBD from May 2013- May 2015 at UCSD. Patients with a history of prior SLN biopsy or axillary lymph node dissection were excluded. Patients undergoing neoadjuvant chemotherapy or receiving &amp;gt; 3 months of neoadjuvant endocrine therapy were grouped and compared to patients undergoing initial surgical treatment. The SLN identification and node-positivity rates were compared with the X2 test. To compare the number of SLNs evaluated between groups, a zero-truncated negative binomial (ZTNB) count model was constructed to assess the effect of NAT and other covariates on the SLN count. Covariates included age, body mass index (BMI), gender, surgeon, mastectomy vs. lumpectomy, node positivity, pathologist, T-stage, and receptor status. A p-value &amp;lt; 0.05 was used for statistical significance. Results: Of the 417 total SLN cases identified, 72 (17.2%) cases were in patients who had received NAT (61- chemo, 11- endocrine). The SLN identification rate was 100% in both groups (p= 1.0). Overall, there were 68 (16.3%) cases of SLN-positivity, 14 (19.4%) in the NAT group versus 54 (15.7%) in the non-NAT group (p= 0.54). The median number of identified nodes was 3 in both groups. In the ZTNB count model, age, surgeon and evaluating pathologist were significant predictors of the total number of SLN evaluated. The use of NAT did not significantly affect the number SLNs evaluated. Incident rate ratios, confidence intervals and p-values are reported in the attached table. Sentinel Lymph Node Count ModelVariabeIRR95% CI LL95% CI ULp-valueAge per 5 years0.960.930.990.03Surgeon #21.231.051.450.01NAT1.140.921.410.22Pathologist #20.720.570.900.005Pathologist #31.010.841.220.90Pathologist #40.930.661.320.70IRR: incident rate ratio, NAT: neoadjuvant chemoendocrine therapy, CI: confidence interval, LL: lower limit, UL: upper limit Discussion: Prior studies have indicated that NAT may induce fibrosis and inflammation that may obscure lymphatic mapping procedures. For SLN biopsy with TcTM in VBD in our study, the use of NAT did not change the identification rate or node-positivity rate. Additionally, when controlling for covariates, the use of NAT did not change the total number of SLNs evaluated. While NAT might induce fibrosis and inflammation, SLN biopsy with TcTM and VBD is technically successful in clinically node-negative patients undergoing neoadjuvant chemotherapy. Citation Format: Unkart JT, Wallace AM. The use of Tc-99 tilmanocept in sentinel lymph node biopsy after neoadjuvant chemotherapy in clinically node-negative patients with breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-01-05.

Pathology of Breast Carcinomas After Neoadjuvant Chemotherapy: An Overview With Recommendations on Specimen Processing and Reporting

Currently, more women are being treated with chemotherapy or hormonal agents before surgery (neoadjuvant chemoendocrine therapy) for earlier-stage operable breast carcinoma. The pathologic examination of these specimens can be quite challenging. To give an overview of (1) pathologic changes that occur during treatment, (2) systems for evaluating response to treatment, and (3) recommendations for pathologic examination and reporting of such cases. The recommendations are based on the review of selected literature on breast carcinoma after neoadjuvant therapy and the authors' personal experience with the clinical and pathologic characteristics of cases from each of the authors' own institutions. Pathologists play a key role in the evaluation of pathologic response, which is extremely important as a prognostic factor for individual patients, as a short-term endpoint for clinical trials, and as an adjunct for research studies. Therefore, surgical pathologists must be familiar with the gross examination, sampling, and reporting of breast carcinomas after neoadjuvant therapy.

Good clinical response of breast cancers to neoadjuvant chemoendocrine therapy is associated with improved overall survival

BackgroundWe present extended follow-up from a prospective randomised trial evaluating the role of neoadjuvant chemoendocrine therapy in the treatment of operable breast cancer. Patients and methods309 women were randomised to primary surgery followed by eight cycles of adjuvant mitoxantrone, methotrexate with tamoxifen (2MT) or 2MT with mitomycin-C (3MT) versus the same regimen for four cycles before followed by four cycles after surgery. For this analysis the median follow-up of patients was 112 months. ResultsAfter 10 years follow-up there is still no statistically significant difference in disease-free survival (DFS) (71% versus 71%) or overall survival (OS) (63% versus 70%) when comparing adjuvant versus neoadjuvant treatment, respectively. Of 144 evaluable patients in the neoadjuvant arm, 74 achieved a good clinical response and 70 patients achieved a poor clinical response. Good responders had a superior DFS (80% versus 64%, P=0.01) and OS (77% versus 63%, P=0.03) compared to poor responders. ConclusionsAt 10 years, neoadjuvant and adjuvant treatment continue to have equivalent OS and DFS. Good clinical response to neoadjuvant chemotherapy is associated with superior DFS and OS. This supports the use of clinical response of primary breast cancer to neoadjuvant therapy as a surrogate marker of survival benefit.

Estrogen-receptor-directed neoadjuvant therapy for breast cancer: Results of a randomised trial using formestane and methotrexate, mitozantrone and mitomycin C (MMM) chemotherapy

We wanted to determine whether neoadjuvant systemic chemoendocrine therapy guided by the estrogen receptor (ER) status of the primary breast cancer, followed by conventional surgery and/or radiotherapy, reduces local and distant recurrence and improves survival compared with adjuvant treatment given conventionally postoperatively. Two hundred ten patients with primary breast cancer (T1-T4, N0, N1-2) were randomised to receive treatment with neoadjuvant chemoendocrine therapy or conventional post-operative chemoendocrine therapy. Systemic therapy was based on the estrogen receptor (ER) status of the primary tumour obtained by trucut core biopsy. ER-negative patients received MMM chemotherapy (methotrexate (30 mg/m2), mitozantrone (7 mg/m2) and mitomycin (7 mg/m2) three-weekly for three months and ER-positive patients who were premenopausal received goserelin (3.75 mg monthly), and post menopausal women formestane (250 mg every two weeks) over three months. With a minimum of five years follow-up, there is no evidence of any survival benefit from the pretreatment neoadjuvant therapy regimen, with five year overall survival being 79% +/- 4.7% (neoadjuvant) and 87% +/- 3.4% (adjuvant). Similarly, there was no apparent benefit in terms of disease-free survival. There was, however, a significant reduction in the incidence of distant metastases in responders (4 of 51; 8%) compared with non-responders (17 of 49; 35%) (P < 0.01). There was a reduction in the need for surgery in responding patients with T1 and T2 tumours, since 10 of 74 (14%) had no detectable residual tumour, without any apparent increase in the risk of local or distant recurrence. In this study neoadjuvant treatment with endocrine or chemotherapy provided no obvious survival benefit to women with breast cancer. However, it does allow avoidance of surgery in some cases. Also, the patients whose tumours respond to neoadjuvant systemic therapy have a lower incidence of distant metastases after five year follow-up compared to those whose tumours fail to respond.

Axillary lymph node scarring and the association with tumour response following neoadjuvant chemoendocrine therapy for breast cancer

We observed that the axillary lymph nodes of some of our breast cancer patients who received neoadjuvant chemoendocrine therapy (NCT) showed evidence of scarring. The purpose of this study is to determine whether such scarring exists and, if so, whether it is confined to neoadjuvant patients and may be related to response to therapy of the primary tumour. We examined the axillary lymph nodes of a consecutive series of 255 breast cancer patients, all of whom had undergone radical axillary dissection. Fifty-three had received NCT; the remainder formed the control group. A scar was defined as an area of cellular fibrous tissue>0.25 mm in diameter and for each patient scar count, median size and score were recorded. Nodes with scars were stained immunohistochemically (IHC) with 2 epithelial markers for the presence of occult micrometastases. The nodes of 20.7% of patients who had received NCT contained scars compared with 13.4% of controls. The median scar size was significantly greater in neoadjuvant patients (P<0.001) and within this group scar count and score were significantly higher (P=0.026 and 0.020) in those with no or minimal evidence of residual primary tumour. Scars which were IHC-positive for micrometastases were almost exclusively confined to neoadjuvant patients. Our results suggest that axillary lymph node scarring does exist, but is not a common phenomenon. It is more significant in neoadjuvant patients and within this group is most marked in those with the greatest primary tumour response to therapy. We believe that scarring is likely to represent downstaging of axillary disease. A prospective study involving a larger group of patients receiving NCT is indicated, to confirm these preliminary findings and establish whether scarring has prognostic or predictive potential.

Reduction in angiogenesis after neoadjuvant chemoendocrine therapy in patients with operable breast carcinoma

BACKGROUND The intensity of angiogenesis, as measured by microvessel density, is a strong independent predictor of survival in breast carcinoma patients. The impact of chemotherapy and/or endocrine therapy on this process is unknown. METHODS Histologic samples from patients randomized to a trial of neoadjuvant (NEO) versus adjuvant (ADJ) chemoendocrine therapy for operable breast carcinoma were obtained. Samples from 195 patients (90 NEO samples and 105 ADJ samples) were analyzed. Immunostaining was performed with the CD34 monoclonal antibody and the scoring of microvessels was performed using the Chalkley method. RESULTS The median score of the NEO patients was 5.7 (95% confidence interval [CI], 5.3-6.0) and the median score of the ADJ patients was 6.3 (95% CI, 6-6.7) (P = 0.025). Using previously validated scoring categories, there were fewer samples with a poor prognosis (score ≥ 7) in the NEO group (26%) compared with the ADJ group (32%) (P = 0.04). CONCLUSIONS The results of the current study suggest that NEO chemoendocrine therapy causes a reduction in microvessel density in primary breast carcinomas, which could be secondary to tumor regression or due to a direct effect on angiogenesis. Cancer 1999;85:1996–2000. © 1999 American Cancer Society.

A reduction in the requirements for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in primary breast cancer

A prospective randomised trial was undertaken to evaluate the role of neoadjuvant chemoendocrine therapy prior to surgery in primary operable breast cancer. Three hundred nine women (median age 56 years, range 27-70) with primary operable breast cancer confirmed on fine needle aspiration (FNA) cytology were recruited to this study. They were treated with a combination of mitozantrone and methotrexate (+/- mitomycin-C) combined with tamoxifen (2MT). Patients received eight cycles of 2MT (four prior to surgery in the neoadjuvant group) and tamoxifen for five years with appropriate surgery and radiotherapy. The two groups were comparable for age, menopausal status, stage and surgical requirements. The clinical response rates to neoadjuvant therapy were as follows: 22% complete response (CR), 29% minimal residual disease (MRD), 33% partial response (PR), 15% no change (NC) and only two patients had clinical evidence of progressive disease. Surgical requirements were reduced from 31 patients (22%) of the adjuvant group having mastectomy to 14 (10%) in the neoadjuvant group (P < 0.003). At a median follow-up of 48 months (range 10-70 months) there is no statistically significant difference between the two groups in terms of local relapse, metastatic relapse or overall survival. Symptomatic and haematologic acute toxicity was low and similar for adjuvant and neoadjuvant therapy. This randomised trial has shown a significant reduction in the surgical requirements for mastectomy, after treatment with neoadjuvant chemoendocrine therapy, with no deterioration in local or distal relapse.

52 Rates of local recurrence with neoadjuvant chemoendocrine therapy for primary breast cancer

Breast conservation surgery for early breast cancer is associated with equivalent survival, but higher rates of local relapse than mastectomy. Pathological margin status and EIC are major determinants of relapse risk. In a randomised trial of chemoendocrine therapy administered either prior to or following primary surgery and radiotherapy, we have assessed neoadjuvant and adjuvant regimens on rates of loco-regional relapse. The first 200 patients (≤age 70 years) with operable stage I and II breast cancer diagnosed on fine needle aspirate have been analysed. Those in the adjuvant group received 6 months of chemotherapy together with tamoxifen (continued for 5 years) whilst 3 months of chemoendocrine therapy before and after appropriate surgery and radiotherapy was given as a neoadjuvant schedule. Overall clinical response rates for the latter have been high (85%), and at a median follow up of 28 months, only 4 patients have relapsed locally in either the breast (2 adjuvant, 1 neoadjuvant) or axilla (1 adjuvant). Lower rates of recurrence have occurred in the neoadjuvant group despite a greater proportion of positive pathological margins (28% neoadjuvant, 24% adjuvant). Tumour grade and extent of DCIS were similar for the two groups ( P > 0.05), with significantly more rumours ≤2 cm present in the neoadjuvant group ( P

668 P53 Mutation and chemosensitivity in breast cancer patients

Mutations of the p53 tumour suppressor gene are the commonest genetic change in breast cancer patients. There are theoretical arguments for both increased and decreased chemosensitivity in tumours with mutated p53. We have investigated the relationship between p53 status and clinical response of the tumour to neoadjuvant chemoendocrine therapy (prior to surgery) in 57 patients with primary breast cancer. AH these patients received 4 cycles of chemotherapy with mitozantrone 11 mg/m 2 and methotrexate 35 mg/m 2 together with tamoxifen 20 mg daily prior to surgery. FNAs were taken from these patients prior to treatment and cytospin slides were prepared. Enzyme immunocytochemistry for p53 was performed using a cocktail of antibodies, (PAbl801 and PAb240 as supplied by DAKO). According to UICC criteria, of 36 patients with p53 −ve tumours 29 (80%) had an objective response (CR or PR) compared to 21 patients with p53 + ve tumours of whom 16 (76%) had an objective response ( P > 0.1). The remaining 12 patients ail had stable disease prior to surgery. We have thus found no significant correlation between expression of p53 protein and clinical response to chemoendocrine therapy. This indicates a lack of correlation between p53 mutation and chemosensitivity although an interaction with tamoxifen in our combined endocrine chemotherapy cannot be excluded with these data.

36. Rates of local recurrence with neoadjuvant chemoendocrine therapy for primary breast cancer J. R. Benson, T. J. Powles, A. Makris, G. Knee,

36. Rates of local recurrence with neoadjuvant chemoendocrine therapy for primary breast cancer J. R. Benson, T. J. Powles, A. Makris, G. Knee,