Florentia Peintinger

Measurement of Residual Breast Cancer Burden to Predict Survival After Neoadjuvant Chemotherapy

PURPOSE To measure residual disease after neoadjuvant chemotherapy in order to improve the prognostic information that can be obtained from evaluating pathologic response. PATIENTS AND METHODS Pathologic slides and reports were reviewed from 382 patients in two different treatment cohorts: sequential paclitaxel (T) then fluorouracil, doxorubicin, and cyclophosphamide (FAC) in 241 patients; and a single regimen of FAC in 141 patients. Residual cancer burden (RCB) was calculated as a continuous index combining pathologic measurements of primary tumor (size and cellularity) and nodal metastases (number and size) for prediction of distant relapse-free survival (DRFS) in multivariate Cox regression analyses. RESULTS RCB was independently prognostic in a multivariate model that included age, pretreatment clinical stage, hormone receptor status, hormone therapy, and pathologic response (pathologic complete response [pCR] v residual disease [RD]; hazard ratio = 2.50; 95% CI 1.70 to 3.69; P < .001). Minimal RD (RCB-I) in 17% of patients carried the same prognosis as pCR (RCB-0). Extensive RD (RCB-III) in 13% of patients was associated with poor prognosis, regardless of hormone receptor status, adjuvant hormone therapy, or pathologic American Joint Committee on Cancer stage of residual disease. The generalizability of RCB for prognosis of distant relapse was confirmed in the FAC-treated validation cohort. CONCLUSION RCB determined from routine pathologic materials represented the distribution of RD, was a significant predictor of DRFS, and can be used to define categories of near-complete response and chemotherapy resistance.

High Risk of Recurrence for Patients With Breast Cancer Who Have Human Epidermal Growth Factor Receptor 2–Positive, Node-Negative Tumors 1 cm or Smaller

PURPOSE To evaluate the risk of recurrence in women diagnosed with T1a and T1b, node-negative, human epidermal growth factor receptor 2 (HER2) -positive breast cancer. METHODS We reviewed 965 T1a,bN0M0 breast cancers diagnosed at our institution between 1990 and 2002. Dedicated breast pathologists confirmed HER2 positivity if 3+ by immunohistochemistry or if it had a ratio of 2.0 or greater by fluorescence in situ hybridization (FISH). Patients who received adjuvant chemotherapy or trastuzumab were excluded. Kaplan-Meier product was used to calculate recurrence-free survival (RFS) and distant recurrence-free survival (DRFS). Cox proportional hazard models were fit to determine associations between HER2 status and survival after adjustment for patient and disease characteristics. Additionally, 350 breast cancers from two other institutions were used for validation. RESULTS Ten percent of patients had HER2-positive tumors. At a median follow-up of 74 months, there were 72 recurrences. The 5-year RFS rates were 77.1% and 93.7% in patients with HER2-positive and HER2-negative tumors, respectively (P < .001). The 5-year DRFS rates were 86.4% and 97.2% in patients with HER2-positive and HER2-negative tumors, respectively (P < .001). In multivariate analysis, patients with HER2-positive tumors had higher risks of recurrence (hazard ratio [HR], 2.68; 95% CI, 1.44 to 5.0; P = .002) and distant recurrence (HR, 5.3; 95% CI, 2.23 to 12.62; P < .001) than those with HER2-negative tumors. Patients with HER2-positive tumors had 5.09 times (95% CI, 2.56 to 10.14; P < .0001) the rate of recurrences and 7.81 times (95% CI, 3.17 to 19.22; P < .0001) the rate of distant recurrences at 5 years compared with patients who had hormone receptor-positive tumors. CONCLUSION Patients with HER2-positive T1abN0M0 tumors have a significant risk of relapse and should be considered for systemic, anti-HER2, adjuvant therapy.

Residual Ductal Carcinoma In Situ in Patients With Complete Eradication of Invasive Breast Cancer After Neoadjuvant Chemotherapy Does Not Adversely Affect Patient Outcome

PURPOSE To determine whether residual ductal carcinoma in situ (DCIS) after completion of preoperative chemotherapy affects the outcome of patients with histologically defined complete eradication of invasive cancer. PATIENTS AND METHODS Retrospective analysis of a database including 2,302 breast cancer patients treated with neoadjuvant chemotherapy at The University of Texas M.D. Anderson Cancer Center between 1980 and 2004 was performed. The overall survival (OS), disease-free survival (DFS), and local recurrence-free survival were compared for patients with no residual invasive or in situ cancer (pathologic complete response [pCR]) and patients with no residual invasive cancer but persistent in situ disease (pCR+DCIS). RESULTS The mean follow-up time was 250 months. Of the 2,302 treated patients, 78 (3.4%) had pCR, 199 (8.6%) had pCR+DCIS, and 2,025 (88%) had residual invasive cancer. For patients with pCR and pCR+DCIS, the 5-year DFS rates (87.1% in both groups) and 10-year DFS rates (81.3% v 81.7%, respectively) were similar; the 5-year OS rates (91.9% v 92.5%, respectively) and 10-year OS rates (91.8% v 92.5%, respectively) were also similar and significantly better than the rate of patients with residual invasive cancer (74.4%; P < .001). The 5-year locoregional recurrence-free survival rates were also not different between patients with pCR (92.8%; 95% CI, 86.1% to 96.4%) and patients with pCR+DCIS (90.9%; 95% CI, 77.3% to 96.5%; P = .63). CONCLUSION Residual DCIS in patients who experience complete eradication of the invasive cancer in the breast and lymph nodes does not adversely affect survival or local recurrence rate. Inclusion of patients with residual DCIS in the definition of pCR is justified when this outcome is used as an early surrogate for long-term survival.

Genomic Index of Sensitivity to Endocrine Therapy for Breast Cancer

PURPOSE We hypothesize that measurement of gene expression related to estrogen receptor α (ER; gene name ESR1) within a breast cancer sample represents intrinsic tumoral sensitivity to adjuvant endocrine therapy. METHODS A genomic index for sensitivity to endocrine therapy (SET) index was defined from genes coexpressed with ESR1 in 437 microarray profiles from newly diagnosed breast cancer, unrelated to treatment or outcome. The association of SET index and ESR1 levels with distant relapse risk was evaluated from microarrays of ER-positive breast cancer in two cohorts who received 5 years of tamoxifen alone as adjuvant endocrine therapy (n = 225 and 298, respectively), a cohort who received neoadjuvant chemotherapy followed by tamoxifen and/or aromatase inhibition (n = 122), and two cohorts who received no adjuvant systemic therapy (n = 208 and 133, respectively). RESULTS The SET index (165 genes) was significantly associated with distant relapse or death risk in both tamoxifen-treated cohorts (hazard ratio [HR] = 0.70, 95% CI, 0.56 to 0.88, P = .002; and HR = 0.76, 95% CI, 0.63 to 0.93, P = .007) and in the chemo-endocrine-treated cohort (HR = 0.19; 95% CI, 0.05 to 0.69, P = .011) independently from pathologic response to chemotherapy, but was not prognostic in two untreated cohorts. No distant relapse or death was observed after tamoxifen alone if node-negative and high SET or after chemo-endocrine therapy if intermediate or high SET. CONCLUSION The SET index of ER-related transcription predicted survival benefit from adjuvant endocrine therapy, not inherent prognosis. Prior chemotherapy seemed to enhance the efficacy of adjuvant endocrine therapy related to SET index.

Impact of Preoperative Versus Postoperative Chemotherapy on the Extent and Number of Surgical Procedures in Patients Treated in Randomized Clinical Trials for Breast Cancer

Objective:To determine the effect of preoperative chemotherapy on the volume of tissue excised and the number of breast operations in patients undergoing breast-conserving therapy (BCT). Summary Background Data:Preoperative chemotherapy is increasingly being used for breast cancer and increases rates of BCT. Its impact on the extent of surgery and the number of surgical procedures in BCT has never been fully defined. The extent of surgery in BCT directly affects cosmesis. Methods:We reviewed the records of 509 consecutive patients with T1–T3, N0–N2 breast cancer who were treated in prospective randomized clinical trials of chemotherapy between 1998 and 2005. We analyzed the final surgical procedure (BCT or mastectomy), the number of operations, and, in patients who underwent BCT, re-excision rates, and the total volume of breast tissue excised [4Π/3(width/2 × length/2 × height/2)]. Results:A total of 241 patients underwent BCT, and 268 patients underwent mastectomy. Among BCT patients who had initial tumor size >2.0 cm, patients who received preoperative chemotherapy had significantly smaller volumes of breast tissue excised compared with patients who received postoperative chemotherapy (113 cm3 vs. 213 cm3, P = 0.004). The re-excision rate and total number of breast operations did not significantly differ between the groups. Among BCT patients who had initial tumor size ≤2 cm, preoperative chemotherapy had no impact on volume of breast tissue excised, re-excision rate, or number of breast operations (P > 0.05). Conclusions:Among patients treated with BCT for larger breast tumors, patients treated with preoperative chemotherapy have less extensive resection, with no change in rates of re-excision.

Local Recurrence Rates in Breast Cancer Patients Treated with Intraoperative Electron-Boost Radiotherapy Versus Postoperative External-Beam Electron-Boost Irradiation A Sequential Intervention Study

Background and Purpose:The purpose of this sequential intervention study was to determine the rate of local recurrences and the rate of distant metastases in patients with invasive breast cancer who had been treated with breast-conserving surgery and postoperative radiation therapy to the whole breast either with postoperative electron boost in group 1 or with intraoperative electron boost (IORT) in group 2.Patients and Methods:After breast-conserving surgery, 378 women with invasive breast cancer of tumor sizes T1 and T2 received 51–56.1 Gy of postoperative radiation therapy to the whole breast in 1.7-Gy fractions. 188 of those patients additionally received a postoperative electron boost of 12 Gy in group 1 from January 1996 to October 1998. Consecutively, from October 1998 to March 2001, 190 patients received intraoperative electron-boost radiotherapy of 9 Gy to the tumor bed in group 2. The groups were comparable with regard to age, menopausal status, tumor size, grading, and nodal status. All statistical tests were twosided.Results:During a median follow-up period of 55.3 months in group 1 and 25.8 months in group 2, local recurrences were observed in eight of 188 patients (4.3%) in group 1, and no local recurrence was seen in group 2 (p = 0.082). Distant metastases occurred in 15 of the 188 patients (7.9%) in group 1 and in two of the 190 patients (1.1%) in group 2 (p = 0.09). The 4-year actuarial rates of local recurrence were 4.3% (95% confidence interval, 1.8–8.2%) and 0.0% (95% confidence interval, 0.0–1.9%) and the 4-year actuarial rates of distant metastases were 7.9% (95% confidence interval, 4.5–12.8%) and 1.1% (95% confidence interval, 0.1–3.8%).Conclusion:Immediate IORT boost yielded excellent local control figures in this prospective investigation and appears to be superior to conventional postoperative boost in a short-term follow-up.Hintergrund und Ziel:Ziel dieser sequentiellen Interventionsstudie war die Bestimmung der Lokalrezidiv- und Fernmetastasenrate von Patientinnen mit invasivem Mammakarzinom, die mit brusterhaltender Operation und anschließender Bestrahlung der gesamten Brust, aber verschiedenen Boostbestrahlungen therapiert worden waren. Gruppe 1 erhielt eine postoperative Boostbestrahlung und Gruppe 2 eine intraoperative Radiotherapie (IORT) in Boostmodalität.Patienten und Methodik:Nach brusterhaltender Operation erhielten 378 Patientinnen mit invasivem Mammakarzinom mit T1- und T2-Tumoren eine postoperative Bestrahlung der gesamten Brust von 51–56.1 Gy in 1.7-Gy-Fraktionen. Von Januar 1996 bis Oktober 1998 bekamen 188 Patientinnen in Gruppe 1 postoperativ zusätzlich eine Elektronenboostbestrahlung von 12 Gy. Von Oktober 1998 bis März 2001 erhielten 190 Patientinnen in Gruppe 2 eine intraoperative Elektronenboostbestrahlung von 9 Gy direkt auf das Tumorbett. Beide Gruppen waren bezüglich Alter, Menopausenstatus, Tumorgröße, Grading und Nodalstatus vergleichbar. Die statistische Analyse erfolgte zweiseitig.Ergebnisse:Nach einer mittleren Nachbeobachtungszeit von 55,3 Monaten in Gruppe 1 und 25,8 Monaten in Gruppe 2 traten bei acht der 188 Patientinnen in Gruppe 1 (4,3%) Lokalrezidive auf, während es in Gruppe 2 zu keinem Lokalrezidiv kam (p = 0.082). Fernmetastasen ereigneten sich bei 15 der 188 Patientinnen (7,9%) in Gruppe 1 und zwei der 190 Patientinnen (1,1%) in Gruppe 2 (p = 0.09). Die 4-Jahres-Raten für Lokalrezidive betrugen 4,3% (95%-Konfidenzintervall 1,8–8,2%) und 0% (95%- Konfidenzintervall 0–1,9%) und die 4-Jahres-Raten für Fernmetastasen 7,9% (95%-Konfidenzintervall 4.5–12,8%) und 1,1% (95%-Konfidenzintervall 0,1–3,8%).Schlussfolgerung:Die intraoperative Boostbestrahlung zeigt exzellente Ergebnisse bezüglich der Lokalrezidivrate und scheint der postoperativen Boostbestrahlung in der Kurzzeitnachbeobachtung überlegen zu sein.

Local recurrence rates in breast cancer patients treated with intraoperative electron-boost radiotherapy versus postoperative external-beam electron-boost irradiation

Background and Purpose:The purpose of this sequential intervention study was to determine the rate of local recurrences and the rate of distant metastases in patients with invasive breast cancer who had been treated with breast-conserving surgery and postoperative radiation therapy to the whole breast either with postoperative electron boost in group 1 or with intraoperative electron boost (IORT) in group 2.Patients and Methods:After breast-conserving surgery, 378 women with invasive breast cancer of tumor sizes T1 and T2 received 51–56.1 Gy of postoperative radiation therapy to the whole breast in 1.7-Gy fractions. 188 of those patients additionally received a postoperative electron boost of 12 Gy in group 1 from January 1996 to October 1998. Consecutively, from October 1998 to March 2001, 190 patients received intraoperative electron-boost radiotherapy of 9 Gy to the tumor bed in group 2. The groups were comparable with regard to age, menopausal status, tumor size, grading, and nodal status. All statistical tests were twosided.Results:During a median follow-up period of 55.3 months in group 1 and 25.8 months in group 2, local recurrences were observed in eight of 188 patients (4.3%) in group 1, and no local recurrence was seen in group 2 (p = 0.082). Distant metastases occurred in 15 of the 188 patients (7.9%) in group 1 and in two of the 190 patients (1.1%) in group 2 (p = 0.09). The 4-year actuarial rates of local recurrence were 4.3% (95% confidence interval, 1.8–8.2%) and 0.0% (95% confidence interval, 0.0–1.9%) and the 4-year actuarial rates of distant metastases were 7.9% (95% confidence interval, 4.5–12.8%) and 1.1% (95% confidence interval, 0.1–3.8%).Conclusion:Immediate IORT boost yielded excellent local control figures in this prospective investigation and appears to be superior to conventional postoperative boost in a short-term follow-up.Hintergrund und Ziel:Ziel dieser sequentiellen Interventionsstudie war die Bestimmung der Lokalrezidiv- und Fernmetastasenrate von Patientinnen mit invasivem Mammakarzinom, die mit brusterhaltender Operation und anschließender Bestrahlung der gesamten Brust, aber verschiedenen Boostbestrahlungen therapiert worden waren. Gruppe 1 erhielt eine postoperative Boostbestrahlung und Gruppe 2 eine intraoperative Radiotherapie (IORT) in Boostmodalität.Patienten und Methodik:Nach brusterhaltender Operation erhielten 378 Patientinnen mit invasivem Mammakarzinom mit T1- und T2-Tumoren eine postoperative Bestrahlung der gesamten Brust von 51–56.1 Gy in 1.7-Gy-Fraktionen. Von Januar 1996 bis Oktober 1998 bekamen 188 Patientinnen in Gruppe 1 postoperativ zusätzlich eine Elektronenboostbestrahlung von 12 Gy. Von Oktober 1998 bis März 2001 erhielten 190 Patientinnen in Gruppe 2 eine intraoperative Elektronenboostbestrahlung von 9 Gy direkt auf das Tumorbett. Beide Gruppen waren bezüglich Alter, Menopausenstatus, Tumorgröße, Grading und Nodalstatus vergleichbar. Die statistische Analyse erfolgte zweiseitig.Ergebnisse:Nach einer mittleren Nachbeobachtungszeit von 55,3 Monaten in Gruppe 1 und 25,8 Monaten in Gruppe 2 traten bei acht der 188 Patientinnen in Gruppe 1 (4,3%) Lokalrezidive auf, während es in Gruppe 2 zu keinem Lokalrezidiv kam (p = 0.082). Fernmetastasen ereigneten sich bei 15 der 188 Patientinnen (7,9%) in Gruppe 1 und zwei der 190 Patientinnen (1,1%) in Gruppe 2 (p = 0.09). Die 4-Jahres-Raten für Lokalrezidive betrugen 4,3% (95%-Konfidenzintervall 1,8–8,2%) und 0% (95%- Konfidenzintervall 0–1,9%) und die 4-Jahres-Raten für Fernmetastasen 7,9% (95%-Konfidenzintervall 4.5–12,8%) und 1,1% (95%-Konfidenzintervall 0,1–3,8%).Schlussfolgerung:Die intraoperative Boostbestrahlung zeigt exzellente Ergebnisse bezüglich der Lokalrezidivrate und scheint der postoperativen Boostbestrahlung in der Kurzzeitnachbeobachtung überlegen zu sein.

Higher parity and shorter breastfeeding duration: association with triple-negative phenotype of breast cancer.

The combination of increased parity and shorter breastfeeding duration might increase the odds of the least differentiated triple‐negative breast cancer (BC) phenotype, theoretically because an expanded progenitor cell population from each pregnancy would incompletely differentiate postpartum.

Recommendations for standardized pathological characterization of residual disease for neoadjuvant clinical trials of breast cancer by the BIG-NABCG collaboration

Neoadjuvant systemic therapy (NAST) provides the unique opportunity to assess response to treatment after months rather than years of follow-up. However, significant variability exists in methods of pathologic assessment of response to NAST, and thus its interpretation for subsequent clinical decisions. Our international multidisciplinary working group was convened by the Breast International Group-North American Breast Cancer Group (BIG-NABCG) collaboration and tasked to recommend practical methods for standardized evaluation of the post-NAST surgical breast cancer specimen for clinical trials that promote accurate and reliable designation of pathologic complete response (pCR) and meaningful characterization of residual disease. Recommendations include multidisciplinary communication; clinical marking of the tumor site (clips); and radiologic, photographic, or pictorial imaging of the sliced specimen, to map the tissue sections and reconcile macroscopic and microscopic findings. The information required to define pCR (ypT0/is ypN0 or ypT0 yp N0), residual ypT and ypN stage using the current AJCC/UICC system, and the Residual Cancer Burden system were recommended for quantification of residual disease in clinical trials.

Efficacy and Safety of Neoadjuvant Trastuzumab Combined With Paclitaxel and Epirubicin A Retrospective Review of the M. D. Anderson Experience

A previously published prospective randomized phase 3 trial showed that administration of 24 weeks of primary systemic chemotherapy (PST) with paclitaxel and FEC75 (fluorouracil, epirubicin, cyclophosphamide) concurrently with trastuzumab in patients with HER2‐positive primary breast cancer resulted in a 60% pathologic complete response rate (PCR) with no associated severe cardiac toxicity. The purpose of this study was to review the efficacy and safety of a similar regimen outside the setting of a clinical trial.