Treatment Of High-risk Breast Cancer Research Articles

Monitoring of neoadjuvant chemotherapy response of breast cancer with ultrasound localization microscopy

Neoadjuvant chemotherapy (NAC) is the standard treatment for high-risk breast cancer, but less than 30% of patients exhibit a complete response, necessitating better preselection and monitoring. Ultrasound localization microscopy (ULM) offers potential improvements by providing super-resolution images of vasculature and functional features. To assess its efficacy, we applied ULM to breast cancer patients undergoing NAC, comparing their responses based on ULM features. Patients were evaluated before their first, second, and fourth NAC cycles, assessing tumor volume and employing contrast-enhanced ultrasound (CEUS) in split-screen mode. CEUS videos underwent postprocessing, involving MB localization and tracking, and motion compensation. ULM images, derived from tracked MBs, generated parameter maps for analyzing vascular changes and differences between responders and non-responders. Preliminary results of 14 patients revealed that during the first three cycles of NAC, the tumor volume as well as vessel coverage (i.e., ratio of vessel to tumor surface) of responders noticeably dropped. In contrast, non-responders showed only minor tumor size reduction and overall no decrease in coverage. Furthermore, the mean distance to the closest track was noticeably higher in non-responders. These findings, though preliminary, hint at ULM's potential for enhancing preselection and monitoring of NAC patients.

Adherence to Cancer Prevention Lifestyle Recommendations Before, During, and 2 Years After Treatment for High-risk Breast Cancer

The American Institute for Cancer Research and American Cancer Society regularly publish modifiable lifestyle recommendations for cancer prevention. Whether these recommendations have an impact on high-risk breast cancer survival remains unknown. To investigate whether adherence to cancer prevention recommendations before, during, and 1 and 2 years after breast cancer treatment was associated with disease recurrence or mortality. The Diet, Exercise, Lifestyles, and Cancer Prognosis Study (DELCaP) was a prospective, observational cohort study designed to assess lifestyles before diagnosis, during treatment, and at 1 and 2 years after treatment completion, implemented ancillary to the Southwest Oncology Group (SWOG) S0221 trial, a multicenter trial that compared chemotherapy regimens in breast cancer. Participants were chemotherapy-naive patients with pathologic stage I to III high-risk breast cancer, defined as node-positive disease with hormone receptor-negative tumors larger than 1 cm or any tumor larger than 2 cm. Patients with poor performance status and comorbidities were excluded from S0221. The study was conducted from January 1, 2005, to December 31, 2010; mean (SD) follow-up time for those not experiencing an event was 7.7 (2.1) years through December 31, 2018. The analyses reported herein were performed from March 2022 to January 2023. An aggregated lifestyle index score comprising data from 4 time points and 7 lifestyles, including (1) physical activity, (2) body mass index, (3) fruit and vegetable consumption, (4) red and processed meat intake, (5) sugar-sweetened beverage consumption, (6) alcohol consumption, and (7) smoking. Higher scores indicated healthier lifestyle. Disease recurrence and all-cause mortality. A total of 1340 women (mean [SD] age, 51.3 [9.9] years) completed the baseline questionnaire. Most patients were diagnosed with hormone-receptor positive breast cancer (873 [65.3%]) and completed some education beyond high school (954 [71.2%]). In time-dependent multivariable analyses, patients with highest vs lowest lifestyle index scores experienced a 37.0% reduction in disease recurrence (hazard ratio, 0.63; 95% CI, 0.48-0.82) and a 58.0% reduction in mortality (hazard ratio, 0.42; 95% CI, 0.30-0.59). In this observational study of patients with high-risk breast cancer, strongest collective adherence to cancer prevention lifestyle recommendations was associated with significant reductions in disease recurrence and mortality. Education and implementation strategies to help patients adhere to cancer prevention recommendations throughout the cancer care continuum may be warranted in breast cancer.

Assessment of Residual Cancer Burden and Event-Free Survival in Neoadjuvant Treatment for High-risk Breast Cancer

Residual cancer burden (RCB) distributions may improve the interpretation of efficacy in neoadjuvant breast cancer trials. To compare RCB distributions between randomized control and investigational treatments within subtypes of breast cancer and explore the relationship with survival. The I-SPY2 is a multicenter, platform adaptive, randomized clinical trial in the US that compares, by subtype, investigational agents in combination with chemotherapy vs chemotherapy alone in adult women with stage 2/3 breast cancer at high risk of early recurrence. Investigational treatments graduated in a prespecified subtype if there was 85% or greater predicted probability of higher rate of pathologic complete response (pCR) in a confirmatory, 300-patient, 1:1 randomized, neoadjuvant trial in that subtype. Evaluation of a secondary end point was reported from the 10 investigational agents tested in the I-SPY2 trial from March 200 through 2016, and analyzed as of September 9, 2020. The analysis plan included modeling of RCB within subtypes defined by hormone receptor (HR) and ERBB2 status and compared control treatments with investigational treatments that graduated and those that did not graduate. Neoadjuvant paclitaxel plus/minus 1 of several investigational agents for 12 weeks, then 12 weeks of cyclophosphamide/doxorubicin chemotherapy followed by surgery. Residual cancer burden (pathological measure of residual disease) and event-free survival (EFS). A total of 938 women (mean [SD] age, 49 [11] years; 66 [7%] Asian, 103 [11%] Black, and 750 [80%] White individuals) from the first 10 investigational agents were included, with a median follow-up of 52 months (IQR, 29 months). Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (HR-positive/ERBB2-negative: hazard ratio [HZR], 1.75; 95% CI, 1.45-2.16; HR-positive/ERBB2-positive: HZR, 1.55; 95% CI, 1.18-2.05; HR-negative/ERBB2-positive: HZR, 2.39; 95% CI, 1.64-3.49; HR-negative/ERBB2-negative: HZR, 1.99; 95% CI, 1.71-2.31). Prognostic information from RCB was similar from treatments that graduated (HZR, 2.00; 95% CI, 1.57-2.55; 254 [27%]), did not graduate (HZR, 1.87; 95% CI, 1.61-2.17; 486 [52%]), or were control (HZR, 1.79; 95% CI, 1.42-2.26; 198 [21%]). Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) and ERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis. In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy. ClinicalTrials.gov Identifier: NCT01042379.

Postmastectomy radiation therapy can improve survival for breast cancer patients with 1-3 positive axillary lymph nodes: a retrospective cohort study using the SEER database.

BackgroundPostmastectomy radiation (PMRT) is an important adjuvant treatment for high-risk breast cancer. However, evidence concerning its efficacy in promoting survival of patients with 1–3 positive axillary lymph nodes remains insufficient.MethodsWe identified 57,793 patients, diagnosed from 2010–2015, from the Surveillance, Epidemiology, and End Results database, including 15,126 cases treated with beam radiation and 42,667 cases with none/unknown radiation. A Kaplan–Meier curve was utilized to compare survival of the two groups. We used univariate and multivariate Cox proportional hazard models to identify independent prognostic factors presented as hazard ratios (HRs) and 95% confidence intervals (CIs). For subgroup analysis, patients were stratified according to lymph node status, tumor size, and molecular subtypes.ResultsThe PMRT group showed more aggressive clinicopathological features, including higher grades (P<0.001), larger tumor sizes (P<0.001), more lymph nodes (P<0.001), younger ages (P<0.001), more ER-negative cases (P<0.001), more PR-negative cases (P<0.001), and more HER2 overexpression (P<0.001). In addition, the PMRT group received more radical surgeries (P<0.001) and more chemotherapy (P<0.001). In the multivariate Cox proportional hazard regression analysis, the PMRT group exhibited improved survival in terms of breast cancer specific survival (BCSS) (HR, 0.74; 95% CI, 0.68–0.81; P<0.001) and overall survival (OS) (HR, 0.72; 95% CI, 0.67–0.78; P<0.001). After stratification according to positive axillary lymph nodes, the PMRT group showed improved BCSS and OS in the LN 1 to 3 subgroup (HR, 0.74; 95% CI, 0.64–0.85; P<0.001 and HR, 0.68; 95% CI, 0.60–0.78; P<0.001, respectively). For patients with 1–3 positive axillary lymph nodes and T1–2 tumors, the PMRT group still showed improved BCSS and OS (HR, 0.823; 95% CI, 0.69–0.99; P=0.04 and HR, 0.75; 95% CI, 0.64–0.88; P<0.001, respectively). In the subgroup analysis, PMRT remained a significant favorable prognostic factor in T2 and HER2−/HR+ subtype (P<0.05).ConclusionsThis study suggests that PMRT can confer a survival benefit to breast cancer patients with 1–3 positive axillary lymph nodes, even with modern treatment options. Furthermore, for patients with 1–3 positive axillary lymph nodes and T1–2 tumors, PMRT can still provide survival benefits.

Preoperative Radiotherapy Trials to Facilitate Immediate Breast Reconstruction after Mastectomy

Postmastectomy radiotherapy (PMRT) is often a component of treatment algorithms for locally advanced or node-positive breast cancer. Breast reconstruction may be delayed or not performed due to negative effects of PMRT on the reconstruction. Administering radiotherapy in the preoperative setting allows for immediate breast reconstruction (IBR) to be performed in patients who have indications for PMRT and desire IBR. This review summarizes the current literature on this new concept. Most prospective treatment protocols included neoadjuvant systemic therapy followed by radiotherapy (RT) dose of 50–50.4 Gy conventionally fractionated and mastectomy with immediate autologous reconstruction after 6–8 weeks. There were no cases of IBR being aborted due to technical complications and overall postoperative complications ranged from 3 to 36%. These were typically non-operatively managed, and cosmetic results when evaluated were favorable. Initial oncologic outcomes indicate low locoregional recurrence rates (≤ 10%) and high 5-year overall survival rates of 87–98%. Although published studies are heterogeneous in nature, they suggest that preoperative RT followed by mastectomy with IBR is technically feasible and safe. Larger prospective studies with longer follow-up times may establish this as a new standard in the multidisciplinary treatment of high-risk breast cancer.

Abstract P6-15-06: SOLTI-0702 CAPRICE: Final results of a phase II study of pegylated liposomal doxorubicin plus cyclophosphamide followed by paclitaxel as neoadjuvant chemotherapy in elderly or cardiotoxicity-prone patients with high-risk breast cancer: 5-year overall survival disease free survival and late cardiac safety

Abstract Background: Anthracycline and taxane-based chemotherapy is the standard treatment for high-risk breast cancer. However, conventional anthracyclines are not commonly used in elderly patients or those patients prone to cardiotoxicity and there is a potential risk leaving them undertreated. Pegylated liposomal doxorubicin (PLD) has comparable efficacy, but significantly less cardiotoxicity than conventional anthracyclines. We conducted a phase II trial to assess the efficacy and safety of a neoadjuvant chemotherapy (NC) based on PLD and paclitaxel (PTX) in this group of patients. The pathological complete response, breast conservative surgery (BCS) and safety data at a 35-month follow-up were published (Gil-Gil et al. Breast Cancer Res Treat 2015). Here we present the final analysis of 5-year overall survival (OS) and 5-year disease-free survival (DFS) and cardiac safety after 60 months of follow-up. Methods: Fifty patients with stage II (48%) and III (52%) breast cancer (seven cases were T4d) and with at least one risk factor for developing cardiotoxicity were included. NC schedule: PLD 35 mg/m2 plus cyclophosphamide 600 mg/m2 every 4 weeks for four cycles, followed by 80 mg/m2 weekly PTX for 12. Median age was 73 years old (84% were older than 65 years). Forty-eight (96%) of tumors were triple negative (TN). Secondary objectives included 5-year DFS, 5year OS and cardiac safety measured by a decrease in left ventricular ejection fraction (LVEF), electrocardiogram (ECG) anda cardiac questionnaire performed every 3 months during the first year, every 6 months year 2-3 and every 12 months year 4-5 of follow-up. Results: Forty-eight patients (96%) completed the 4 cycles of PLD plus CPM, while only 26 patients (52%) could complete the 12 weeks of PTX. Forty-six patients (92%) underwent surgery. After surgery: 27 patients received radiotherapy, 2 letrozole and 1 trastuzumab. The 5-year OS was 56% (95% CI 41.2-68.4) and the 5-year DFS was 54.4% [95% CI: 38.3-67.9].No significant decrease in LVEF was seen (mean baseline LVEF was 66.6 (52-86) and mean LVEF after 60 months was 66 (54.5-73). Four patients (8%) developed cardiotoxicity (in 2 cases G3). There were 5 non-cancer deaths (10%): 3 during treatment (all in patients &amp;gt; 80 years: a sudden death one month after surgery, a haemorrhagic stroke 30 days after completing chemotherapy and a non-neutropenic pneumonia); and 2 during follow-up (1 Amyotrophic Lateral Sclerosis and 1 intestinal ischemia). Conclusions: PLD followed by PTX as NC was feasible in a fragile population of patients who were not candidates for conventional doxorubicin. The 5 year DFS and 5 year OS in elderly patients with bulky TN tumors were similar tothe reported in the literature. This regimen could be an option for the neoadjuvant treatment of cardiotoxicity-prone patients or elderly patients who present high-risk breast cancer. Citation Format: Gil-Gil M, Bellet M, Morales S, Barnadas A, Manso L, Morilla Ruiz I, Azaro A, Ciruelos Gil E, Garcia Martínez E, Marínez N, Melé M, Soler T, Villagrasa P, Pernas S. SOLTI-0702 CAPRICE: Final results of a phase II study of pegylated liposomal doxorubicin plus cyclophosphamide followed by paclitaxel as neoadjuvant chemotherapy in elderly or cardiotoxicity-prone patients with high-risk breast cancer: 5-year overall survival disease free survival and late cardiac safety [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 P6-15-06.

Hypofractionated Radiation Therapy After Mastectomy for the Treatment of High-Risk Breast Cancer: 5-Year Follow-Up Result of a Randomized Trial

Hypofractionated Radiation Therapy After Mastectomy for the Treatment of High-Risk Breast Cancer: 5-Year Follow-Up Result of a Randomized Trial

Paclitaxel-induced pneumonitis in patients with breast cancer: case series and review of the literature

Doxorubicin plus cyclophosphamide followed by paclitaxel is a common adjuvant treatment for high-risk breast cancer. It has been associated with pulmonary toxicity in several case reports. We describe three patients in whom interstitial pneumonitis developed immediately after the first paclitaxel exposure and worsened clinically over time. All reported dyspnoea, fever and progressive respiratory distress. Imaging revealed diffuse bilateral pulmonary infiltrates. Other causes of respiratory failure were excluded with laboratory work-up, imaging, biopsy studies and results of antibiotic treatment. The respiratory decline was reversed only after administration of high-dose steroids, an empirical treatment previously reported to be beneficial in similar cases. Although chemotherapy using concomitant or sequential drugs may make identification of the toxic agent difficult, we noted a clear temporal relationship between exposure to paclitaxel and the development of pulmonary toxicity. Furthermore, according to the available literature, it is less likely that a respiratory decline would be caused by either cyclophosphamide or trastuzumab. In conclusion, clinicians should be aware of the potentially life-threatening risk of pulmonary toxicity following paclitaxel treatment. If paclitaxel is halted early and the patient has good lung reserve, pulmonary toxicity can be reversed with high-dose steroid administration.

Abstract P4-04-05: Differential mRNA expression patterns in breast tumors with high vs. low quantity of stromal tumor–Infiltrating lymphocytes

Abstract Background: Tumor-infiltrating lymphocytes (TIL) have prognostic and potentially predictive significance in the (neo)adjuvant treatment of high-risk breast cancer. However, quantitative TIL measurement is not routinely performed. It is unclear why some tumors attract large quantities of TIL while others do not. We sought to confirm the association between TIL and pathologic complete response rate (pCR) and to further use next generation sequencing (NGS) to identify genes and gene pathways associated with the presence/absence of TIL. Methods: We studied 140 women with high risk stage I-III breast cancer, enrolled in the Breast Cancer Genome Guided Therapy Study (BEAUTY), obtaining serial biopsies for DNA/RNA sequencing and MRI imaging to assess response to neoadjuvant chemotherapy (NAC) with taxane (+/- trastuzumab+/-pertuzumab for HER2+ disease) followed by AC or (F)EC. Diagnostic pre-NAC core needle biopsies and surgical resection specimens post-NAC were available from 110 patients. Stromal TIL were semi-quantitated on a scale of 1-4 (with 1: ≤10/hpf, 2: subtle infiltrate &amp;gt;10/hpf, 3: moderate infiltrate readily visible at low power magnification, 4: dense infiltrate with innumerable lymphocytes). For this analysis, low TIL was defined as scores of 1-2 vs. high defined as 3-4. Using pre-NAC biopsies, RNAseq was performed using the Illumina HiSeq2000 and the Mayo Analysis Pipeline for RNAseq (MAP-Rseq) for quality control, sequence alignment, and gene counts. The quantity of TIL was associated with transcripts across the transcriptome after conditional quantile normalization. Differentially expressed genes were obtained using EdgeR analysis, using a false discovery rate of 0.05, and pathways were evaluated using GAGE methods. Results: The pCR and residual cancer burden (RCB)-0/I rates by stromal TIL status within each molecular subtype are presented in the table. A diverse spectrum of 1344 genes with differential expression between tumors with high vs. low stromal TIL was identified. The genes with &amp;gt;2.0-fold change (FC) and p&amp;lt;1e-09 included S100A7 (4.49 FC), LCN2 (2.48 FC), and ART3 (2.82 FC) (genes known to be involved in immune regulation), as well as TDRD1 (2.71 FC) (a gene related to ERG [ETS-related gene] expression). In addition, the "regulation of actin cytoskeleton" pathway was upregulated in tumors with high TIL, while the "Hedgehog signaling" and "Wnt signaling" pathways were downregulated. Molecular SubtypeStromal TILspCR rate n (%)RCB-0/I rateLuminal AHigh------Luminal ALow0/9 (0%)0/9 (0%)Luminal BHigh1/9 (11.1%)1/8 (12.5%)Luminal BLow3/24 (12.5%)6/23 (26.1%)ER+/HER2+High3/9 (33.3%)4/9 (44.4%)ER+/HER2+Low1/6 (16.7%)1/6 (16.7%)ER-/HER2+High8/9 (88.9%)7/7 (100%)ER-/HER2+Low4/8 (50.0%)6/8 (75.0%)Triple NegativeHigh10/19 (52.6%)13/19 (68.4%)Triple NegativeLow7/14 (50.0%)9/13 (69.2%) Conclusions: We identified genes and gene pathways associated with high TIL expression in breast tumors prior to NAC that provide insight into the interactions between TIL and tumors. TIL can be easily semi-quantitated on H&amp;E and along with these novel biomarkers, may contribute to the personalization of breast cancer therapy. Citation Format: Moyer AM, Boughey JC, Kalari KR, Suman VJ, McLaughlin SA, Moreno-Aspitia A, Northfelt DW, Gray RJ, Sinnwell JP, Carlson EE, Dockter TJ, Jones KN, Felten SJ, Conners AL, Wieben ED, Ingle JN, Wang L, Weinshilboum RM, Visscher DW, Goetz MP. Differential mRNA expression patterns in breast tumors with high vs. low quantity of stromal tumor–Infiltrating lymphocytes. [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 P4-04-05.

Long-term follow-up of autologous hematopoietic stem cell transplantation for stage II/III breast cancer.

7121 Background: In the 1980s and 1990s, adjuvant chemotherapy with high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) was utilized for the treatment of high-risk breast cancer. Previous studies showed that ASCT significantly reduced the risk of relapse in these patients, but failed to provide evidence of improved overall survival when compared with standard therapy in randomized trials. Due to the mortality, morbidity, and cost associated with ASCT and lack of a clear overall survival benefit, the use of HDC with ASCT for high-risk breast cancer was halted. In this retrospective, observation study, we analyzed the toxicity and efficacy of ASCT in high-risk breast cancer at a large community hospital. Methods: The study population consisted of 57 women diagnosed with high-risk primary breast cancer who underwent treatment with HDC followed by ASCT from 1991-1999. Women receiving treatment for metastatic breast cancer were excluded. The medical records of the study population were retrospectively reviewed, with particular attention to long-term toxicities and efficacy. Results: Fifty seven patients were evaluated: 54 with ductal and/or lobular breast cancer and 3 with inflammatory breast cancer. Median age was 44 years (29- 61). Twenty six patients (46%) were alive at time of review. Twelve patients (21%) experienced a recurrence of their breast cancer. Four patients (7%) developed secondary malignancies. Two patients (4%) experienced cardiac toxicities. Estrogen/progesterone receptor-positive breast cancers accounted for 42% of recurrences, 100% of secondary malignancies, and 50% of cardiac toxicities. HER-2/neu status analysis revealed amplification in 17% of breast cancer recurrences, but in no cases of secondary malignancy or cardiac toxicity. Conclusions: High-dose chemotherapy and ASCT can be effective in reducing long-term recurrences in women with high-risk, Stage II/III breast cancer. This treatment, however, carries an associated risk of secondary malignancies and cardiac toxicities. Estrogen/progesterone receptor-positive breast cancer appears to have a greater association with disease recurrence and secondary malignancies.

Toxicity Analysis in the ADEBAR Trial: Sequential Anthracycline-Taxane Therapy Compared with FEC120 for the Adjuvant Treatment of High-Risk Breast Cancer

Background: Data from meta-analyses have shown taxane-containing therapies to be superior to anthracycline-based treatments for high-risk breast cancer. Patients and Methods: The ADEBAR trial was a multicenter phase III trial in which patients with lymph node-positive breast cancer were prospectively randomized for either sequential anthracycline-taxane or FEC120 therapy. Patients received 4× epirubicin (90 mg/m²) and cyclophosphamide (600 mg/m²) every 3 weeks (q3w), followed by 4× docetaxel (100 mg/m²) q3w (EC-Doc arm), or 6× epirubicin (60 mg/m²) and 5-fluorouracil (500 mg/m²) on days 1 and 8 and cyclophosphamide (75 mg/m²) on days 1–14, q4w (FEC arm). We compared both arms with respect to toxicity and feasibility. Results: Hematological toxicity was found significantly more often in the FEC arm. Febrile neutropenia was seen in 11.3% of patients in the FEC arm and in 8.4% of patients in the EC-Doc arm (p = 0.027). Non-hematological side effects of grade 3/4 were rarely seen in either arm. Therapy was terminated due to toxicity in 3.7% of the patients in the EC-Doc arm and in 8.0% of the patients in the FEC arm (p = 0.0009). Conclusion: The sequential anthracycline-taxane regimen is a well-tolerated and feasible alternative to FEC120 therapy.

Cost-effectiveness of intensive adjuvant chemotherapy for high-risk breast cancer: Is tailored and dose-escalated chemotherapy with growth factor support (GFS) more costly and less effective than marrow-supported high-dose chemotherapy – results from a randomized study

Based on randomized studies bone-marrow supported (BMS) high-dose chemotherapy (HDCT) is not superior to conventional CT as adjuvant treatment for high-risk breast cancer. To compare the cost-effectiveness of these treatments we examined the data of Finnish patients in the SBG9401 trial . Patients were randomized to receive either dose-escalated (de FEC) (group A, n =59) or FEC and HDCT+BMS (group B, n =70). They received adjuvant radiotherapy (RT) + tamoxifen. All direct health care costs of first line treatment at the oncology units were considered as well as productivity costs within the first 3 years of follow-up. Effectiveness was measured by the number of survival days during 5 years of follow-up. The mean direct health care costs were significantly higher in group B (25 829 € in group A vs. 36 605 € in group B, p <0.001), mainly due to a higher number of hospital days. Half of the costs in group A was due to the use of filgrastim (15 335 € in A and 2969 € in B, p <0.001). The costs of RT were only 5% of total costs. There was no statistically significant difference between the groups in the number of survival days, but sensitivity analysis based on bootstrapping suggested that treatment A would be a less costly and more effective alternative in a great majority of cases.

2–48 Comparison of Rapidly Cycled Tandem High-Dose Chemotherapy Plus Peripheral-Blood Stem-Cell Support Versus Dose-dense Conventional Chemotherapy for Adjuvant Treatment of High-Risk Breast Cancer: Results of a Multicentre Phase III Trial

2–48 Comparison of Rapidly Cycled Tandem High-Dose Chemotherapy Plus Peripheral-Blood Stem-Cell Support Versus Dose-dense Conventional Chemotherapy for Adjuvant Treatment of High-Risk Breast Cancer: Results of a Multicentre Phase III Trial

Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial

Breast cancer with extensive axillary-lymph-node involvement has a poor prognosis after conventional treatment. In trials with historical controls, high-dose chemotherapy produced improved outcomes. We compared an intensive double-cycle high-dose chemotherapy regimen with an accelerated conventionally dosed regimen in high-risk breast cancer in a multicentre trial. Patients with at least nine positive nodes were randomly assigned either two courses of accelerated (2-week intervals, with filgrastim support), conventionally dosed epirubicin and cyclophosphamide followed by two courses of high-dose chemotherapy (epirubicin, cyclophosphamide, and thiotepa supported by peripheral-blood progenitors) or four identical cycles of epirubicin and cyclophosphamide followed by three cycles of accelerated cyclophosphamide, methotrexate, and fluorouracil. The primary endpoint was event-free survival. Analyses were done both by intention to treat and per protocol. 403 patients were enrolled; 201 were assigned high-dose chemotherapy and 202 conventional treatment. The mean number of positive nodes was 17.6, and median follow-up was 48.6 months. 4-year event-free survival (intention-to-treat analysis) was 60% (95% CI 53-67) in the high-dose chemotherapy group and 44% (37-52) in the control group (p=0.00069). The corresponding overall survival was 75% (69-82) versus 70% (64-77; p=0.02). There were no treatment-related deaths. Our finding of significant improvements in both event-free and overall survival for high-dose chemotherapy compared with a dose-dense conventional regimen contrasts with the results of other studies. The discrepancy might be due partly to design differences (tandem, brief induction) between our regimen and those studied in other trials. This approach merits further study.

Conservative surgery and chemotherapy for breast carcinoma during pregnancy

Surgery 2002;131:108-10.

Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial

Chemotherapy drug distribution varies greatly among individual patients. Therefore, we developed an individualised fluorouracil, epirubicin, cyclophosphamide (FEC) regimen to improve outcomes in patients with high-risk early breast cancer. We then did a randomised trial to compare this individually tailored FEC regimen with conventional adjuvant chemotherapy followed by consolidation with high-dose chemotherapy with stem-cell support. 525 women younger than 60 years of age with high-risk primary breast cancer were randomised after surgery to receive nine cycles of tailored FEC to haematological equitoxicity with granulocyte colony-stimulating factor (G-CSF) support (n=251), or three cycles of FEC at standard doses followed by high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin (CTCb), and peripheral-blood stem-cell or bone-marrow support (n=274). Both groups received locoregional radiation therapy and tamoxifen for 5 years. The primary outcome measure was relapse-free survival, and analysis was by intention to treat. At a median follow-up of 34.3 months, there were 81 breast-cancer relapses in the tailored FEC group versus 113 in the CTCb group (double triangular method p=0.04). 60 deaths occurred in the tailored FEC group and 82 in the CTCb group (log-rank p=0.12). Patients in the CTCb group experienced more grade 3 or 4 acute toxicity compared with the tailored FEC group (p<0.0001). Two treatment-related deaths (0.7%) occurred in the CTCb group. Six patients in the tailored FEC group developed acute myeloid leukaemia and three developed myelodysplastic syndrome. Tailored FEC with G-CSF support resulted in a significantly improved relapse-free survival and fewer grade 3 and 4 toxicities compared with marrow-supported high-dose chemotherapy with CTCb as adjuvant therapy of women with high-risk primary breast cancer.

The status of high-dose chemotherapy in breast cancer.

High-dose chemotherapy in breast cancer is a subject of considerable controversy. Preliminary results from several randomized trials have shown that it is certainly not the breakthrough hoped for in the early 1990s. The available data are, however, compatible with a modest but potentially important effect on relapse-free survival in the adjuvant treatment of high-risk breast cancer. To prove such an effect, several more years of maturation are required for a number of randomized studies. At this point in time, there is no justification for the use of high-dose chemotherapy in breast cancer outside clinical studies.

High-dose chemotherapy and autologous stem cell transplantation as treatment for high-risk breast cancer.

High-dose chemotherapy with autologous stem cell transplantation has emerged as a common treatment for patients with breast cancer who have a poor prognosis. The success of this approach appears to depend on the tumor burden and the sensitivity of the disease to chemotherapy because treatment techniques have been refined and treatment-related mortality has declined. Phase II studies in patients with stage II and III disease are encouraging and suggest that treatment with high-dose chemotherapy before the development of metastatic disease may provide an advantage in terms of relapse-free and overall survival. However, tumor cells may contaminate stem cell collections and contribute to relapse after transplantation. Therefore it may be important to separate and select purified CD34+ cells which are not contaminated. It has been suggested that selection bias contributes to the favorable preliminary results observed in phase II studies of high-risk patients. Such issues, together with patient and physician bias regarding the benefits of this strategy, emphasize the need to complete the prospective randomized trials now underway.

High-dose chemotherapy and stem-cell rescue in the treatment of high-risk breast cancer: prognostic indicators of progression-free and overall survival.

To examine the predictive value of tumor- and treatment-specific prognostic indicators of relapse-free survival (RFS) and overall survival (OS) in patients with high-risk breast cancer (HRBC) treated with high-dose chemotherapy (HDCT) and stem-cell rescue. Between June 1989 and September 1994, 114 patients with HRBC (stage II with > or = 10 axillary lymph nodes involved, stage IIIA, and stage IIIB inflammatory carcinoma) received adjuvant chemotherapy followed by HDCT with etoposide, cyclophosphamide, and either doxorubicin (CAVP) or cisplatin (CCVP). Variables analyzed included stage, tumor size, number of axillary nodes involved, grade and receptor status, and types of adjuvant chemotherapy and radiation therapy and HDCT. With a median follow-up time of 46 months (range, 23 to 93), Kaplan-Meier estimates of 3.5-year OS for stage II, IIIA, and IIIB HRBC are 82% (95% confidence interval [CI], 67% to 97%), 79% (95% CI, 67% to 91%), and 72% (95% CI, 53% to 91%); RFS estimates are 71% (95% CI, 56% to 85%), 57% (95% CI, 43% to 72%), and 50% (95% CI, 29% to 71%) irrespective of the HDCT regimen. In univariate analysis, the risk of relapse was lower for patients with progesterone receptor (PR)-positive tumors (risk ratio [RR], 0.43; 95% CI, 0.22 to 0.81; P = .01) and higher for patients with inflammatory carcinoma (RR, 2.20; 95% CI, 1.02 to 4.76; P = .05). OS was better for patients with PR (RR, 0.16; 95% CI, 0.05 to 0.55; P = .003) and estrogen receptor (ER)-positive tumors (RR, 0.42; 95% CI, 0.17 to 1.02; P = .05); OS was worse for patients with high-grade primary tumors (RR, 4.08; 95% CI, 1.21-13.7; P = .02). In multivariate analysis, PR positivity was associated with improved RFS (P = .01) and OS (P = .001). HDCT in selected patients with HRBC is safe and warrants further evaluation. Patients with receptor-negative, high-grade, or inflammatory tumors require improvement in their therapeutic options. Better assessment of the role of HDCT awaits completion of ongoing randomized trials.

Quantum leaps in treatment of high-risk breast cancer? Prove it!

Quantum leaps in treatment of high-risk breast cancer? Prove it!