Efficacy of Neoadjuvant Endocrine Therapy Versus Neoadjuvant Chemotherapy in ER-positive Breast Cancer: Results From a Prospective Institutional Database

BackgroundAlthough neoadjuvant chemotherapy (NACT) has been established as a standard for medically fit patients with locally advanced breast cancer, there has been renewed interest in utilizing neoadjuvant endocrine therapy (NET) for women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Rates of pathologic complete response (pCR) are known to be low, but data regarding down-staging and long-term outcomes are inconsistent.Patients and MethodsA prospective institutional database of patients with breast cancer treated with neoadjuvant therapy from 2012 to 2017 was analyzed to identify patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Patients who received NET were compared with those who received NACT. A matched analysis (age, stage, grade) was performed to compare rates of down-staging, pCR, breast conserving surgery, and CPS+EG scores.ResultsA total of 176 patients met eligibility criteria. Of these, 111 (63%) patients received NACT, 51 (29%) received NET, and 14 (8%) received both sequentially. Women prescribed NET were older (65.5 vs. 51.2 years; P < .0001) and presented with lower clinical stage (P < .0001). The median duration of NET was 90 days. When matched, clinical down-staging was more frequent with NACT (20/51; 39%) compared with NET (11/51; 22%) (P = .032). Of these, 2% achieved pCR in each cohort. Conversion rates to breast conserving surgery eligibility were low (8% and 13% with NET and NACT; P = .70). No significant differences in CPS+EG scores were identified.ConclusionsSignificantly higher rates of down-staging were achieved with NACT compared with NET when patients were matched. This study highlights the importance of establishing tumor biology and the need for biomarkers that can be used as predictive tools to inform treatment.     

Predictive value of BRCA1/2 mRNA expression for response to neoadjuvant chemotherapy in BRCA‐negative breast cancers

It is well known that BRCA1 and BRCA2 play a central role in DNA repair, but the relationship between BRCA1 and BRCA2 mRNA expression and response to neoadjuvant chemotherapy in sporadic breast cancer patients has not been well established. Here, we investigate the association between BRCA1 or BRCA2 mRNA expression levels and pathological response in 674 BRCA1/2 mutation‐negative breast cancer patients who received neoadjuvant chemotherapy. BRCA1 and BRCA2 mRNA expression were assessed using quantitative real‐time polymerase chain reaction in core biopsy breast cancer tissue obtained prior to the initiation of neoadjuvant chemotherapy. A total 129 patients (19.1%) achieved pathological complete response (pCR) after neoadjuvant chemotherapy. Among patients treated with anthracycline‐based chemotherapy (n = 531), BRCA1 mRNA low expression patients had a significantly higher pCR rate than intermediate or high BRCA1 mRNA expression groups (24.6% vs 16.8% or 14.0%, P = .031) and retained borderline significance (OR = 1.54, 95% CI = 0.93‐2.56, P = .094) in multivariate analysis. Among the 129 patients who received a taxane‐based regimen, pCR rate showed no differences in BRCA1 low, intermediate, and high mRNA level subgroups (19.6%, 26.8% and 21.4%, respectively; P = .71). BRCA2 mRNA level was not associated with pCR rate in the anthracyline‐based treated subgroup (P = .60) or the taxane‐based regimen subgroup (P = .82). Taken together, our findings suggested that BRCA1 mRNA expression could be used as a predictive marker in BRCA1/2 mutation‐negative breast cancer patients who received neoadjuvant anthracycline‐based treatment.     

Prognostic value of Smac expression in rectal cancer patients treated with neoadjuvant therapy

The objective was to evaluate expression of second mitochondria-derived activator of caspase (Smac) expression before and after treatment in patients treated with preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer and to correlate the clinicopathological characteristics and level of Smac expression with pathologic response and outcome. Expression of biomarker was evaluated by immunohistochemistry in tumor samples from 98 patients with clinical Stage II and III rectal cancer treated with preoperative pelvic radiotherapy plus concurrent chemotherapy. All patients received a standardized total mesorectal excision procedure after a long interval of 4–6 weeks. For Smac, patients with a good response to neoadjuvant CRT tended to have higher pre-therapy levels (P = 0.007). The level of Smac expression decreased after neoadjuvant therapy (P = 0.016). High expression of Smac before CRT, and high Dworak’s tumor regression grade (TRG) were significantly associated with improved 5-year disease-free survival (P < 0.05). Pretreatment nodal status also was significantly associated with 5-year disease-free survival and 5-year local relapse-free survival (P < 0.05). Multivariate analysis confirmed that the pretreatment expression of Smac and Lymph nodal status were independent prognostic factors. Our study suggests that high expression of Smac before neoadjuvant CRT could predict good outcome in locally advanced rectal cancer patients.     

A Single-Nucleotide Polymorphism in the MDR1 Gene as a Predictor of Response to Neoadjuvant Chemotherapy in Breast Cancer

BackgroundThe single-nucleotide polymorphism (SNP) 3435C > T in exon 26 of the MDR1 gene has been shown to correlate with the functioning of P-glycoprotein. We studied the frequency of SNP in exon 26 of the MDR1 gene in breast cancer and its role in predicting response to neoadjuvant chemotherapy in breast cancer.Patients and MethodsNinety-six patients with locally advanced breast carcinoma were enrolled. Genotyping of exon 26 of the MDR1 gene was performed, and computed tomography scans were performed before and after neoadjuvant chemotherapy. Response to 3 cycles of the 5-fluorouracil/doxorubicin/cyclophosphamide (FAC) regimen was assessed. The prevalence of SNP was compared with that of historical controls. Association of the response was compared with the genotypes.ResultsThe frequency of genotypes was different from that of healthy sex-matched historical controls. Prevalence of TT genotype was significantly increased in breast cancer patients (P = .025). The patients with TT genotype had 2.26 times the chance of responding to neoadjuvant chemotherapy when compared with patients with the CC genotype (P = .44).ConclusionSignificantly higher prevalence of 3435TT genotype in exon 26 of the MDR1 gene in patients with breast cancer might suggest the possibility of increased breast cancer susceptibility. The genotypes did not show any significant association to response to chemotherapy in the population studied.     

Predictive value of MGMT,hMLH1, hMSH2 and BRCA1 protein expression for pathological complete response to neoadjuvant chemotherapy in basal-like breast cancer patients

Purpose  

To evaluate the importance of biological markers to predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) in patients with locally advanced basal-like breast cancers (BLBCs).     

HER-2/neu expression as a predictive factor for response to anthracycline-based chemotherapy in a Mexican Population of locally advanced breast cancer patients

Breast cancer is the second most frequent tumor in Mexico—30–50% are diagnosed in locally advanced stages requiring neoadjuvant chemotherapy. The overexpression of HER-2/neu has been identified as a chemotherapy response predictor. The objective of our study was to identify response predictive factors to anthracycline-based neoadjuvant chemotherapy in locally advanced breast cancer. Data were collected from clinical records of patients with neoadjuvant anthracycline-based chemotherapy, for clinical stage III breast cancer from 1992 to 1997. Paraffin blocks were reviewed to determine histologic grade, HER-2/neu expression, and ploidy. Patients were divided in two groups: A, 56 cases responding to chemotherapy and, B, 20 nonresponders. Mean age was 50.1 and 45.4 for groups A and B, respectively (OR 7.02, p=0.004), and those premenopausal were 43% and 70%, respectively (OR 3.1, p=0.04). Mean tumor size was 5 cm in responders and 8 cm for nonresponders (OR 4, p=0.02). Clinical stage III-B 16% and 70% for groups A and B (OR 12.2, p=0.000); tumors were aneuploid in 39% of responders and 18.7% for nonresponders. HER-2/neu was overexpressed in 64.2% and 50% for groups A and B (OR 3.6, p=0.06). On multivariate analysis significance was conserved only for age, clinical stage, and size. HER-2/neu lost significance. Age and size were importantly related to tumor response, a higher percentage of HER-2/neu overexpression was observed in responders, without significance due to small sample size. It would be important to study a larger number of patients to obtain more conclusive results.     

Elevated chemokine receptor CXCR4 expression in primary tumors following neoadjuvant chemotherapy predicts poor outcomes for patients with locally advanced breast cancer (LABC)

Purpose Patients with locally advanced breast cancer (LABC) have a poor outcome. A molecular predictor to identify at-risk patients is sorely needed. CXCR4 is a chemokine receptor that has been linked to breast cancer invasion and metastasis. We postulate that in patients with LABC, CXCR4 overexpression levels in cancer specimens following neoadjuvant chemotherapy predict cancer outcome. Experimental design 54 patients with LABC were prospectively accrued and analyzed. All had neoadjuvant chemotherapy and definitive surgical therapy. Study homogeneity was maintained by standardized treatment, surveillance, and compliance protocols. A 1 cm³ cancer from the surgical specimens of each patient was retrieved for analysis. CXCR4 levels were detected using Western blots, and results were quantified against 1 μg of protein from HeLa cells. CXCR4 expression was defined as low (<6.6-fold) or high (≥6.6-fold). Primary endpoints were cancer recurrence and death. Statistical analysis performed included independent samples t-test, chi-square test, Spearman Rank analysis, Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazard model. Results With a median follow-up of 30 months, patients with high CXCR4 overexpression (≥6.6-fold) had a significantly higher incidence of recurrence (P = 0.0006) and cancer death (P = 0.0128) than those with low CXCR4 overexpression (<6.6-fold). The relative risks for recurrence and death in the high CXCR4 group were 27.3-fold (95% CI: 6.2–120.8; P = 0.001) and 4.8-fold (95% CI: 1.5–15.0; P = 0.0076) higher, respectively than those in the low CXCR4 group. Conclusion High CXCR4 overexpression in specimens from LABC patients receiving neoadjuvant chemotherapy was predictive of cancer outcome. Neal T. Holm was the recipient of the American Society of Clinical Oncology 2007 Merit Award     

SerpinB3, a new prognostic tool in breast cancer patients treated with neoadjuvant chemotherapy

It is unclear which patients with breast cancer benefit from anthracycline-based neoadjuvant chemotherapy and whether taxanes increase survival. Hsp70 and serpinB3 inhibit a lysosomal cell death pathway induced in anthracycline and taxane treated cells, which may be critical for breast cancer cell survival. Thus we evaluated serpinB3 and Hsp70 as putative prognostic biomarkers in breast cancer patients treated with neoadjuvant chemotherapy. SerpinB3 and Hsp70 were measured by immunohistochemistry in residual breast tumours of patients without a complete pathological response [pCR] (n = 250), from a retrospective cohort of 296 patients treated with anthracycline-based chemotherapy with or without sequential docetaxel prior to surgical resection. SerpinB3 (P = 0.02) and Hsp70 (P = 0.008) positivity in residual tumour were associated with a poor pathological response and serpinB3 was an independent prognostic biomarker (HR 2.1 (95% CI 1.2–3.8), P = 0.02). Docetaxel significantly improved overall survival of breast cancer patients treated with neoadjuvant chemotherapy. Furthermore, serpinB3 positivity predicted poor survival in patients treated with anthracycline-based chemotherapy alone (P = 0.02), but those with serpinB3 negative tumours had as equally good survival as those also treated with docetaxel (P = 0.7). Survival was independent of serpinB3 expression in patients who received sequential docetaxel. The Nottingham prognostic index (NPI), calculated at surgical resection, predicted overall survival in these neoadjuvantly treated patients (P < 0.001) and serpinB3 status segregated patients with a moderate NPI into distinct prognostic subgroups. The use of clinical (NPI) and molecular (serpinB3) biomarkers measured at surgical resection to provide accurate prognostication in patients who do not achieve a pCR following neoadjuvant chemotherapy could facilitate optimal post-operative clinical management of these patients and is of significant clinical value. Furthermore, serpinB3 status in residual tumour is a biomarker of neoadjuvant docetaxel benefit in patients not achieving a pCR and use of serpinB3 molecular subtyping for adjuvant docetaxel treatment planning warrants further investigation.     

Epidermal growth factor receptor and AKT1 gene copy numbers by multi‐gene fluorescence in situ hybridization impact on prognosis in breast cancer

The epidermal growth factor receptor (EGFR)/PI3K/AKT signaling pathway aberrations play significant roles in breast cancer occurrence and development. However, the status of EGFR and AKT1 gene copy numbers remains unclear. In this study, we showed that the rates of EGFR and AKT1 gene copy number alterations were associated with the prognosis of breast cancer. Among 205 patients, high EGFR and AKT1 gene copy numbers were observed in 34.6% and 27.8% of cases by multi‐gene fluorescence in situ hybridization, respectively. Co‐heightened EGFR/AKT1 gene copy numbers were identified in 11.7% cases. No changes were found in 49.3% of patients. Although changes in EGFR and AKT1 gene copy numbers had no correlation with patients' age, tumor stage, histological grade and the expression status of other molecular makers, high EGFR (P = 0.0002) but not AKT1 (P = 0.1177) gene copy numbers correlated with poor 5‐year overall survival. The patients with co‐heightened EGFR/AKT1 gene copy numbers displayed a poorer prognosis than those with tumors with only high EGFR gene copy numbers (P = 0.0383). Both Univariate (U) and COX multivariate (C) analyses revealed that high EGFR and AKT1 gene copy numbers (P = 0.000 [U], P = 0.0001 [C]), similar to histological grade (P = 0.001 [U], P = 0.012 [C]) and lymph node metastasis (P = 0.046 [U], P = 0.158 [C]), were independent prognostic indicators of 5‐year overall survival. These results indicate that high EGFR and AKT1 gene copy numbers were relatively frequent in breast cancer. Co‐heightened EGFR/AKT1 gene copy numbers had a worse outcome than those with only high EGFR gene copy numbers, suggesting that evaluation of these two genes together may be useful for selecting patients for anti‐EGFR‐targeted therapy or anti‐EGFR/AKT1‐targeted therapy and for predicting outcomes.     

Clinical significance of axillary nodal ratio in stage II/III breast cancer treated with neoadjuvant chemotherapy

Purpose Neoadjuvant chemotherapy may modify the yield of involved axillary lymph nodes. The purpose of this study was to identify the clinical significance of the involved nodal ratios in patients with stage II/III breast cancer treated with neoadjuvant chemotherapy. Methods Two hundred and five stage II and III breast cancer patients who received neoadjuvant docetaxel/doxorubicin chemotherapy were enrolled in this prospective study. The patients received three cycles of neoadjuvant chemotherapy followed by curative surgery, either breast-conserving surgery or mastectomy with axillary lymph node dissection, and received three additional cycles of docetaxel/doxorubicin chemotherapy as adjuvant. Adjuvant radiotherapy and hormonal therapy were given after adjuvant chemotherapy when indicated. Results The median follow-up duration was 28.9 months. The overall response rate (RR) for neoadjuvant chemotherapy was 77.6%. The mean nodal ratio was 0.29 (range, 0–1.0; nodal ratio ≤0.25, 121 [59.0%] vs. >0.25, 84 [41.0%]). Relapse free survival (RFS) of the patients who had a nodal ratio >0.25 was significantly shorter (Hazard Ratio (HR) = 2.701, P = 0.001). A nodal ratio >0.25 was also associated with a shorter overall survival (OS) (HR = 4.109, P = 0.006). However, RFS and OS were not different according to the absolute number of involved nodes (ANIN) (P = 0.166, P = 0.248, respectively). In multivariate analysis, the nodal ratio was an independent prognostic factor for RFS and OS (HR = 4.246, P < 0.001; HR = 7.764, P < 0.001). Conclusion Axillary nodal ratios have an independent prognostic value in stage II/III breast cancer treated with neoadjuvant chemotherapy. Nodal ratio might be a useful tool to identify the patients at high risk of relapse in the neoadjuvant setting.     

Preliminary results of a phase III randomized study comparing chemotherapy neoadjuvantly or concurrently with radiotherapy for locoregionally advanced nasopharyngeal carcinoma

The current study was conducted to compare neoadjuvant chemotherapy (NACT) with concurrent chemotherapy for efficacy, toxicities and compliance of locoregionally advanced nasopharyngeal carcinoma (NPC). Eligible patients were randomized to NACT + radiotherapy (RT) + adjuvant chemotherapy (AC) arm or concurrent chemoradiotherapy(CCRT) + AC arm. Two arms received same conventional RT at a planned dose of 70 Gy. Neoadjuvant chemotherapy comprised cisplatin 90 mg/m² (30 mg/m²/day) and 5-fluorouracil 1,500 mg/m² (500 mg/m²/day) over 3 days for two 21-day cycles. The same regimen at equal dosage was administered on the 1st and 22nd days of the radiotherapy as concurrent chemotherapy. Four cycles of the same chemotherapy regimen were given to both two arms as AC. A total of 338 NPC patients were recruited. 170 patients were randomized to NACT arm and 168 patients to CCRT arm. The median duration of follow-up was 38 months. The 3-year OS and DFS rates were 95.9 versus 94.5% (P = 0.54) and 78.5 versus 82.5% (P = 0.16), respectively, in NACT and CCRT arms. An unplanned subgroup analysis according to the N-classification suggested that CCRT improves MFS in patients with N0-1 disease (80.1 vs. 94.9%, P = 0.034). Among the acute toxicities observed, the rates of grade 3/4 mucositis (52.4 vs. 35.9% P = 0.023) and vomiting (13.7 vs. 4.7% P = 0.000) were significantly higher in CCRT arm. Our preliminary results only showed an advantage of CCRT over NACT in NPC patients with limited N disease in MFS. More acute toxicities were observed in CCRT arm and a trend of better tolerance was observed in NACT arm.     

The expression and clinical significance of the androgen receptor and E-cadherin in triple-negative breast cancer

Triple-negative breast cancer (TNBC) has a poor prognosis and lacks prognostic indicators. The androgen receptor (AR) and E-cadherin are involved in the pathogenesis of breast cancer, but their roles are not clearly defined. We designed this study to evaluate AR and E-cadherin expression and to determine their relationships with the clinicopathologic parameters of triple-negative breast cancer. The present study included 127 TNBC patients. Immunohistochemical stains for AR and E-cadherin were performed, and the relationships between AR and E-cadherin expression and clinicopathologic data and prognosis were analyzed. We found that in TNBC patients, AR was expressed in 16(12.6%) cases, and E-cadherin was expressed in 41(33.0%) cases. AR expression was associated with tumor grade (P = 0.004) and menopausal status (P = 0.017), and E-cadherin expression was associated with node status (P= 0.016). A multivariate analysis demonstrated that tumor size, tumor grade, lymph node status, and E-cadherin were of prognostic significance for disease-free interval and overall survival. Compared with AR-positive patients, AR-negative patients showed significantly poorer outcomes with respect to the disease-free interval (P = 0.047) and overall survival (P = 0.038). E-cadherin-negative patients experienced shorter disease-free interval (P = 0.016) and poorer overall survival (P = 0.012) than did E-cadherin-positive patients. An AR-positive and E-cadherin-negative expression profile was associated with recurrence or metastasis (P = 0.036). Moreover, as the expression of nuclear AR increased (25% vs. 33.3%, P = 0.361), less E-cadherin staining was observed in TNBC samples. This finding suggested that AR and E-cadherin expression could be a useful prognostic marker for classifying subgroups of TNBC.     

Specific kinesin expression profiles associated with taxane resistance in basal-like breast cancer

Breast cancer is a genetically heterogenous disease with subtypes differing in prognosis and chemosensitivity. The basal-like breast cancer (BLBC) molecular subtype is associated with poorer outcomes, but is more responsive to taxane-based chemotherapy. Kinesins are intracellular transport proteins that interact with microtubules, which are also the mechanistic target for taxanes. We investigated the relationship between taxane resistance in BLBC and kinesins using both expression and functional studies. Kinesin (KIF) expression was evaluated in three settings in relation to taxane resistance: (i) the NCI-60 cancer cell lines, (ii) pre-treatment samples from four BLBC patient cohorts receiving neoadjuvant chemotherapy regimens with and without taxanes, and (iii) post-treatment samples from residual breast cancer following neoadjuvant taxane-containing chemotherapy. We used a novel functional approach to gene modification, validation-based insertional mutagenesis, to select kinesin-overexpressing clones of BLBC cells for evaluation of related mechanisms of taxane resistance. In the NCI-60 cell line dataset, overexpression of the kinesin KIFC3 is significantly correlated with resistance to both docetaxel (P < 0.001) and paclitaxel (P < 0.001), but not to platinum-based chemotherapy, including carboplatin (P = 0.49) and cisplatin (P = 0.10). Overexpression of KIFC3 and KIF5A in pre-chemotherapy samples similarly predicted resistance to paclitaxel in the MDACC cohorts (P = 0.01); no KIF predicted resistance to fluorouracil–epirubicin–cyclophosphamide or cisplatin in BLBC patient cohorts treated without taxanes. KIF12 is the most overexpressed KIF gene in post-chemotherapy taxane-resistant residual breast cancers (2.8-fold-change). Functional studies established that overexpression of KIFC3, KIF5A, and KIF12 were specific in mediating resistance to docetaxel and not vincristine or doxorubicin. Mutation of the ATP-binding domain of a kinesin abolished its ability to mediate docetaxel resistance. Overall, kinesin overexpression correlates with specific taxane resistance in BLBC cell lines and tissues. Our results suggest a novel approach for drug development to overcome taxane resistance in breast cancer through concurrent or sequential use of kinesin inhibitors.     

The role of topoisomerase IIα in predicting sensitivity to anthracyclines in breast cancer patients: a meta-analysis of published literatures

Topoisomerase IIα is not only a proliferation marker of tumor cells, but is also a target for anthracycline-based chemotherapy. Both in vitro and in vivo studies have shown that there is a relationship between topo IIα and chemosensitivity to anthracyclines, but the predictive role of topo IIα in breast cancer patients is still controversial. A meta-analysis based on published studies was performed to obtain an accurate assessment of the association between topo IIα and sensitivity to anthracycline-based chemotherapy. A total of 13 eligible studies, including 2,633 cases and 2,118 controls were identified. Topo IIα was associated with sensitivity to anthracyclines in locally advanced breast cancer patients who received neoadjuvant chemotherapy [five studies, including three using fluorescence in situ hybridization (FISH) and two using immunohistochemistry (IHC): relative risk (RR) = 1.93, 95% confidence interval (95% CI): 1.27–2.94, P = 0.002; two using FISH and three using IHC: RR = 1.98, 95% CI: 1.37–2.86, P < 0.001]. This association existed among three studies using FISH (RR = 2.03, 95% CI: 1.14–3.61, P = 0.017), but did not exist among three studies using IHC (P > 0.05). In early-stage breast cancer patients who received anthracycline-based adjuvant chemotherapy compared with non-taxane-based polychemotherapy, amplification [hazard ratio (HR) = 0.64, 95% CI: 0.49–0.83, P = 0.001; HR = 0.59, 95% CI: 0.35–1.01, P = 0.056] or deletion (HR = 0.82, 95% CI: 0.67–1.00, P = 0.051; HR = 0.58, 95% CI: 0.35–0.97, P = 0.036) of topo IIα was significantly associated with better recurrence-free survival and overall survival. In summary, the present meta-analysis suggests that topo IIα is a predictive factor for breast cancer patients who receive anthracycline-based chemotherapy. Larger and well-designed prospective studies are required to further evaluate the predictive role of topo IIα in clinical practice.     

mFOLFOXIRI versus mFOLFOX6 as neoadjuvant chemotherapy in locally advanced rectal cancer: A Propensity Score Matching Analysis

BackgroundPreoperative chemoradiotherapy (CRT) is the standard treatment for locally advanced rectal cancer (LARC). However, CRT failed to impact metastatic recurrence and the risk of side effects on bowel and genitourinary remained a concern. Neoadjuvant chemotherapy alone with mFOLFOX6 or FOLFOXIRI had been investigated in LARC. Here, we tried to compare the efficacy of mFOLFOXIRI with mFOLFOX6 as neoadjuvant chemotherapy in LARC.Patients and MethodsBetween January 2014 and December 2019, patients with LARC receiving neoadjuvant chemotherapy with mFOLFOXIRI or mFOLFOX6 were retrospective analyzed, including data from a prospective trial (NCT02217020). All patients underwent total mesorectal excision (TME). The propensity-score matching was preformed to adjust baseline potential confounders and to estimate differences in outcomes between patients receiving mFOLFOXIRI and mFOLFOX6. Survival analysis was done using Kaplan–Meier analysis and Cox proportional regression analysis.ResultsThe median follow-up time was 31.1 months. After propensity score matching, 156 patients were available for comparison in each group. The pathological complete response (pCR) rate was 17.9% vs. 5.1% (P< .001), the incidence rate of anastomotic fistula was 3.2% vs. 9% (P = .03), the 3 year disease-free survival (DFS) rate was 75% vs. 66.7% (P = .047) and the distant metastasis rate was 16.4% versus 26.6% (P = .013) for mFOLFOXIRI and mFOLFOX6 group, respectively. Patients receiving mFOLFOXIRI had higher incidence of grade III and/or IV nausea and/or vomiting (7.6% vs. 2.5%, P = .04).ConclusionsNeoadjuvant mFOLFOXIRI regimens improved pCR rate and survival outcome, reduced the rate of distant metastasis and anastomotic fistula when comparing with propensity-score matched controls of mFOLFOX6 neoadjuvant chemotherapy.MicroAbstractThis trial assessed the short-term and long-term effects of neoadjuvant chemotherapy with mFOLFOXIRI and mFOLFOX6 in patients with locally advanced rectal cancer. Comparing with propensity-score matched historical control of chemoradiotherapy, neoadjuvant mFOLFOXIRI chemotherapy was well tolerated and led to higher rates of 3 year disease-free survival in patients with locally advanced rectal cancer.     

Zoledronate for patients with invasive residual disease after anthracyclines-taxane-based chemotherapy for early breast cancer – The Phase III NeoAdjuvant Trial Add-oN (NaTaN) study (GBG 36/ABCSG 29)

BackgroundPatients with invasive residual disease after neoadjuvant chemotherapy (NACT) are considered to have chemo-resistant breast cancer. Bisphosphonates are an established treatment for bone metastases and are of potential benefit as adjuvant treatment in early breast cancer.Patients and methodsPatients who had invasive tumour residuals (ypT1-4 and/or ypN+) after a minimum of four cycles of anthracycline-taxane-containing NACT were eligible for the NeoAdjuvant Trial Add-oN study. Patients were randomised within 3 years after surgery to receive zoledronate 4 mg i.v. for 5 years versus observation. Zoledronate was given every 4 weeks for the first 6 months, every 3 months for the following 2 years, and every 6 months for the last 2.5 years. Primary objective was disease-free survival.ResultsAfter a median time of 54.7 months no difference in disease-free survival was observed between the zoledronate and observation groups (hazard ratio [HR] 0.960, 95% confidence interval [CI] 0.709–1.30, log rank P = 0.789). Various subgroups were examined without identifying a treatment effect of zoledronate. Patients over 55 years of age showed a HR of 0.832 in favour of zoledronate, but the result was not significant (P = 0.480). A similar result was obtained for overall survival with a HR of 1.19 (95% CI 0.79–1.79; log rank P = 0.408). Zoledronate was well tolerated and no new toxicity signal was identified.ConclusionPostneoadjuvant treatment with zoledronate does not improve outcome in patients without pathological complete response after neoadjuvant anthracycline-taxane-based chemotherapy for early breast cancer.     

Neoadjuvant chemotherapy and radiotherapy for locally advanced breast cancer: Safety and efficacy of reverse sequence compared to standard technique?

BackgroundThe reverse sequence of neoadjuvant chemotherapy, preoperative radiotherapy, mastectomy then immediate breast reconstruction is currently proposed for selected patients with locally advanced breast cancer. Few studies have compared it to the standard sequence of neoadjuvant chemotherapy, mastectomy and radiotherapy with or without differed reconstruction. Our study compares overall (OS) and recurrence-free (RFS) survivals of breast cancer patients treated with reverse sequence compared to the standard technique.MethodsIn this retrospective, single center study at a Comprehensive Cancer Center in France, patients were included if: female, age <65y, had received neoadjuvant chemotherapy, mastectomy and radiotherapy, and were M0. Outcomes for patients treated by reverse sequence (RS) are compared to those for patients treated by standard sequence (ST). Data was collected from medical records.ResultsFrom January 2009 to April 2018, 222 eligible patients were treated, 46 by RS and 176 by ST. Mean follow-up was 61.7 months. Five-year OS and RFS did not differ between groups. 5-yr OS: 88.4% 95%CI [74.1–95.0] for RS and 81.5% 95%CI [74.0–87.0] for ST (P = 0.4412); 5-yr RFS: 78.3% 95%CI [61.9–88.3] for RS and 70.1% 95%CI [62.2–76.7] for ST (P = 0.3003). Overall treatment time was significantly shorter in the RS group, and the rate of severe surgical complications did not differ between groups.ConclusionsFor locally advanced breast cancer patients with an indication for radiation therapy the reverse sequence offers similar safety and efficacy results as the standard treatment while allowing immediate breast reconstruction. However, careful patient selection is necessary, particularly with regard to preoperative lymph node invasion.     

The predictive and prognostic significance of pre- and post-treatment topoisomerase IIα in anthracycline-based neoadjuvant chemotherapy for local advanced breast cancer

Objective

To investigate the predictive and prognostic value of topoisomerase IIα (Topo IIα, Topo II) expression in the primary tumors and residual tumors of local advanced breast cancer (LABC) patients being treated with anthracycline-based neoadjuvant chemotherapy (NCT).

Methods

The data from 283 LABC patients who had been treated with anthracycline-based neoadjuvant chemotherapy were collected. The expression of Topo IIα, HER-2 and other biomarkers was determined via immunohistochemical analysis in pre- and post-chemotherapy specimens. The status of pre-treatment biomarkers was correlated with the clinical response determined by the RECIST 1.1 criteria, whereas the post-treatment biomarkers were studied for prognostic value using the Cox model.

Results

By analyzing the complete data from 99 patients, the co-expression of HER-2/Topo IIα was found to be significantly correlated with the clinical response to chemotherapy (Logistic regression P = 0.042). Notably, a 20% alteration in the Topo IIα status during neoadjuvant chemotherapy was found, which could also influence the sensitivity to treatment. With a survival analysis performed in 245 patients with residual tumors after NCT, node metastasis, HER-2 and Ki-67 were independent predictors of patient outcome. However, post-treatment Topo IIα expression demonstrated significant prognostic value in HER-2+ patients (P = 0.002). A relatively lower disease-free survival and overall survival was observed in HER-2+/Topo- patients (log rank P = 0.010 for DFS and P < 0.001 for OS).

Conclusion

Topo IIα, together with HER-2, might help to select for patients who could benefit from anthracycline-based neoadjuvant chemotherapy and identify non-complete responders at a higher risk of disease recurrence or death.     

Impact of neoadjuvant chemotherapy on surgical complications in breast cancer: A systematic review and meta-analysis

BackgroundThe increased use of neoadjuvant chemotherapy (NACT) facilitates an increase in breast-conserving surgery and immediate breast reconstruction. While NACT is considered to have the same oncological safety as adjuvant chemotherapy, evidence on the impact of NACT on surgical outcomes following breast surgery is unclear and varies across studies. The aim of this systematic review and meta-analysis was to assess the impact of NACT on surgical complications in breast cancer patients undergoing any kind of breast surgery.MethodsDatabase searches were conducted (March 26, 2021) to identify studies assessing the impact of NACT on postoperative complications. Studies were included if they compared a group of patients treated with NACT to a control group that was not, and if they reported at least one of our defined outcomes. Primary effect measures were odds ratios (ORs) and mean difference with a 95% confidence interval. Study quality was assessed by the Newcastle-Ottawa Scale.ResultsTwenty-six studies comprising 134,191 patients were included. NACT was not associated with an increased complication rate for overall complications (OR: 1.13, 95% CI: 0.86 to 1.47, p = 0.38), individual postoperative complications, nor surgery duration. There was a non-significant trend towards NACT increasing the risk of seroma, wound complications, skin or nipple necrosis, flap ischemia or loss, and implant loss. A significant difference in blood loss was found, favouring NACT (MD = ?75.85, 95% CI: -107.47 to ?44.23, p < 0.00001). Heterogeneity was significant between the studies (I²>50%).ConclusionCompared to a control group, NACT was not found to affect the surgical complications adversely.     

Experience of intravenous digital subtraction angiography (IV-DSA) in evaluation of neoadjuvant chemotherapy for advanced breast cancer

 Intravenous digital subtraction angiography (IV-DSA) was performed before and after neoadjuvant chemotherapy (NACT) in five patients with locally advanced breast cancer, and the efficacy of NACT was evaluated on the basis of the results of IV-DSA and histopathological examination. Following NACT, the maximum density of tumor enhancement (MAX) in the IV-DSA image decreased by 61.6% in case 1, 50% in case 2, 58.1% in case 3, 90.8% in case 4, and 97.2% in case 5. In all five patients, the efficacy of chemotherapy was rated as a partial response in terms of tumor size, while histological efficacy was rated as slightly effective in cases 1–4 and moderately effective in case 5. The pathological efficacy of NACT was highest in case 5, which showed the greatest decrease in MAX. These results indicate that variations in MAX reflect clinical efficacy, and, to some extent, also permit prediction of pathological efficacy. Received: March 4, 2002 / Accepted: June 10, 2002 Correspondence to:O. Watanabe