Adjuvant Chemotherapy For Triple-negative Breast Cancer Research Articles

Adjuvant treatment for triple negative breast cancer with residual tumor after neo-adjuvant chemotherapy. A single institutional retrospective analysis

PurposeIncomplete response to neoadjuvant chemotherapy (NACT) in triple negative breast cancer (TNBC) patients is correlated to high risk of relapse. This study aimed to evaluate the role of adjuvant chemotherapy in TNBC with residual tumor after NACT. MethodsWe retrospectively reviewed the outcome of patients with TNBC with residual tumor at surgery after a neoadjuvant treatment, followed by either adjuvant chemotherapy or observation. Primary endpoints were Disease Free Survival (DFS) and Overall Survival (OS). ResultsBetween January 2000 and December 2016, 223 patients with early TNBC operated at the European Institute of Oncology were eligible. A total of 83.4 % of patients received adjuvant chemotherapy after surgery. 90 patients received standard dose infusional regimens, while 96 patients (51.6 %) received oral metronomic chemotherapy. Adjusting the analysis by surgical stage and Ki67 value there was a benefit for DFS and OS in favor of the group that received postoperative chemotherapy (DFS-HR 0.58 p = 0.04; OS-HR 0.54, p = 0.02). At a subgroup analysis according to the different adjuvant treatments received, a benefit for metronomic chemotherapy versus no chemotherapy both for DFS (HR 0.46, p = 0.008) and OS (HR 0.45, p = 0.009) was reported. ConclusionOur retrospective analysis in a large cohort of TNBC patients with residual disease after NACT confirms the benefit of adding a postoperative treatment to reduce risk of relapse and death. Based on these results, we suggest that the adjuvant therapy based on metronomic cyclophosphamide and methotrexate deserves further investigation in this patients population.

Adjuvant addition of capecitabine to early-stage triple-negative breast cancer patients receiving standard chemotherapy: a meta-analysis.

Triple-negative breast cancer (TNBC) pertains to a breast cancer subtype that has the highest metastatic and recurrence rates. The effectiveness of capecitabine as adjuvant chemotherapy for TNBC has remained unclear. This study conducted a meta-analysis of the efficacy of capecitabine as adjuvant chemotherapy for early-stage TNBC treated with taxane-/anthracycline-based chemotherapy. We identified relevant research reports in online databases until May 2019. We finally included seven randomized clinical trials to perform this meta-analysis. Altogether, the seven trials enrolled 3151 early-stage TNBC patients, with 1552 receiving standard (neo)adjuvant chemotherapy regimens and 1599 receiving addition of capecitabine in the adjuvant settings besides standard regimens. A meta-analysis of the seven trials revealed a significant increase in disease-free survival (DFS) with the addition of capecitabine (Hazard ratio (HR) = 0.77, 95% CI 0.66-0.90). This improvement in DFS was significant both in trials conducted in America-Europe and in Asia. In trials involving six to eight cycles of capecitabine addition, we observed a significant improvement in DFS. Furthermore, in the meta-analysis of six trials, we detected a significant increase in overall survival (OS) favoring capecitabine (HR = 0.69, 95% CI 0.56-0.85). Adjuvant addition of capecitabine to early-stage TNBC patients receiving standard chemotherapy showed significant DFS and OS improvement. Future studies involving the selection of patients that may have the highest survival benefit from adding capecitabine are warranted.

A randomized phase III trial comparing dose-dense epirubicin and cyclophosphamide (ECdd) followed by paclitaxel (T) with paclitaxel plus carboplatin (PCdd) as adjuvant chemotherapy for early triple-negative breast cancer patients with high-recurrence risk.

528 Background: There are no well-established adjuvant chemotherapy (AC) regimens for early triple negative breast cancer (TNBC). Our randomized phase III trial was designed to compare dose dense paclitaxel plus carboplatin (PCdd) with commonly used dose dense epirubicin and cyclophosphamide, followed by paclitaxel (ECdd-T) regimen as AC for TNBC with high recurrence risk. Methods: Between May 2011 and November 2015, TNBC patients were randomized in 1:1 ratio to receive PCdd or ECdd-T regimen as AC every two weeks for 8 cycles with administration of granulocyte stimulating factor (G-CSF) support. The primary endpoint was 3-year disease free survival (DFS).The secondary endpoints included overall survival (OS) and safety. Survival analyses were also performed for different subgroups stratified by age status (≤40 years vs >40 years), Ki 67(<50 vs ≥50), tumor size (<2cm vs ≥2cm), nodal status (N- vs N+) and treatment free survival (TFS) (<30 days vs ≥30 days). Results: In total, 132 patients with a median age of 49 years (PCdd 64 patients, ECdd-T 68 patients) were enrolled. After a median follow-up of 57.3 months, 23 events were observed (18 in ECdd-T, 5 in PCdd). Patients in the PCdd arm had significantly higher DFS rate than that in the ECdd-T arm (log-rank p = 0.0046, hazard ratio (HR) 0.305, 95% confidence interval (CI) = 0.134-0.693). The 3-year DFS rate was 93.7% with PCdd versus 77.9% with ECdd-T,respectively. Difference in 3-year OS rate was observed between the two arms (98.4% vs 92.6%), significantly higher in the PCdd arm ( p = 0.0268). Both regimens were well tolerated with manageable adverse events(AEs). Worse neutropenia (Grade 3/4: 48.5% in ECdd-T vs. 21.9% in PCdd, p=0.002) was found in ECdd-T arm. 3-year DFS rate for PCdd was superior in the following subgroups, age>40 years, clinically evaluated lymph nodes, TFS <30 days, with statistical significance ( p <0.05). Conclusions: Our data suggested that PCdd was superior to ECdd-T as AC for early TNBC in terms of improving 3-year DFS and OS. PCdd with lower hematological toxicity might be an appropriate regimen for early TNBC patients with high recurrence risk. Clinical trial information: NCT01378533.

Abstract 1776: Impact of homologous recombination deficiency (HRD) biomarkers on outcomes in triple-negative breast cancer (TNBC) patients treated with AC chemotherapy (SWOG S9313)

Abstract Introduction: There is a critical need to develop biomarkers of response and resistance to adjuvant chemotherapy for TNBC. In preliminary studies, homologous recombination deficiency (HRD)-causing alterations have been reported in TNBC patients. HRD may impact response to standard chemotherapy as well as investigational therapies, such as PARP inhibitors and platinum agents. We report on the prognostic impact of two such markers in a large cohort of early stage TNBC patients who were uniformly treated with adjuvant doxorubicin (A) and cyclophosphamide (C). Aims: To investigate BRCA1 promoter methylation (PM) and HRD score as prognostic markers in TNBC patients treated with adjuvant AC on S9313. Methods: SWOG protocol S9313 accrued 3,125 women with early stage breast cancer to two alternative dose schedules of AC with no difference in outcomes between the two arms (J Clin Oncol 2007). We identified 425 (14%) patients with centrally determined TNBC status for whom tissue was available. BRCA1 PM (methylation specific PCR) and HRD score (composite of loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions, Myriad Genetics Inc.) were performed on genomic DNA isolated from pre-treatment FFPE breast tumor tissue. HRD was classified as positive if there was either a deleterious tumor(t) BRCA1 or BRCA2 mutation and/or a pre-defined HRD score > 42. The markers were tested for prognostic effect on DFS and OS using a Cox regression model with adjustment for randomized treatment assignment. Results: For 425 TNBC patients median age was 45 years (range 22-74) and at a median follow up of 10.2 years there are 166 DFS and 129 OS events (5 year DFS and OS = 74% and 82%, respectively; 10-year DFS and OS = 66% and 73%). BRCA1 PM was determined in 82% (348/425) and was detected in 32% of patients. Presence of BRCA1 PM was suggestive of better DFS, but not statistically significant (HR=0.74; 95% CI 0.50-1.08, p=0.12). HRD results were determined in 91% (379/425) and 67% were HRD positive (27% with tBRCA mutation and 40% tBRCA negative but HRD score >42). HRD positive status was associated with a better DFS (HR = 0.69; 95% CI 0.49-0.96 (p=0.027)) and OS (HR= 0.67; 95% CI 0.47-0.97 (p=0.032)). High HRD score (≥42) in tBRCA negative patients (n=274) was also associated with better DFS (HR = 0.62; 95% CI 0.42-0.92). tBRCA status (positive versus negative) did not impact DFS (p = 0.78). Conclusions: Two thirds of TNBC patients receiving adjuvant AC chemotherapy had tumor HRD positivity. HRD was associated with better DFS and OS, perhaps due to high responses to AC. HRD status has the potential to be used as a selection criterion to identify TNBC patients who receive significant benefit from anthracycline chemotherapy, and may also be of value in selecting patients suitable for treatment with other DNA damaging agents like platinum salts/PARP-inhibitors. Citation Format: Priyanka Sharma, William Barlow, Andrew K. Godwin, Harsh Pathak, Kamilla Isakova, Anne R. Hartman, Kristen M. Timms, Hannah M. Linden, Debu Tripathy, Gabriel N. Hortobagyi, Daniel F. Hayes. Impact of homologous recombination deficiency (HRD) biomarkers on outcomes in triple-negative breast cancer (TNBC) patients treated with AC chemotherapy (SWOG S9313) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1776. doi:10.1158/1538-7445.AM2017-1776

Prediction of adjuvant chemotherapy response in triple negative breast cancer with discovery and targeted proteomics.

BackgroundTriple-negative breast cancer (TNBC) accounts for 15–20% of all breast cancers and usually requires the administration of adjuvant chemotherapy after surgery but even with this treatment many patients still suffer from a relapse. The main objective of this study was to identify proteomics-based biomarkers that predict the response to standard adjuvant chemotherapy, so that patients at are not going to benefit from it can be offered therapeutic alternatives.MethodsWe analyzed the proteome of a retrospective series of formalin-fixed, paraffin-embedded TNBC tissue applying high-throughput label-free quantitative proteomics. We identified several protein signatures with predictive value, which were validated with quantitative targeted proteomics in an independent cohort of patients and further evaluated in publicly available transcriptomics data.ResultsUsing univariate Cox analysis, a panel of 18 proteins was significantly associated with distant metastasis-free survival of patients (p<0.01). A reduced 5-protein profile with prognostic value was identified and its prediction performance was assessed in an independent targeted proteomics experiment and a publicly available transcriptomics dataset. Predictor P5 including peptides from proteins RAC2, RAB6A, BIEA and IPYR was the best performance protein combination in predicting relapse after adjuvant chemotherapy in TNBC patients.ConclusionsThis study identified a protein combination signature that complements histopathological prognostic factors in TNBC treated with adjuvant chemotherapy. The protein signature can be used in paraffin-embedded samples, and after a prospective validation in independent series, it could be used as predictive clinical test in order to recommend participation in clinical trials or a more exhaustive follow-up.

Prognostic value of histopathology, stromal tumor infiltrating lymphocytes (sTILs) and adjuvant chemotherapy (AdjCT) in early stage triple negative breast cancer (TNBC).

533 Background: Current guidelines define TNBC as complete absence of estrogen (ER) and progesterone receptor (PR), without HER2 amplification. However, the prognostic impact of clinical and histopathological factors, sTILs, and AdjCT in TNBC meeting these strict criteria is unknown. Methods: From a cohort of 9985 women who underwent upfront surgery for M0 breast cancer (BC) at Mayo Clinic Rochester from 1985-2012, 1159 pts with ER negative or low (≤10%) BC were identified for central ER/PR/HER2 staining and HER2 FISH (IHC2+ only) to select those with TNBC by modern definitions. Cox proportional hazards models were used to assess the impact of clinicopathological variables on invasive disease-free (IDFS) and overall survival (OS). Results: Tumors from 605 pts (median age 56.3 yrs) met criteria for TNBC (ER &lt; 1%, PR &lt; 1% and HER2 0, 1 or 2+ and FISH negative). 51% were T1, 65% N0, 88% grade 3, and 75% had Ki67 &gt; 15%. Histologically, 39% were anaplastic, 26% invasive ductal, 16% medullary, 8% metaplastic, 6% apocrine and 5% others. Median sTILs was 20% (0-90%). 55% pts received AdjCT [21% anthracycline (A), 19% A + taxane, and 15% other]. Median follow-up for IDFS and OS were 7.4 and 10.6 yrs, respectively. Multivariate analyses demonstrated that higher N stage (p &lt; 0.01), lower sTILs (p = 0.01) and no AdjCT (p &lt; 0.01) were independently associated with worse IDFS and OS. Histology (medullary subtype) was associated with better IDFS in univariate (HR 0.56, 95% CI, 0.35-0.89) but not in multivariate analyses, once sTILs were accounted for. Among systemically untreated pts (n = 182), higher N (p &lt; 0.01) and lower sTILs (p = 0.04) were associated with worse IDFS. For systemically untreated T1N0 pts (n = 111), the 5-yr IDFS was 70% (95% CI, 61-81) [T1a: 83% (95% CI, 63-100), T1b: 68% (95% CI, 52-88) and T1c: 67% (95% CI, 55-83)], compared to 78% (95% CI, 68-84) for T1N0 pts treated with AdjCT. Conclusions: In TNBC pts, N stage, sTILs and receipt of AdjCT were independently prognostic for IDFS and OS. sTILs remained prognostic for IDFS in systemically untreated TNBC. In N0 TNBC, the risk of recurrence or death was substantial in the absence of chemotherapy, even for those with T1 tumors.

Impact of DNA repair deficiency signature on outcomes in triple negative breast cancer (TNBC) patients treated with AC chemotherapy (SWOG S9313).

529 Background: Biomarkers of response and resistance to adjuvant chemotherapy for TNBC are needed. Deficiency in DNA damage response (DDR) and repair pathways have been reported in TNBC and may impact response to chemotherapy. Aims: To investigate DNA damage response deficiency (DDRD) molecular signature, BRCA1mRNA expression and Tumor Infiltrating Lymphocytes (TILs) as prognostic markers in TNBC patients treated with adjuvant AC on S9313. Methods: S9313 accrued 3125 early stage BC patients to two alternative schedules of AC with no difference in outcomes between the two arms. We identified 425 (14%) patients with centrally determined TNBC with tissue availability. DDRD signature (44 gene signature, Almac Inc.) and BRCA1expression (NanoString nCounter) were performed on RNA isolated from pre-treatment FFPE tumor tissue. DDRD score was classified in quartiles. TILs evaluation was performed using previously described criteria. Markers were tested for prognostic effect on DFS and OS using Cox regression model with adjustment for randomized treatment assignment. Results: For 425 TNBC patients median age: 45 yrs, and 5 year DFS and OS = 74% and 82%, respectively. DDRD signature was successfully evaluated in 89.6% (381/425) but only 267 (62.8%) met 60% tumor content criterion for inclusion. DDRD score quartiles were associated with DFS (5 year DFS 59% &amp; 82% in the lowest &amp; highest quartiles respectively, p = 0.0005) and OS (5 year OS 74% and 86% in lowest and highest quartiles respectively, p = 0.008). BRCA1 expression and TILs were successfully determined in 78% and 99% samples, respectively. BRCA1expression was not associated with DFS. TILs were associated with DFS (10% increase HR = 0.88; 95% CI 0.79-0.97; p = 0.016) and OS (HR = 0.84; 95% CI 0.74-0.94; p = 0.0005). DDRD score and TILs were highly correlated (Pearson = 0.62). In multivariate model of DFS including TILs and DDRD quartiles, only DDRD remains significant (p = 0.018). Conclusions: DDRD signature was prognostic in TNBC patients treated with AC chemotherapy and has the potential to be used as a selection criterion to identify TNBC patients whose prognosis is sufficiently poor to justify evaluation of alternative treatment.

Treatment recommendations for older women with breast cancer: A survey among surgical, radiation and medical oncologists

PurposeAs older women with breast cancer (BC) are underrepresented in trials, it is often unclear what represents the best treatment option for this patient group. To understand how oncologists approach the management of BC in older patients, we assessed their treatment recommendations. MethodsIn an online survey, 106 surgical, 37 radiation and 31 medical oncologists provided a treatment recommendation for hypothetical patients aged >70 years. Scenarios included loco-regional therapy with patient age varying at 76 and 84 years; systemic therapy with Karnofsky performance score varying at 90 and 50%; neo-adjuvant therapy; and adjuvant chemotherapy in triple-negative BC. ResultsParticipants would less often recommend breast-conserving surgery plus radiotherapy for an 84 versus a 76-year-old patient (56% versus 73%, p = 0.001). They would more often accept omission of radiotherapy after breast-conserving surgery in older than in younger patients, if the patient wished to avoid this therapy (26% versus 4%, p < 0.001). All participants would propose systemic therapy for a high-recurrence risk patient with a good performance score, and 92% would still recommend therapy if the patient had a poor score (p < 0.001). Neo-adjuvant hormonal therapy followed by breast-conserving surgery for a large tumour was recommended by 27% of the participants. Adjuvant chemotherapy for an otherwise healthy woman with triple-negative BC was considered by 83% of the participants. ConclusionsPatient age and performance status influenced specialists' treatment recommendations. The observed recommendations for the treatment scenarios under investigation differ from older women's actual treatment. This discrepancy highlights the need for studies specifically targeting older patients.

Aflibercept and Ang1 supplementation improve neoadjuvant or adjuvant chemotherapy in a preclinical model of resectable breast cancer.

Phase III clinical trials evaluating bevacizumab (an antibody to the angiogenic ligand, VEGF-A) in breast cancer have found improved responses in the presurgical neoadjuvant setting but no benefits in the postsurgical adjuvant setting. The objective of this study was to evaluate alternative antiangiogenic therapies, which target multiple VEGF family members or differentially modulate the Angiopoietin/Tie2 pathway, in a mouse model of resectable triple-negative breast cancer (TNBC). Neoadjuvant therapy experiments involved treating established orthotopic xenografts of an aggressive metastatic variant of the MDA-MB-231 human TNBC cell line, LM2-4. Adjuvant therapies were given after primary tumor resections to treat postsurgical regrowths and distant metastases. Aflibercept (‘VEGF Trap’, which neutralizes VEGF-A, VEGF-B and PlGF) showed greater efficacy than nesvacumab (an anti-Ang2 antibody) as an add-on to neoadjuvant/adjuvant chemotherapy. Concurrent inhibition of Ang1 and Ang2 signaling (through an antagonistic anti-Tie2 antibody) was not more efficacious than selective Ang2 inhibition. In contrast, short-term perioperative BowAng1 (a recombinant Ang1 variant) improved the efficacy of adjuvant chemotherapy. In conclusion, concurrent VEGF pathway inhibition is more likely than Ang/Tie2 pathway inhibition (e.g., anti-Ang2, anti-Ang2/Ang1, anti-Tie2) to improve neoadjuvant/adjuvant chemotherapies for TNBC. Short-term perioperative Ang1 supplementation may also have therapeutic potential in conjunction with adjuvant chemotherapy for TNBC.

Abstract S6-5: Primary results of BEATRICE, a randomized phase III trial evaluating adjuvant bevacizumab-containing therapy in triple-negative breast cancer

Abstract Background: Bevacizumab (BEV), an anti-VEGF antibody, significantly enhanced progression-free survival in metastatic breast cancer (BC) (E2100, AVADO, RIBBON-1, RIBBON-2) and pathologic complete response rates in the neoadjuvant setting (GeparQuinto, NSABP B-40) when combined with chemotherapy (CT). The dependence of micro-metastases on angiogenesis [Holmgren 1995] suggests that patients might benefit from anti-angiogenic strategies applied in the adjuvant setting. The BEATRICE trial was designed to test this hypothesis in patients with triple-negative BC, who have a poor prognosis and lack targeted options for treatment. Methods: In this open-label randomized multinational phase III trial, patients with centrally confirmed triple-negative operable primary invasive BC (pT1a-pT3) were randomized 1:1 after definitive surgery to receive ≥4 cycles of either CT alone or the same CT + 1 year of BEV 5 mg/kg/wk equivalent. CT was anthracycline [anth] and/or taxane-based. Patients were stratified by nodal status (0 vs 1–3 vs ≥4 involved nodes), CT backbone (anth vs anth + taxane vs taxane), hormone receptor status (negative vs low), and surgery (breast-conserving vs mastectomy). The primary objective is to compare invasive disease-free survival (IDFS) [Hudis 2007] with adjuvant CT ± 1 year of BEV. Secondary outcome measures are overall survival (OS), breast cancer-free interval, disease-free survival (DFS), distant DFS, and safety (NCI CTCAE v3.0). The sample size was calculated to provide 80% power for a HR=0.75 at α=0.05 assuming 5-year IDFS of 72.0% with CT vs 78.2% with CT + BEV with 388 events. BEATRICE also includes evaluation of potential predictive and prognostic biomarkers. Results: Between Dec 2007 and Mar 2010, 2591 patients were randomized. At data cut-off (Feb 29, 2012), median follow-up was 32 months. The mean CT exposure was balanced between treatment arms. Median BEV duration was 11.7 months. BEV was associated with an increased incidence of grade ≥3 congestive heart failure/left ventricular dysfunction (3% vs &amp;lt;1% with CT), grade ≥3 hypertension (12% vs &amp;lt;1%), and treatment discontinuation (BEV and/or CT: 20% vs 2%) but no increase in the risk of fatal adverse events (0.3% vs 0.2%). No new safety signals were observed. Conclusion: There was no statistically significant improvement in IDFS with the addition of 1 year's BEV to adjuvant CT for triple-negative BC. Further follow-up is required to assess the impact of BEV on OS. The safety profile was consistent with previous reports in metastatic BC with a low incidence of fatal adverse events. Protocol-specified biomarker analyses are ongoing. Updated OS results are expected in 2013. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S6-5.