Circulating Tumor DNA as a Predictive Marker of Recurrence for Patients With Stage II-III Breast Cancer Treated With Neoadjuvant Therapy

BackgroundPatients with stage II to III breast cancer have a high recurrence rate. The early detection of recurrent breast cancer remains a major unmet need. Circulating tumor DNA (ctDNA) has been proven to be a marker of disease progression in metastatic breast cancer. We aimed to evaluate the prognostic value of ctDNA in the setting of neoadjuvant therapy (NAT).MethodsPlasma was sampled at the initial diagnosis (defined as before NAT) and after breast surgery and neoadjuvant therapy(defined as after NAT). We extracted ctDNA from the plasma and performed deep sequencing of a target gene panel. ctDNA positivity was marked by the detection of alterations, such as mutations and copy number variations.ResultsA total of 95 patients were enrolled in this study; 60 patients exhibited ctDNA positivity before NAT, and 31 patients exhibited ctDNA positivity after NAT. A pathologic complete response (pCR) was observed in 13 patients, including one ER(+)Her2(-) patient, six Her2(+) patients and six triple-negative breast cancer (TNBC) patients. Among the entire cohort, multivariate analysis showed that N3 classification and ctDNA positivity after NAT were independent risk factors that predicted recurrence (N3, hazard ratio (HR) 3.34, 95% confidence interval (CI) 1.26 – 8.87, p = 0.016; ctDNA, HR 4.29, 95% CI 2.06 – 8.92, p < 0.0001). The presence of ctDNA before NAT did not affect the rate of recurrence-free survival. For patients with Her2(+) or TNBC, patients who did not achieve pCR were associated with a trend of higher recurrence (p = 0.105). Advanced nodal status and ctDNA positivity after NAT were significant risk factors for recurrence (N2 – 3, HR 3.753, 95% CI 1.146 – 12.297, p = 0.029; ctDNA, HR 3.123, 95% CI 1.139 – 8.564, p = 0.027). Two patients who achieved pCR had ctDNA positivity after NAT; one TNBC patient had hepatic metastases six months after surgery, and one Her2(+) breast cancer patient had brain metastasis 13 months after surgery.ConclusionsThis study suggested that the presence of ctDNA after NAT is a robust marker for predicting relapse in stage II to III breast cancer patients.

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Circulating tumor DNA as a predictive marker of recurrence for patients with stage II-III breast cancer treated with neoadjuvant therapy

10.21203/rs.3.rs-598665/v1 ◽

2021 ◽

Author(s):

Po-Han Lin ◽

Ming-Yang Wang ◽

Chiao Lo ◽

Li-Wei Tsai ◽

Tzu-Chun Yen ◽

...

Keyword(s):

Breast Cancer ◽

Risk Factors ◽

Neoadjuvant Therapy ◽

Cancer Patients ◽

Pathologic Complete Response ◽

Circulating Tumor Dna ◽

Stage Ii ◽

Breast Cancer Patients ◽

Her2 Breast Cancer ◽

Tumor Dna

Abstract Background:Patients with stage II to III breast cancer have a high recurrence rate. The early detection of recurrent breast cancer remains a major unmet need. Circulating tumor DNA (ctDNA) has been shown to be a marker to detect disease progression in metastatic breast cancer. We aimed to evaluate the prognostic value of ctDNA in the setting of neoadjuvant therapy (NAT).Methods:Plasma was sampled at the initial diagnosis (defined as before NAT) and after NAT and breast surgery (defined as after NAT). We extracted ctDNA from the plasma and performed deep sequencing of a target gene panel. The detection of alterations, such as mutations and copy number variations, were considered to indicate ctDNA positivity.Results:A total of 95 patients were enrolled in this study; 60 patients exhibited ctDNA positivity before NAT, and 31 patients had ctDNA positivity after NAT. A pathologic complete response (pCR) was observed in 13 patients, including one ER(+)Her2(-) patient, six Her2(+) patients and six triple-negative breast cancer (TNBC) patients. Among the entire cohort, multivariate analysis showed that an N3 classification and ctDNA positivity after NAT were independent risk factors that predicted recurrence (N3, hazard ratio (HR) 3.34, 95% confidence interval (CI) 1.26 – 8.87, p = 0.016; ctDNA, HR 4.29, 95% CI 2.06 – 8.92, p < 0.0001). The presence of ctDNA before NAT did not affect the rate of recurrence-free survival. For patients with Her2(+) or TNBC, non-pCR breast cancer patients were associated with a trend of higher recurrence (p = 0.105). Advanced nodal status and ctDNA positivity after NAT were significant risk factors for recurrence (N2 – 3, HR 3.753, 95% CI 1.146 – 12.297, p = 0.029; ctDNA, HR 3.123, 95% CI 1.139 – 8.564, p = 0.027). Two patients who achieved a pCR had ctDNA positivity after NAT; one TNBC patient had hepatic metastases six months after surgery, and one Her2(+) breast cancer patient had brain metastasis 13 months after surgery.Conclusions:This study suggested that the presence of ctDNA after NAT is a robust marker for predicting relapse in stage II to III breast cancer patients.

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Abstract 720: Analysis of circulating tumor DNA after neoadjuvant therapy to predict disease relapse in patients with stage II-III breast cancer

10.1158/1538-7445.am2020-720 ◽

2020 ◽

Author(s):

Po-Han Lin ◽

Sung-Sheng Kuo ◽

Chiun-Sheng Huang

Keyword(s):

Breast Cancer ◽

Neoadjuvant Therapy ◽

Circulating Tumor Dna ◽

Stage Ii ◽

Disease Relapse ◽

Tumor Dna

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Circulating tumor DNA in neoadjuvant treated breast cancer reflects response and survival

10.1101/2020.02.03.20019760 ◽

2020 ◽

Cited By ~ 1

Author(s):

Mark Jesus M. Magbanua ◽

Lamorna Brown-Swigart ◽

Hsin-Ta Wu ◽

Gillian L. Hirst ◽

Christina Yau ◽

...

Keyword(s):

Breast Cancer ◽

Residual Disease ◽

Pathologic Complete Response ◽

Circulating Tumor Dna ◽

Patient Specific ◽

Breast Cancer Patients ◽

Metastatic Recurrence ◽

Excellent Outcome ◽

Increased Risk ◽

Tumor Dna

AbstractPathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk of metastatic recurrence in 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL. Cell-free DNA (cfDNA) was isolated from 291 plasma samples collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect 16 patient-specific mutations (from whole exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. At T0, 61 of 84 (73%) patients were ctDNA-positive, which decreased over time (T1-35%; T2-14%; T3-9%). Patients who remained ctDNA-positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared to those who cleared ctDNA (52% non-pCR; OR 4.33, P=0.012). After NAC, all patients who achieved pCR were ctDNA-negative (n=17, 100%). For those who did not achieve pCR (n=43), ctDNA-positive patients (14%) had significantly increased risk of metastatic recurrence (HR 10.4; 95% CI, 2.3–46.6); interestingly, patients who did not achieve pCR but were ctDNA-negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI, 0.15–13.5). Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival regardless of pCR status. Personalized monitoring of ctDNA during NAC may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.

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Personalized circulating tumor DNA analysis to detect residual disease after neoadjuvant therapy in breast cancer

Science Translational Medicine ◽

10.1126/scitranslmed.aax7392 ◽

2019 ◽

Vol 11 (504) ◽

pp. eaax7392 ◽

Cited By ~ 31

Author(s):

Bradon R. McDonald ◽

Tania Contente-Cuomo ◽

Stephen-John Sammut ◽

Ahuva Odenheimer-Bergman ◽

Brenda Ernst ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Therapy ◽

Dna Analysis ◽

Residual Disease ◽

Circulating Tumor Dna ◽

Patient Specific ◽

Molecular Response ◽

Curative Intent ◽

Current Limit ◽

Tumor Dna

Longitudinal analysis of circulating tumor DNA (ctDNA) has shown promise for monitoring treatment response. However, most current methods lack adequate sensitivity for residual disease detection during or after completion of treatment in patients with nonmetastatic cancer. To address this gap and to improve sensitivity for minute quantities of residual tumor DNA in plasma, we have developed targeted digital sequencing (TARDIS) for multiplexed analysis of patient-specific cancer mutations. In reference samples, by simultaneously analyzing 8 to 16 known mutations, TARDIS achieved 91 and 53% sensitivity at mutant allele fractions (AFs) of 3 in 104 and 3 in 105, respectively, with 96% specificity, using input DNA equivalent to a single tube of blood. We successfully analyzed up to 115 mutations per patient in 80 plasma samples from 33 women with stage I to III breast cancer. Before treatment, TARDIS detected ctDNA in all patients with 0.11% median AF. After completion of neoadjuvant therapy, ctDNA concentrations were lower in patients who achieved pathological complete response (pathCR) compared to patients with residual disease (median AFs, 0.003 and 0.017%, respectively, P = 0.0057, AUC = 0.83). In addition, patients with pathCR showed a larger decrease in ctDNA concentrations during neoadjuvant therapy. These results demonstrate high accuracy for assessment of molecular response and residual disease during neoadjuvant therapy using ctDNA analysis. TARDIS has achieved up to 100-fold improvement beyond the current limit of ctDNA detection using clinically relevant blood volumes, demonstrating that personalized ctDNA tracking could enable individualized clinical management of patients with cancer treated with curative intent.

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Abstract P6-17-18: Pathologic complete response (pCR) in locally advanced HER2+ (HER2+) breast cancer (BC) treated with anthracycline-free neoadjuvant therapy

10.1158/1538-7445.sabcs18-p6-17-18 ◽

2019 ◽

Author(s):

G Somlo ◽

J Waisman ◽

Y Yuan ◽

L Kruper ◽

P Frankel ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Therapy ◽

Locally Advanced ◽

Pathologic Complete Response ◽

Complete Response ◽

Her2 Breast Cancer

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Impact of neoadjuvant HER2-directed therapy on HER2 status in breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e12130 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e12130-e12130

Author(s):

Nicholas Manguso ◽

Jeffrey Johnson ◽

Reva Kakkar Basho ◽

Heather L. McArthur ◽

Hisashi Tanaka ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Therapy ◽

Residual Disease ◽

Pathologic Complete Response ◽

Residual Tumor ◽

Her2 Status ◽

Her2 Positive ◽

Her2 Breast Cancer ◽

Copy Numbers ◽

Pre Treatment

e12130 Background: Neoadjuvant chemotherapy (NAC) with HER2-directed therapy has become standard-of-care for most women with potentially curable HER2-positive (HER2+) breast cancer and is associated with a high pathologic complete response (pCR) rate. The HER2 status of residual disease after NAC is not well characterized and could potentially inform clinical decisions about additional systemic therapy. We describe tumoral HER2 status before and after NAC with HER2-directed therapy. Methods: An institutional database was screened to identify patients with stage 1-3 HER2+ breast cancer by fluorescence in situ hybridization (FISH) and/or immunohistochemistry (IHC) who received NAC with HER2-directed therapy followed by resection between 2011 and 2015. Clinicopathologic data was collected. Change in HER2 status by FISH and IHC following treatment was described. Results: 99 patients were identified. Median age was 49 years (range 26-85). Pre-treatment median HER2/CEP17 copy number ratio (CNR) for all tumors was 6.3 (range 1.9-20.7) by FISH and 84 (84.8%) tumors were IHC 3+. 44 (44.4%) patients achieved a pCR. Of the 55 patients with residual disease, 35 had sufficient residual tumor to evaluate HER2 status and 14/35 (40%) were HER2- by FISH and IHC (table). Tumors converting from HER2+ to HER2- had lower pre-treatment median HER2 copy numbers (11.9, range 4.6-22) compared to tumors that remained HER2+ (18.3, range 5.1-48.6; p=0.04) after neoadjuvant therapy. Additionally, pre-treatment median HER2/CEP17 CNR was lower among tumors that converted from HER2+ to HER2- (3.0, range 2.2-8.2) compared to those remaining HER2+ (6.8, range 2-15.7; p=0.02). Conclusions: While pCR rates are high with NAC and HER2-directed therapy, many patients still have residual tumor. In this cohort, 40% of patients with evaluable residual disease after NAC had HER2+ tumors that became HER2-. HER2 conversion was associated with lower pre-treatment HER2 copy numbers and HER2/CEP17 CNR. Conversion from HER2+ to HER2- in patients undergoing neoadjuvant therapy may have clinical significance and biological implications. [Table: see text]

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Effect of neoadjuvant pertuzumab-containing regimens on pathologic complete response rates in stage II-III HER2-neu positive breast cancer: A retrospective, single institutional experience.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.580 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 580-580

Author(s):

Rashmi Krishna Murthy ◽

Takeo Fujii ◽

Kenneth R. Hess ◽

Akshara Singareeka Raghavendra ◽

Bora Lim ◽

...

Keyword(s):

Breast Cancer ◽

Targeted Therapy ◽

Clinical Stage ◽

Pathologic Complete Response ◽

Neoadjuvant Treatment ◽

Complete Response ◽

Stage Ii ◽

Her2 Positive ◽

Her2 Breast Cancer ◽

Positive Breast Cancer

580 Background: Pertuzumab (P) in combination with trastuzumab (H) based chemotherapy is currently FDA- approved as a standard neoadjuvant treatment for patients with clinical stage II-III HER2-positive (HER2+) breast cancer (BC). The chemotherapy backbone of HER2-targeted therapy varies and may include taxane (T) and/or anthracycline (A), or carboplatin (C). The goal of this study was to retrospectively evaluate the pathologic complete response (pCR) rate for HP-containing regimens compared to H containing regimens for stage II-III HER2+ BC. Methods: We identified all patients (n = 1150) with stage II-III HER2+ BC who received neoadjuvant HER2-targeted therapy from 2005 to 2016 through an institutional database. All patients underwent primary breast and lymph node surgery. pCR was defined as ypT0/is, ypN0. Univariate/multivariate logistic regression and chi-squared test for comparing proportions was used for the statistical analysis. Results: pCR was significantly higher for the HP group (n = 200) compared to the H group (n = 950): 44% vs. 41%, odds ratio = 1.8 (95% CI = 1.3, 2.5; P = 0.0002). Even with adjustment for all clinically significant factors (age, stage, tumor grade, hormone receptor (HR) status, A or C exposure), the improvement was statistically significant (adjusted OR = 2.1 (95% CI = 1.5, 2.9; P < 0.0001). The pCR rate by stage and HR status for the HP group is 62% vs. 55% (stage II vs. III) and 71% vs. 51% (HR- vs. HR+). The effect of P was not modified by HR status (HR-, OR = 2.3; HR+, OR = 1.7, P = 0.39) or by A (A-yes, OR = 1.8; A-no, OR = 2.6) (P = 0.28 for interaction) or C (C-yes, OR 2.6; C-no, OR = 1.8) (P = 0.30 for interaction). P was significantly more likely to be given to patients without A (36% vs. 10%, P < 0.0001) and more likely to be given to patients with C (30% vs. 14%, P < 0.001). In both groups, significant predictors of pCR were found to be stage, HR status, and C exposure. Conclusions: Pertuzumab containing regimens yield higher pCR rates compared to non-Pertuzumab containing regimens in stage II- III HER-2 positive breast cancer. The effect of Pertuzumab is not modified by anthracycline or carboplatin use.

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Serial Circulating Tumor DNA Identification Associated with the Efficacy and Prognosis of Neoadjuvant Chemotherapy in Breast Cancer

10.21203/rs.3.rs-220659/v1 ◽

2021 ◽

Author(s):

Yidong Zhou ◽

Yaping Xu ◽

Changjun Wang ◽

Yuhua Gong ◽

Yanyan Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Pathologic Complete Response ◽

Distant Metastases ◽

Circulating Tumor Dna ◽

College Hospital ◽

Primary Tumors ◽

Blood Samples ◽

Tumor Dna

Abstract Background: Circulating tumor DNA (ctDNA) provides a promising noninvasive alternative to evaluate the efficacy of neoadjuvant chemotherapy (NCT) in breast cancer. Methods: Herein, we collected 63 tissue (aspiration biopsies and resected tissues) and 206 blood samples (baseline, during chemotherapy (Chemo), after chemotherapy (Post-Chemo), after operation (Post-Op), during follow-up) from 32 patients, and preformed targeted deep sequencing with a customed 1,021-gene panel. Results: As the results, TP53 (43.8%) and PIK3CA (40.6%) were the most common mutant genes in the primary tumors. At least one tumor-derived mutation was detected in the following number of blood samples: 21, baseline; 3, Chemo; 9, Post-Chemo; and 5, Post-Op. Four patients with pathologic complete response had no tissue mutation in Chemo and Post-Chemo blood. Compared to patients with mutation-positive Chemo or Post-Chemo blood, the counterparts showed a superior primary tumor decrease (median, 86.5% versus 54.6%) and lymph involvement (median, one versus 3.5). All five patients with mutation-positive Post-Op developed distant metastases during follow-up, and the sensitivity of detecting clinically relapsed patients was 71.4% (5/7). The median DFS was 9.8 months for patients with mutation-positive Post-Op but not reached for the others (HR 23.53; 95% CI, 1.904–290.9; p < 0.0001). Conclusions: Our study shows that sequential monitoring of blood ctDNA was an effective method for evaluating NCT efficacy and patient survival. Integrating ctDNA profiling into the management of LABC patients might improve clinical outcome.Trial registration: This prospective study recruited LABC patients at Peking Union Medical College Hospital (ClinicalTrials.gov Identifier: NCT02797652).

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