Clinical biomarkers to identify patients unlikely to benefit from CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy (ET) are lacking. We implemented a comprehensive circulating tumor ...DNA (ctDNA) analysis to identify genomic features for predicting and monitoring treatment resistance.
ctDNA was isolated from 216 plasma samples collected from 51 patients with hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) on a phase II trial of palbociclib combined with letrozole or fulvestrant (NCT03007979). Boosted whole-exome sequencing (WES) was performed at baseline and clinical progression to evaluate genomic alterations, mutational signatures, and blood tumor mutational burden (bTMB). Low-pass whole-genome sequencing was performed at baseline and serial timepoints to assess blood copy-number burden (bCNB).
High bTMB and bCNB were associated with lack of clinical benefit and significantly shorter progression-free survival (PFS) compared with patients with low bTMB or low bCNB (all P < 0.05). Dominant APOBEC signatures were detected at baseline exclusively in cases with high bTMB (5/13, 38.5%) versus low bTMB (0/37, 0%; P = 0.0006). Alterations in ESR1 were enriched in samples with high bTMB (P = 0.0005). There was a high correlation between bTMB determined by WES and bTMB determined using a 600-gene panel (R = 0.98). During serial monitoring, an increase in bCNB score preceded radiographic progression in 12 of 18 (66.7%) patients.
Genomic complexity detected by noninvasive profiling of bTMB and bCNB predicted poor outcomes in patients treated with ET and CDK4/6i and identified early disease progression before imaging. Novel treatment strategies including immunotherapy-based combinations should be investigated in this population.
Preclinical studies have suggested that radiation therapy (RT) enhances antitumor immune response and can act synergistically when administered with immunotherapy. However, this effect in melanoma ...brain metastasis is not well studied. We aim to explore the clinical effect of combining RT and immunotherapy in patients with melanoma brain metastasis (MBM).
Patients with MBM between 2011 and 2013 were obtained from the National Cancer Database. Patients who did not have identifiable sites of metastasis and who did not receive RT for the treatment of their MBM were excluded. Patients were separated into cohorts that received immunotherapy versus patients who did not. Univariable and multivariable analyses were performed using Cox model to determine predictors of OS. Kaplan–Meier method was used to compare OS. Univariable and multivariable analyses using logistic regression model were used to determine the factors predictive for the use of immunotherapy. Propensity score analysis was used to account for differences in baseline patient characteristics between the RT and RT + immunotherapy groups. Significance was defined as a P value ≤ 0.05.
A total of 1104 patients were identified: 912 received RT alone and 192 received RT plus immunotherapy. The median follow-up time was 6.4 (0.1–56.8) months. Patients with extracranial disease (OR 1.603, 95% CI 1.146–2.243, P = 0.006), and patients receiving SRS (OR 1.955, 95% CI 1.410–2.711, P < 0.001) as compared to WBRT, had a higher likelihood of being treated with immunotherapy. The utilization of immunotherapy had nearly doubled between 2011 and 2013 (12.9–22.8%). On multivariable analysis, factors associated with superior OS were younger age, lower medical comorbidities, lack of extracranial disease, and treatment with immunotherapy and SRS. The median OS was 11.1 (8.9–13.4) months in RT plus immunotherapy vs. 6.2 (5.6–6.8) months in RT alone (P < 0.001), which remained significant after propensity score matching.
An increase in trend for the use of immunotherapy was noted, however, an overwhelming majority of the patients with this disease are still treated without immunotherapy. Addition of immunotherapy to RT is associated with improved OS in MBM. Given the selection biases that are inherent in this analysis, prospective trials investigating the combination of RT, especially SRS and immunotherapy are warranted.
Purpose
The purpose of the study was to assess the utility of tumor biomarkers, ultrasound (US) and US-guided diffuse optical tomography (DOT) in early prediction of breast cancer response to ...neoadjuvant therapy (NAT).
Methods
This prospective HIPAA compliant study was approved by the institutional review board. Forty one patients were imaged with US and US-guided DOT prior to NAT, at completion of the first three treatment cycles, and prior to definitive surgery from February 2017 to January 2020. Miller-Payne grading was used to assess pathologic response. Receiver operating characteristic curves (ROCs) were derived from logistic regression using independent variables, including: tumor biomarkers, US maximum diameter, percentage reduction of the diameter (%US), pretreatment maximum total hemoglobin concentration (HbT) and percentage reduction in HbT (%HbT) at different treatment time points. Resulting ROCs were compared using area under the curve (AUC). Statistical significance was tested using two-sided two-sample student
t
-test with
P
< 0.05 considered statistically significant. Logistic regression was used for ROC analysis.
Results
Thirty-eight patients (mean age = 47, range 24–71 years) successfully completed the study, including 15 HER2 + of which 11 were ER + ; 12 ER + or PR + /HER2−, and 11 triple negative. The combination of HER2 and ER biomarkers, %HbT at the end of cycle 1 (EOC1) and %US (EOC1) provided the best early prediction, AUC = 0.941 (95% CI 0.869–1.0). Similarly an AUC of 0.910 (95% CI 0.810–1.0) with %US (EOC1) and %HbT (EOC1) can be achieved independent of HER2 and ER status. The most accurate prediction, AUC = 0.974 (95% CI 0.933–1.0), was achieved with %US at EOC1 and %HbT (EOC3) independent of biomarker status.
Conclusion
The combined use of tumor HER2 and ER status, US, and US-guided DOT may provide accurate prediction of NAT response as early as the completion of the first treatment cycle.
Clinical Trial Registration number:
NCT02891681.
https://clinicaltrials.gov/ct2/show/NCT02891681
, Registration time: September 7, 2016
Purpose
Patients with triple-negative breast cancer (TNBC) who do not achieve pathological complete response (pCR) following neoadjuvant chemotherapy have a high risk of recurrence and death. ...Molecular characterization may identify patients unlikely to achieve pCR. This neoadjuvant trial was conducted to determine the pCR rate with docetaxel and carboplatin and to identify molecular alterations and/or immune gene signatures predicting pCR.
Experimental design
Patients with clinical stages II/III TNBC received 6 cycles of docetaxel and carboplatin. The primary objective was to determine if neoadjuvant docetaxel and carboplatin would increase the pCR rate in TNBC compared to historical expectations. We performed whole-exome sequencing (WES) and immune profiling on pre-treatment tumor samples to identify alterations that may predict pCR. Thirteen matching on-treatment samples were also analyzed to assess changes in molecular profiles.
Results
Fifty-eight of 127 (45.7%) patients achieved pCR. There was a non-significant trend toward higher mutation burden for patients with residual cancer burden (RCB) 0/I versus RCB II/III (median 80 versus 68 variants,
p
0.88).
TP53
was the most frequently mutated gene, observed in 85.7% of tumors.
EGFR
,
RB1
,
RAD51AP2
,
SDK2
,
L1CAM
,
KPRP
,
PCDHA1
,
CACNA1S
,
CFAP58
,
COL22A1
, and
COL4A5
mutations were observed almost exclusively in pre-treatment samples from patients who achieved pCR. Seven mutations in
PCDHA1
were observed in pre-treatment samples from patients who did not achieve pCR. Several immune gene signatures including IDO1, PD-L1, interferon gamma signaling, CTLA4, cytotoxicity, tumor inflammation signature, inflammatory chemokines, cytotoxic cells, lymphoid, PD-L2, exhausted CD8, Tregs, and immunoproteasome were upregulated in pre-treatment samples from patients who achieved pCR.
Conclusion
Neoadjuvant docetaxel and carboplatin resulted in a pCR of 45.7%. WES and immune profiling differentiated patients with and without pCR.
Trial registration
: Clinical trial information: NCT02124902, Registered 24 April 2014 & NCT02547987, Registered 10 September 2015.
Background
Triple-negative breast cancer (TNBC) is an aggressive subtype shown to have a high risk of locoregional recurrence (LRR). The purpose of this study was to determine the impact of operation ...type on LRR in TNBC patients.
Methods
A total of 1325 patients with TNBC who underwent breast-conserving therapy (BCT) or mastectomy from 1980 to the present were identified. Clinical and pathological factors were compared by the chi-square test. LRR-free survival (LRRFS), distant metastasis-free survival, and overall survival were estimated by the Kaplan–Meier method. Multivariate analysis was performed by the Cox proportional hazard models.
Results
BCT was performed in 651 patients (49%) and mastectomy in 674 (51%). The mastectomy group had larger tumors, a higher incidence of lymphovascular invasion, and higher pathologic N stage (all
P
< 0.001). At 62-month median follow-up, LRR was seen in 170 (26%) in the BCT group and 203 (30%) in the mastectomy group. Five-year LRRFS rates were higher in the BCT group (76% vs. 71%,
P
= 0.032), as was distant metastasis-free survival (68% vs. 54%,
P
< 0.0001) and overall survival (74% vs. 63%,
P
< 0.0001). On multivariate analysis, T stage (hazard ratio HR 1.37,
P
= 0.006), high nuclear grade (HR 1.92,
P
= 0.002), lymphovascular invasion (HR 1.93,
P
< 0.0001), close/positive margins (HR 1.89,
P
< 0.0001), and use of non–anthracycline or taxane-based adjuvant chemotherapy (HR 2.01,
P
< 0.0001) increased the LRR risk, while age >50 years was protective (HR 0.73,
P
= 0.007). Operation type (mastectomy vs. BCT, HR 1.07,
P
= 0.55) was not statistically significant.
Conclusions
BCT is not associated with increased LRR rates compared to mastectomy. TNBC should not be considered a contraindication for breast conservation.
The therapeutic landscape for metastatic breast cancer (MBC) has expanded greatly over the last three decades with an increasing availability of targeted therapies for specific breast cancer ...subtypes. However, cytotoxic chemotherapy remains an essential component for the management of endocrine refractory or triple negative MBC. Multiple chemotherapy agents have demonstrated activity in MBC as single agents and in combination. While taxanes are frequently recommended as the initial treatment of metastatic disease, capecitabine is a convenient oral therapy with well received toxicity profile. Eribulin is the only agent that demonstrated overall survival (OS) benefit in a phase III clinical trial when compared to treatment of physician choice in heavily pre-treated patients. Ixabepilone, gemcitabine, vinorelbine and platinum agents have demonstrated activity and, therefore, constitute additional therapeutic options. In this review, we will discuss the data supporting the use of different cytotoxic agents and the general principles in guiding the use of chemotherapy.
Long-term tumor control and cosmetic outcomes for accelerated partial breast radiation (APBI) delivered with 3-dimensional conformal external beam radiation (3D-CRT) remain limited. We seek to ...address these concerns by reporting our experience of 3D-CRT APBI with extended follow-up.
All patients treated with APBI delivered with 3D-CRT from January 2006 through December 2012 at a single institution were identified. Those with more than a year of follow-up were analyzed for ipsilateral breast tumor recurrence (IBTR), progression-free survival (PFS), cosmesis, and pain. Disease outcomes were analyzed by margin status (<2 mm, ≥2 mm), total radiation dose prescribed, presence of invasive disease, and American Society for Radiation Oncology (ASTRO) 2016 updated consensus groupings (suitable, cautionary, and unsuitable).
Two hundred ninety-three patients were identified, of whom 266 had >1 year of follow-up. Median follow-up was 87 months (range, 13-156). Of the 266, 162 (60.9%) were ASTRO "suitable," 87 (32.7%) were "cautionary," and 17 (6.4%) were "unsuitable." Seven-year rates of IBTR and PFS were 1.8% and 95.2%, respectively. Margin status, invasive versus in situ disease, prescribed dose, and ASTRO grouping were not prognostic for either IBTR or PFS on univariate analysis. Cosmesis was good to excellent in 75.2%. Two patients (0.8%) had subsequent plastic surgery owing to poor cosmesis. Narcotic medication for treatment site pain was needed by 6 (2.3%).
External beam APBI results in excellent long-term disease control. Good to excellent cosmetic outcomes are achieved in most patients, although increasing dose per fraction and greater percentage of irradiated breast were predictive of adverse posttreatment cosmetic outcomes. Select patients in "cautionary" and "unsuitable" consensus groupings do not appear to have inferior outcomes.
Metastatic hormone-sensitive prostate cancer (mHSPC) is an incurable disease, and despite a high response rate to androgen-deprivation therapy (ADT), outcomes have not significantly changed for many ...decades. Earlier attempts at multitargeted strategies with the addition of cytotoxic chemotherapy to ADT did not affect survival. As more effective therapies are emerging, including cytotoxic therapy for patients with metastatic castrate-resistant prostate cancer (mCRPC), there is increasing interest for testing these drugs earlier in the disease course. The premise is that agents with clinical benefit in advanced mCRPC may have a better effect if used preemptively before the development of significant resistance and to attack earlier de novo androgen resistant/independent clones. The recent results of the phase III clinical trial E3805 investigating ADT with or without docetaxel in mHSPC provide compelling support for this strategy. Docetaxel combined with ADT significantly improved overall survival from 44 to 57.6 months (p=0.0003), particularly in patients with high-volume disease (from 32.2 to 49.2 months; p=0.0006). Longer follow-up is needed to assess the effect on patients with low disease burden. Further studies are needed to further maximize the antitumor effect in patients with mHSPC and to investigate the effects of advancing therapy to this disease setting on the efficacy of respective agents in the castration-resistant setting.
BackgroundMost patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L ...is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here.MethodsPatients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For an hypothesized HR of 0.625, one-sided alpha of 0.10, and power 80%, target enrollment was 325 patients.ResultsFor randomized patients (n=347), arms were well-balanced, and treatment-emergent adverse events were similar for seviprotimut-L and placebo. For the primary intent-to-treat endpoint of RFS, the estimated HR was 0.881 (95% CI: 0.629 to 1.233), with stratified logrank p=0.46. However, estimated HRs were not uniform over the stage randomized strata, with HRs (95% CIs) for stages IIB/IIC, IIIA, IIIB/IIIC of 0.67 (95% CI: 0.37 to 1.19), 0.72 (95% CI: 0.35 to 1.50), and 1.19 (95% CI: 0.72 to 1.97), respectively. In the stage IIB/IIC stratum, the effect on RFS was greatest for patients <60 years old (HR=0.324 (95% CI: 0.121 to 0.864)) and those with ulcerated primary melanomas (HR=0.493 (95% CI: 0.255 to 0.952)).ConclusionsSeviprotimut-L is very well tolerated. Exploratory efficacy model estimation supports further study in stage IIB/IIC patients, especially younger patients and those with ulcerated melanomas.Trial registration numberNCT01546571.
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