Publications by authors named "Lori J Pierce"

119 Publications

Comparative Effectiveness Analysis of 3D-Conformal Radiotherapy versus Intensity Modulated Radiotherapy (IMRT) in a Prospective Multicenter Cohort of Breast Cancer Patients.

Int J Radiat Oncol Biol Phys 2021 Oct 8. Epub 2021 Oct 8.

University of Michigan, Ann Arbor, MI.

Purpose: Simple intensity modulation of radiation therapy reduces acute toxicity compared to two-dimensional techniques in adjuvant breast cancer treatment, but it remains unknown whether more complex or inverse-planned intensity modulated radiotherapy (IMRT) offers an advantage over forward-planned, three-dimensional conformal radiotherapy (3DCRT).

Methods And Materials: Using prospective data regarding patients receiving adjuvant whole breast RT without nodal irradiation at 23 institutions from 2011-2018, we compared incidence of acute toxicity (moderate-severe pain or moist desquamation) in patients receiving 3DCRT versus IMRT (either inverse planned or, if forward-planned, using ≥5 segments per gantry angle).  We evaluated associations between technique and toxicity using multivariable models with inverse-probability-of-treatment weighting (IPTW), adjusting for treatment facility as a random effect.

Results: Of 1,185 patients treated with 3DCRT and conventional fractionation, 650 (54.9%) experienced acute toxicity; of 774 treated with highly-segmented forward-planned IMRT, 458 (59.2%) did; of 580 treated with inverse-planned IMRT, 245 (42.2%) did.  Of 1,296 patients treated with hypofractionation and 3DCRT 432 (33.3%) experienced acute toxicity; of 709 treated with highly-segmented forward-planned IMRT, 227 (32.0%) did; of 623 treated with inverse-planned IMRT, 164 (26.3%) did. On multivariable analysis with IPTW, the odds ratio for acute toxicity after inverse-planned IMRT versus 3DCRT was 0.64 (95% CI, 0.45-0.91) with conventional fractionation and 0.41 (95% CI, 0.26-0.65) with hypofractionation.

Conclusions: This large, prospective, multicenter comparative effectiveness study found a significant benefit from inverse-planned IMRT compared to 3DCRT in reducing acute toxicity of breast radiotherapy. Future research should identify the dosimetric differences that mediate this association and evaluate cost-effectiveness.
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http://dx.doi.org/10.1016/j.ijrobp.2021.09.053DOI Listing
October 2021

Cardiac Magnetic Resonance Imaging and Blood Biomarkers for Evaluation of Radiation-Induced Cardiotoxicity in Patients With Breast Cancer: Results of a Phase 2 Clinical Trial.

Int J Radiat Oncol Biol Phys 2021 Sep 9. Epub 2021 Sep 9.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan; Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. Electronic address:

Purpose: Radiation therapy (RT) can increase the risk of cardiac events in patients with breast cancer (BC), but biomarkers predicting risk for developing RT-induced cardiac disease are currently lacking. We report results from a prospective clinical trial evaluating early magnetic resonance imaging (MRI) and serum biomarker changes as predictors of cardiac injury and risk of subsequent cardiac events after RT for left-sided disease.

Methods: Women with node-negative and node-positive (N-/+) left-sided BC were enrolled on 2 institutional review board (IRB)-approved protocols at 2 institutions. MRI was conducted pretreatment (within 1 week of starting radiation), at the end of treatment (last day of treatment ±1 week), and 3 months after the last day of treatment (±2 weeks) to quantify left and right ventricular volumes and function, myocardial fibrosis, and edema. Perfusion changes during regadenoson stress perfusion were also assessed on a subset of patients (n = 28). Serum was collected at the same time points. Whole heart and cardiac substructures were contoured using CT and MRI. Models were constructed using baseline cardiac and clinical risk factors. Associations between MRI-measured changes and dose were evaluated.

Results: Among 51 women enrolled, mean heart dose ranged from 0.80 to 4.7 Gy and mean left ventricular (LV) dose from 1.1 to 8.2 Gy, with mean heart dose 2.0 Gy. T1 time, a marker of fibrosis, and right ventricular (RV) ejection fraction (EF) significantly changed with treatment; these were not dose dependent. T2 (marker of edema) and LV EF did not significantly change. No risk factors were associated with baseline global perfusion. Prior receipt of doxorubicin was marginally associated with decreased myocardial perfusion after RT (P = .059), and mean MHD was not associated with perfusion changes. A significant correlation between baseline IL-6 and mean heart dose (MHD) at the end of RT (ρ 0.44, P = .007) and a strong trend between troponin I and MHD at 3 months post-treatment (ρ 0.33, P = .07) were observed. No other significant correlations were identified.

Conclusions: In this prospective study of women with left-sided breast cancer treated with contemporary treatment planning, cardiac radiation doses were very low relative to historical doses reported by Darby et al. Although we observed significant changes in T1 and RV EF shortly after RT, these changes were not correlated with whole heart or substructure doses. Serum biomarker analysis of cardiac injury demonstrates an interesting trend between markers and MHD that warrants further investigation.
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http://dx.doi.org/10.1016/j.ijrobp.2021.08.039DOI Listing
September 2021

Randomized Phase III Trial Evaluating Radiation Following Surgical Excision for Good-Risk Ductal Carcinoma In Situ: Long-Term Report From NRG Oncology/RTOG 9804.

J Clin Oncol 2021 Aug 18:JCO2101083. Epub 2021 Aug 18.

Ohio State University Comprehensive Cancer Center, Columbus, OH.

Purpose: To our knowledge, NRG/RTOG 9804 is the only randomized trial to assess the impact of whole breast irradiation (radiation therapy [RT]) versus observation (OBS) in women with good-risk ductal carcinoma in situ (DCIS), following lumpectomy. Long-term results focusing on ipsilateral breast recurrence (IBR), the primary outcome, are presented here.

Patients And Methods: Eligible patients underwent lumpectomy for DCIS that was mammogram detected, size ≤ 2.5 cm, final margins ≥ 3 mm, and low or intermediate nuclear grade. Consented patients were randomly assigned to RT or OBS. Tamoxifen use was optional. Cumulative incidence was used to estimate IBR, log-rank test and Gray's test to compare treatments, and Fine-Gray regression for hazard ratios (HRs).

Results: A total of six hundred thirty-six women were randomly assigned from 1999 to 2006. Median age was 58 years and mean pathologic DCIS size was 0.60 cm. Intention to use tamoxifen was balanced between arms (69%); however, actual receipt of tamoxifen varied, 58% RT versus 66% OBS ( = .05). At 13.9 years' median follow-up, the 15-year cumulative incidence of IBR was 7.1% (95% CI, 4.0 to 11.5) with RT versus 15.1% (95% CI, 10.8 to 20.2) OBS ( = .0007; HR = 0.36; 95% CI, 0.20 to 0.66); and for invasive LR was 5.4% (95% CI, 2.7 to 9.5) RT versus 9.5% (95% CI, 6.0 to 13.9) OBS ( = .027; HR = 0.44; 95% CI, 0.21 to 0.91). On multivariable analysis, only RT (HR = 0.34; 95% CI, 0.19 to 0.64; = .0007) and tamoxifen use (HR = 0.45; 95% CI, 0.25 to 0.78; = .0047) were associated with reduced IBR.

Conclusion: RT significantly reduced all and invasive IBR for good-risk DCIS with durable results at 15 years. These results are not an absolute indication for RT but rather should inform shared patient-physician treatment decisions about ipsilateral breast risk reduction in the long term following lumpectomy.
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http://dx.doi.org/10.1200/JCO.21.01083DOI Listing
August 2021

Modulating the Radiation Response for Improved Outcomes in Breast Cancer.

JCO Precis Oncol 2021 25;5. Epub 2021 Jan 25.

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI.

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http://dx.doi.org/10.1200/PO.20.00297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232831PMC
January 2021

2021 Presidential Address: Equity: Every Patient. Every Day. Everywhere.

Authors:
Lori J Pierce

J Clin Oncol 2021 Aug 25;39(23):2521-2524. Epub 2021 Jun 25.

ASCO, Alexandria, VA.

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http://dx.doi.org/10.1200/JCO.21.01418DOI Listing
August 2021

NCCN Guidelines® Insights: Breast Cancer, Version 4.2021.

J Natl Compr Canc Netw 2021 05 1;19(5):484-493. Epub 2021 May 1.

26Research Advocacy Network.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer-focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor-positive, HER2-negative breast cancer.
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http://dx.doi.org/10.6004/jnccn.2021.0023DOI Listing
May 2021

Immune Infiltrate in the Primary Tumor Predicts Effect of Adjuvant Radiotherapy in Breast Cancer; Results from the Randomized SweBCG91RT Trial.

Clin Cancer Res 2021 02 4;27(3):749-758. Epub 2020 Nov 4.

Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.

Purpose: Tumor-infiltrating immune cells play a key role in tumor progression. The purpose of this study was to analyze whether the immune infiltrate predicts benefit from postoperative radiotherapy in a large randomized breast cancer radiotherapy trial.

Experimental Design: In the SweBCG91RT trial, patients with stage I and II breast cancer were randomized to breast-conserving surgery (BCS) and postoperative radiotherapy or to BCS only and followed for a median time of 15.2 years. The primary tumor immune infiltrate was quantified through two independent methods: IHC and gene expression profiling. For IHC analyses, the absolute stromal area occupied by CD8 T cells and FOXP3 T cells, respectively, was used to define the immune infiltrate. For gene expression analyses, immune cells found to be prognostic in independent datasets were pooled into two groups consisting of antitumoral and protumoral immune cells, respectively.

Results: An antitumoral immune response in the primary tumor was associated with a reduced risk of breast cancer recurrence and predicted less benefit from adjuvant radiotherapy. The interaction between radiotherapy and immune phenotype was significant for any recurrence in both the IHC and gene expression analyses ( = 0.039 and = 0.035) and was also significant for ipsilateral breast tumor recurrence in the gene expression analyses ( = 0.025).

Conclusions: Patients with an antitumoral immune infiltrate in the primary tumor have a reduced risk of any recurrence and may derive less benefit from adjuvant radiotherapy. These results may impact decisions regarding postoperative radiotherapy in early breast cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3299DOI Listing
February 2021

ARe we there yet? Understanding androgen receptor signaling in breast cancer.

NPJ Breast Cancer 2020 25;6:47. Epub 2020 Sep 25.

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI USA.

The role of androgen receptor (AR) activation and expression is well understood in prostate cancer. In breast cancer, expression and activation of AR is increasingly recognized for its role in cancer development and its importance in promoting cell growth in the presence or absence of estrogen. As both prostate and breast cancers often share a reliance on nuclear hormone signaling, there is increasing appreciation of the overlap between activated cellular pathways in these cancers in response to androgen signaling. Targeting of the androgen receptor as a monotherapy or in combination with other conventional therapies has proven to be an effective clinical strategy for the treatment of patients with prostate cancer, and these therapeutic strategies are increasingly being investigated in breast cancer. This overlap suggests that targeting androgens and AR signaling in other cancer types may also be effective. This manuscript will review the role of AR in various cellular processes that promote tumorigenesis and metastasis, first in prostate cancer and then in breast cancer, as well as discuss ongoing efforts to target AR for the more effective treatment and prevention of cancer, especially breast cancer.
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http://dx.doi.org/10.1038/s41523-020-00190-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519666PMC
September 2020

Toward Improving Patients' Experiences of Acute Toxicity From Breast Radiotherapy: Insights From the Analysis of Patient-Reported Outcomes in a Large Multicenter Cohort.

J Clin Oncol 2020 12 28;38(34):4019-4029. Epub 2020 Sep 28.

University of Michigan, Ann Arbor, MI.

Purpose: Understanding acute toxicities after whole-breast radiotherapy is important to inform patients, guide treatment decisions, and target supportive care. We evaluated patient-reported outcomes prospectively collected from a cohort of patients with breast cancer.

Methods: We describe the maximal toxicity reported by 8,711 patients treated between 2012 and 2019 at 27 practices. Multivariable models identified characteristics associated with (1) breast pain, (2) bother from itching, stinging/burning, swelling, or hurting of the treated breast, and (3) fatigue within 7 days of completing whole-breast radiotherapy.

Results: Moderate or severe breast pain was reported by 3,233 (37.1%): 1,282 (28.9%) of those receiving hypofractionation and 1,951 (45.7%) of those receiving conventional fractionation. Frequent bother from at least one breast symptom was reported by 4,424 (50.8%): 1,833 (41.3%) after hypofractionation and 2,591 (60.7%) after conventional fractionation. Severe fatigue was reported by 2,008 (23.1%): 843 (19.0%) after hypofractionation and 1,165 (27.3%) after conventional fractionation. Among patients receiving hypofractionated radiotherapy, younger age ( < .001), higher body mass index (BMI; < .001), Black ( < .001) or other race ( = .002), smoking status ( < .001), larger breast volume ( = .002), lack of chemotherapy receipt ( = .004), receipt of boost treatment ( < .001), and treatment at a nonteaching center predicted breast pain. Among patients receiving conventionally fractionated radiotherapy, younger age ( < .001), higher BMI ( = .003), Black ( < .001) or other race ( = .002), diabetes ( = .001), smoking status ( < .001), and larger breast volume ( < .001) predicted breast pain.

Conclusion: In this large observational data set, substantial differences existed according to radiotherapy dose fractionation. Race-related differences in pain existed despite controlling for multiple other factors; additional research is needed to understand what drives these differences to target potentially modifiable factors. Intensifying supportive care may be appropriate for subgroups identified as being vulnerable to greater toxicity.
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http://dx.doi.org/10.1200/JCO.20.01703DOI Listing
December 2020

Short-term CDK4/6 Inhibition Radiosensitizes Estrogen Receptor-Positive Breast Cancers.

Clin Cancer Res 2020 12 23;26(24):6568-6580. Epub 2020 Sep 23.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.

Purpose: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have improved progression-free survival for metastatic, estrogen receptor-positive (ER) breast cancers, but their role in the nonmetastatic setting remains unclear. We sought to understand the effects of CDK4/6 inhibition (CDK4/6i) and radiotherapy in multiple preclinical breast cancer models.

Experimental Design: Transcriptomic and proteomic analyses were used to identify significantly altered pathways after CDK4/6i. Clonogenic assays were used to quantify the radiotherapy enhancement ratio (rER). DNA damage was quantified using γH2AX staining and the neutral comet assay. DNA repair was assessed using RAD51 foci formation and nonhomologous end joining (NHEJ) reporter assays. Orthotopic xenografts were used to assess the efficacy of combination therapy.

Results: Palbociclib significantly radiosensitized multiple ER cell lines at low nanomolar, sub IC concentrations (rER: 1.21-1.52) and led to a decrease in the surviving fraction of cells at 2 Gy ( < 0.001). Similar results were observed in ribociclib-treated (rER: 1.08-1.68) and abemaciclib-treated (rER: 1.19-2.05) cells. Combination treatment decreased RAD51 foci formation ( < 0.001), leading to a suppression of homologous recombination activity, but did not affect NHEJ efficiency ( > 0.05). Immortalized breast epithelial cells and cells with acquired resistance to CDK4/6i did not demonstrate radiosensitization (rER: 0.94-1.11) or changes in RAD51 foci. In xenograft models, concurrent palbociclib and radiotherapy led to a significant decrease in tumor growth.

Conclusions: These studies provide preclinical rationale to test CDK4/6i and radiotherapy in women with locally advanced ER breast cancer at high risk for locoregional recurrence.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744368PMC
December 2020

Development of an Illustrated Scale for Acute Radiation Dermatitis in Breast Cancer Patients.

Pract Radiat Oncol 2021 May-Jun;11(3):168-176. Epub 2020 Sep 16.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.

Purpose: Scales for rating acute radiation dermatitis (ARD) have not been validated despite decades of clinical use, and little is known regarding the relationship between toxicity scores and patient-reported symptoms. Skin tone also complicates assessment of ARD, and as such we sought to design an illustrated scale to consistently describe ARD across several skin tone types in breast cancer patients undergoing radiation (RT).

Methods And Materials: Patients undergoing RT for breast cancer were enrolled on a prospective study with photographs obtained at 2-week intervals. Photographs were clustered according to the apparent severity of acute radiation dermatitis and a descriptive photonumeric scale was developed. Four clinically experienced raters used both the illustrated photonumeric scale and the Common Terminology Criteria for Adverse Events to independently score the collection of photographs in 2 independent sessions.

Results: Among 80 unique patients with 192 photographs, 47 patients (59%) completed questionnaires about their symptoms during RT. Physicians completed toxicity forms at the point-of-care for 52 patients (65%). Photonumeric ratings compared against patient reports of dry and moist desquamation demonstrated high specificity (95% and 93%, respectively) and negative predictive value (84% and 92%), indicating correct identification of patients who did not report dry or moist desquamation. The sensitivity and positive predictive value for separate measures of dry and moist desquamation were considerably lower. A combined measure of any desquamation (dry or moist) portrayed higher diagnostic accuracy, resulting in 72% sensitivity, 93% specificity, 75% positive predictive value, and 92% negative predictive value. Photonumeric ratings of dry or moist desquamation were significantly associated with patient reports of itching, burning or stinging, hurting, and swelling.

Conclusions: The Michigan scale for acute radiation dermatitis is a simple grading rubric that is distinguished by characterization of its intra- and interrater reliability and diagnostic accuracy, correlation with patient-reported symptoms of bother and pain, and applicability across the spectrum of skin pigmentation.
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http://dx.doi.org/10.1016/j.prro.2020.09.002DOI Listing
August 2021

A Time to Dig Deeper and Take Meaningful Action.

Authors:
Lori J Pierce

J Clin Oncol 2020 10 12;38(29):3361-3362. Epub 2020 Aug 12.

ASCO, Alexandria, VA.

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http://dx.doi.org/10.1200/JCO.20.02158DOI Listing
October 2020

ASTRO Radiation Therapy Summary of the ASCO-ASTRO-SSO Guideline on Management of Hereditary Breast Cancer.

Pract Radiat Oncol 2020 Jul - Aug;10(4):235-242. Epub 2020 May 21.

Department of Radiation Oncology, Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan. Electronic address:

Purpose: To develop a summary of recommendations regarding locoregional management of patients with breast cancer and germline mutations in breast cancer susceptibility genes based on the American Society of Clinical Oncology/American Society for Radiation Oncology/Society of Surgical Oncology Guideline on Management of Hereditary Breast Cancer.

Methods: The American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology convened an expert panel to develop recommendations based on a systematic review of the literature and a formal consensus process. A total of 58 articles met the eligibility criteria and formed the evidentiary basis for the locoregional therapy recommendations. Additionally, 6 randomized controlled trials of systemic therapy also met eligibility criteria.

Results: A joint evidence-based guideline was developed by a multidisciplinary panel, which has been separately published. From this guideline, the radiation-oncologist authors of the panel extracted pertinent surgical and radiation-specific recommendations of findings that are hereby presented.

Conclusions: Patients with newly diagnosed breast cancer and BRCA1/2 mutations may be considered for breast conserving therapy (BCT), expecting similar rates of local control of the index cancer as noncarriers. The significant risk of contralateral breast cancer in these women (especially younger women), coupled with the higher risk of new cancers in the ipsilateral breast, warrant discussion of bilateral mastectomy. For women with mutations in BRCA1/2 or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or contralateral breast cancer events from radiation exposure in BRCA1/2 carriers. Patients with mutations in moderate-risk genes should be offered BCT as one choice after appropriate counseling. Radiation therapy should not be withheld in ATM carriers if BCT is planned. For patients with germline TP53 mutations, mastectomy is advised and radiation therapy is contraindicated except for those with a significant risk of locoregional recurrence.
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http://dx.doi.org/10.1016/j.prro.2020.04.003DOI Listing
March 2021

Patient Perceptions in a Nonblinded Randomized Trial of Radiation Therapy Technologies: A Novel Survey Study Exploring Therapeutic Misconception.

Int J Radiat Oncol Biol Phys 2020 11 23;108(4):867-875. Epub 2020 May 23.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. Electronic address:

Purpose: Therapeutic misconception is the tendency for a clinical trial participant to overlook the scientific objective of a clinical trial and instead believe that an experimental intervention is intended for personal therapeutic benefit. We sought to evaluate this tendency in the setting of a clinical trial of a new radiation therapy technology.

Methods: Patients with left-sided, node positive breast cancer enrolled in a randomized clinical trial evaluating intensity modulated radiation therapy with deep inspiration breath hold (IMRT-DIBH) versus 3-dimensional conformal radiation therapy (3DCRT). Patients who enrolled completed surveys at baseline, after randomization, and upon completion of radiation therapy to evaluate expectations, satisfaction, and experiences.

Results: Forty women participated in the survey study, with 20 in each arm. Most participants endorsed the perception that participation in the trial might result in better treatment than the current standard treatment (77%) and more medical attention than being off trial (54%). At baseline, most women (74%) believed that a new treatment technology is superior than an established one. Before randomization, 43% of participants believed IMRT-DIBH would be more effective than standard treatment with 3DCRT, none believed that 3DCRT would be more effective, 23% believed that they would be the same, and 34% did not know. None believed that IMRT-DIBH would cause worse long-term side effects, whereas 37% thought that 3DCRT would. Most (71%) reported that they would choose to be treated with IMRT-DIBH; none would have elected 3DCRT if given a choice. Nearly half (44%) in the 3DCRT arm wished that they had been assigned to the IMRT-DIBH arm; none in the IMRT-DIBH arm expressed a wish for crossover.

Conclusions: Most participants reported the perception that trial participation would result in better treatment and more medical attention than off trial, hallmarks of therapeutic misconception. Our observations provide empirical evidence of a fixed belief in the superiority of new technology and highlight the importance of adjusting expectations through informed consent to mitigate therapeutic misconception.
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http://dx.doi.org/10.1016/j.ijrobp.2020.05.021DOI Listing
November 2020

Genetic Factors in the Locoregional Management of Breast Cancer.

J Clin Oncol 2020 07 22;38(20):2220-2229. Epub 2020 May 22.

University of Michigan Medical School, Ann Arbor, MI.

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http://dx.doi.org/10.1200/JCO.19.02859DOI Listing
July 2020

A Signature That May Be Predictive of Early Versus Late Recurrence After Radiation Treatment for Breast Cancer That May Inform the Biology of Early, Aggressive Recurrences.

Int J Radiat Oncol Biol Phys 2020 11 17;108(3):686-696. Epub 2020 May 17.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan; Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. Electronic address:

Purpose: Unmet clinical needs in breast cancer (BC) management include the identification of patients at high risk of local failure despite adjuvant radiation and an understanding of the biology of these recurrences. We previously reported a radiation response signature and here extend those studies to identify a signature predictive of recurrence timing (before or after 3 years).

Methods And Materials: Two independent patient cohorts were used. The training cohort included 119 patients with in-breast tumor recurrence (343 total), and the validation testing cohort had 16 patients with recurrences (112 total). All patients received radiation treatment after breast-conserving surgery. Initial feature selection used Spearman rank correlation, and a linear model was trained and locked before testing and validation. Cox regression was used for univariate and multivariable analyses (UVA and MVA, respectively). Biologically related concepts were identified using gene set enrichment analysis.

Results: Spearman correlation identified 485 genes whose expression was significantly associated with recurrence time (early vs late). Feature reduction further refined the list to 41 genes retained within the signature. In training, the correlation of score to recurrence time was 0.85 (P value < 1.3 × 10) with an area under the curve (AUC) of 0.91. Application of this early versus late signature to an independent BC testing and validation set accurately identified patients with early versus late recurrences (Spearman correlation = 0.75, P value = .001, AUC = 0.92, sensitivity = 0.75, specificity = 1.0, positive predictive value = 1.0, and negative predictive value = 0.8). Unique associations of breast cancer intrinsic subtype to timing of local recurrence were identified. In UVA and MVA the early versus late recurrence signature remained the most significant factor associated with recurrence. Gene set enrichment analysis identified proliferation and epidermal growth factor receptor concepts associated with early recurrences and luminal and ER-signaling pathways associated with late recurrences. Knockdown of genes associated with the early and late recurrences demonstrated novel effects on proliferation and clonogenic survival, respectively.

Conclusions: We report a breast cancer gene signature that may identify patients unlikely to respond to adjuvant radiation and may be used to predict timing of recurrences with implications for potential treatment intensification and duration of follow-up for women with breast cancer treated with radiation.
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http://dx.doi.org/10.1016/j.ijrobp.2020.05.015DOI Listing
November 2020

The Role of Facility Variation on Racial Disparities in Use of Hypofractionated Whole Breast Radiation Therapy.

Int J Radiat Oncol Biol Phys 2020 08 4;107(5):949-958. Epub 2020 May 4.

Rogel Comprehensive Cancer Center at the University of Michigan, Ann Arbor, Michigan. Electronic address:

Purpose: Hypofractionated radiation therapy is a less burdensome and less costly approach that is efficacious for most patients with early-stage breast cancer. Concerns about racial disparities in adoption of medical advances motivate investigation of the use of hypofractionated radiation in diverse populations. The goal of our study was to determine whether hypofractionated whole breast radiation therapy after breast-conserving surgery was being similarly used across racial groups in the state of Michigan.

Methods And Materials: A prospectively collected statewide quality consortium database from 25 institutions was queried for patients with breast cancer who completed hypofractionated (HF) or conventionally fractionated whole breast radiation therapy from January 2012 to December 2018. We used patient-level multivariable modeling to evaluate associations between HF use and race, controlling for patient and facility factors, and multilevel modeling to account for patient clustering within facilities.

Results: Of 9634 patients analyzed, 81% self-reported race as white, 17% as black, and 2% as Asian, similar to statewide and national distributions. In addition, 31.7% of whites were treated at teaching centers compared with 66.7% of blacks and 64.8% of Asians. In 2018, HF was used in 72.7% of whites versus 56.7% of blacks and 67.6% of Asians (P = .0411). On patient-level multivariable analysis, black and Asian races were significantly associated with a lower likelihood of HF receipt (P < .001), despite accounting for treatment year, age, laterality, body mass index, breast volume, comorbidities, stage, triple-negative status, intensity modulated radiation therapy use, teaching center treatment, and 2011 American Society for Radiation Oncology Hypofractionation Guideline eligibility. On multilevel analysis, race was no longer significantly associated with HF receipt.

Conclusions: We observed that black and Asian patients receive hypofractionated whole breast radiation therapy less often than whites, despite more frequent treatment at teaching centers. Multilevel modeling eliminated this disparity, suggesting that differences in facility-specific HF use appear to have contributed. Further inquiry is needed to determine whether reduction of facility-level variation may reduce disparities in accessing HF treatment.
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http://dx.doi.org/10.1016/j.ijrobp.2020.04.035DOI Listing
August 2020

Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2020 04;18(4):452-478

O'Neal Comprehensive Cancer Center at UAB.

Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.
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http://dx.doi.org/10.6004/jnccn.2020.0016DOI Listing
April 2020

Management of Hereditary Breast Cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline.

J Clin Oncol 2020 06 3;38(18):2080-2106. Epub 2020 Apr 3.

Beaumont Health, Royal Oak, MI.

Purpose: To develop recommendations for management of patients with breast cancer (BC) with germline mutations in BC susceptibility genes.

Methods: The American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology convened an Expert Panel to develop recommendations based on a systematic review of the literature and a formal consensus process.

Results: Fifty-eight articles met eligibility criteria and formed the evidentiary basis for the local therapy recommendations; six randomized controlled trials of systemic therapy met eligibility criteria.

Recommendations: Patients with newly diagnosed BC and / mutations may be considered for breast-conserving therapy (BCT), with local control of the index cancer similar to that of noncarriers. The significant risk of a contralateral BC (CBC), especially in young women, and the higher risk of new cancers in the ipsilateral breast warrant discussion of bilateral mastectomy. Patients with mutations in moderate-risk genes should be offered BCT. For women with mutations in / or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or CBC events from radiation exposure in / carriers. Radiation therapy should not be withheld in carriers. For patients with germline mutations, mastectomy is advised; radiation therapy is contraindicated except in those with significant risk of locoregional recurrence. Platinum agents are recommended versus taxanes to treat advanced BC in carriers. In the adjuvant/neoadjuvant setting, data do not support the routine addition of platinum to anthracycline- and taxane-based chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) are preferable to nonplatinum single-agent chemotherapy for treatment of advanced BC in / carriers. Data are insufficient to recommend PARP inhibitor use in the early setting or in moderate-penetrance carriers. Additional information available at www.asco.org/breast-cancer-guidelines.
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http://dx.doi.org/10.1200/JCO.20.00299DOI Listing
June 2020

Seviteronel, a Novel CYP17 Lyase Inhibitor and Androgen Receptor Antagonist, Radiosensitizes AR-Positive Triple Negative Breast Cancer Cells.

Front Endocrinol (Lausanne) 2020 11;11:35. Epub 2020 Feb 11.

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States.

Increased rates of locoregional recurrence (LR) have been observed in triple negative breast cancer (TNBC) despite multimodality therapy, including radiation (RT). Recent data suggest inhibiting the androgen receptor (AR) may be an effective radiosensitizing strategy, and AR is expressed in 15-35% of TNBC tumors. The aim of this study was to determine whether seviteronel (INO-464), a novel CYP17 lyase inhibitor and AR antagonist, is able to radiosensitize AR-positive (AR+) TNBC models. In cell viability assays, seviteronel and enzalutamide exhibited limited effect as a single agent (IC50 > 10 μM). Using clonogenic survival assays, however, AR knockdown and AR inhibition with seviteronel were effective at radiosensitizing cells with radiation enhancement ratios of 1.20-1.89 in models of TNBC with high AR expression. AR-negative (AR-) models, regardless of their estrogen receptor expression, were not radiosensitized with seviteronel treatment at concentrations up to 5 μM. Radiosensitization of AR+ TNBC models was at least partially dependent on impaired dsDNA break repair with significant delays in repair at 6, 16, and 24 h as measured by immunofluorescent staining of γH2AX foci. Similar effects were observed in an AR+ TNBC xenograft model where there was a significant reduction in tumor volume and a delay to tumor doubling and tripling times in mice treated with seviteronel and radiation. Following combination treatment with seviteronel and radiation, increased binding of AR occurred at DNA damage response genes, including genes involved both in homologous recombination and non-homologous end joining. This trend was not observed with combination treatment of enzalutamide and RT, suggesting that seviteronel may have a different mechanism of radiosensitization compared to other AR inhibitors. Enzalutamide and seviteronel treatment also had different effects on AR and AR target genes as measured by immunoblot and qPCR. These results implicate AR as a mediator of radioresistance in AR+ TNBC models and support the use of seviteronel as a radiosensitizing agent in AR+ TNBC.
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http://dx.doi.org/10.3389/fendo.2020.00035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027396PMC
February 2021

TTK inhibition radiosensitizes basal-like breast cancer through impaired homologous recombination.

J Clin Invest 2020 02;130(2):958-973

Department of Radiation Oncology.

Increased rates of locoregional recurrence are observed in patients with basal-like breast cancer (BC) despite the use of radiation therapy (RT); therefore, approaches that result in radiosensitization of basal-like BC are critically needed. Using patients' tumor gene expression data from 4 independent data sets, we correlated gene expression with recurrence to find genes significantly correlated with early recurrence after RT. The highest-ranked gene, TTK, was most highly expressed in basal-like BC across multiple data sets. Inhibition of TTK by both genetic and pharmacologic methods enhanced radiosensitivity in multiple basal-like cell lines. Radiosensitivity was mediated, at least in part, through persistent DNA damage after treatment with TTK inhibition and RT. Inhibition of TTK impaired homologous recombination (HR) and repair efficiency, but not nonhomologous end-joining, and decreased the formation of Rad51 foci. Reintroduction of wild-type TTK rescued both radioresistance and HR repair efficiency after TTK knockdown; however, reintroduction of kinase-dead TTK did not. In vivo, TTK inhibition combined with RT led to a significant decrease in tumor growth in both heterotopic and orthotopic, including patient-derived xenograft, BC models. These data support the rationale for clinical development of TTK inhibition as a radiosensitizing strategy for patients with basal-like BC, and efforts toward this end are currently underway.
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http://dx.doi.org/10.1172/JCI130435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994133PMC
February 2020

Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer: a randomised, phase 3, equivalence trial.

Lancet 2019 12 5;394(10215):2155-2164. Epub 2019 Dec 5.

NRG Oncology, Pittsburgh, PA, USA; University of Pittsburgh, Pittsburgh, PA, USA; Allegheny Health Network Cancer Institute, Pittsburgh, PA, USA.

Background: Whole-breast irradiation after breast-conserving surgery for patients with early-stage breast cancer decreases ipsilateral breast-tumour recurrence (IBTR), yielding comparable results to mastectomy. It is unknown whether accelerated partial breast irradiation (APBI) to only the tumour-bearing quadrant, which shortens treatment duration, is equally effective. In our trial, we investigated whether APBI provides equivalent local tumour control after lumpectomy compared with whole-breast irradiation.

Methods: We did this randomised, phase 3, equivalence trial (NSABP B-39/RTOG 0413) in 154 clinical centres in the USA, Canada, Ireland, and Israel. Adult women (>18 years) with early-stage (0, I, or II; no evidence of distant metastases, but up to three axillary nodes could be positive) breast cancer (tumour size ≤3 cm; including all histologies and multifocal breast cancers), who had had lumpectomy with negative (ie, no detectable cancer cells) surgical margins, were randomly assigned (1:1) using a biased-coin-based minimisation algorithm to receive either whole-breast irradiation (whole-breast irradiation group) or APBI (APBI group). Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with or without a supplemental boost to the tumour bed, and APBI was delivered as 34 Gy of brachytherapy or 38·5 Gy of external bream radiation therapy in 10 fractions, over 5 treatment days within an 8-day period. Randomisation was stratified by disease stage, menopausal status, hormone-receptor status, and intention to receive chemotherapy. Patients, investigators, and statisticians could not be masked to treatment allocation. The primary outcome of invasive and non-invasive IBTR as a first recurrence was analysed in the intention-to-treat population, excluding those patients who were lost to follow-up, with an equivalency test on the basis of a 50% margin increase in the hazard ratio (90% CI for the observed HR between 0·667 and 1·5 for equivalence) and a Cox proportional hazard model. Survival was assessed by intention to treat, and sensitivity analyses were done in the per-protocol population. This trial is registered with ClinicalTrials.gov, NCT00103181.

Findings: Between March 21, 2005, and April 16, 2013, 4216 women were enrolled. 2109 were assigned to the whole-breast irradiation group and 2107 were assigned to the APBI group. 70 patients from the whole-breast irradiation group and 14 from the APBI group withdrew consent or were lost to follow-up at this stage, so 2039 and 2093 patients respectively were available for survival analysis. Further, three and four patients respectively were lost to clinical follow-up (ie, survival status was assessed by phone but no physical examination was done), leaving 2036 patients in the whole-breast irradiation group and 2089 in the APBI group evaluable for the primary outcome. At a median follow-up of 10·2 years (IQR 7·5-11·5), 90 (4%) of 2089 women eligible for the primary outcome in the APBI group and 71 (3%) of 2036 women in the whole-breast irradiation group had an IBTR (HR 1·22, 90% CI 0·94-1·58). The 10-year cumulative incidence of IBTR was 4·6% (95% CI 3·7-5·7) in the APBI group versus 3·9% (3·1-5·0) in the whole-breast irradiation group. 44 (2%) of 2039 patients in the whole-breast irradiation group and 49 (2%) of 2093 patients in the APBI group died from recurring breast cancer. There were no treatment-related deaths. Second cancers and treatment-related toxicities were similar between the two groups. 2020 patients in the whole-breast irradiation group and 2089 in APBI group had available data on adverse events. The highest toxicity grade reported was: grade 1 in 845 (40%), grade 2 in 921 (44%), and grade 3 in 201 (10%) patients in the APBI group, compared with grade 1 in 626 (31%), grade 2 in 1193 (59%), and grade 3 in 143 (7%) in the whole-breast irradiation group.

Interpretation: APBI did not meet the criteria for equivalence to whole-breast irradiation in controlling IBTR for breast-conserving therapy. Our trial had broad eligibility criteria, leading to a large, heterogeneous pool of patients and sufficient power to detect treatment equivalence, but was not designed to test equivalence in patient subgroups or outcomes from different APBI techniques. For patients with early-stage breast cancer, our findings support whole-breast irradiation following lumpectomy; however, with an absolute difference of less than 1% in the 10-year cumulative incidence of IBTR, APBI might be an acceptable alternative for some women.

Funding: National Cancer Institute, US Department of Health and Human Services.
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http://dx.doi.org/10.1016/S0140-6736(19)32514-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199428PMC
December 2019

Mechanical properties of the shoulder and pectoralis major in breast cancer patients undergoing breast-conserving surgery with axillary surgery and radiotherapy.

Sci Rep 2019 11 28;9(1):17737. Epub 2019 Nov 28.

Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.

Breast-conserving surgery (BCS) and radiotherapy reduce breast cancer recurrence but can cause functional deficits in breast cancer survivors. A cross-sectional study quantified the long-term pathophysiological impact of these treatments on biomechanical measures of shoulder stiffness and ultrasound shear wave elastography measures of the shear elastic modulus of the pectoralis major (PM). Nine node-positive patients treated with radiotherapy to the breast and regional nodes after BCS and axillary lymph node dissection (Group 1) were compared to nine node-negative patients treated with radiotherapy to the breast alone after BCS and sentinel node biopsy (Group 2) and nine healthy age-matched controls. The mean follow-up for Group 1 and Group 2 patients was 988 days and 754 days, respectively. Shoulder stiffness did not differ between the treatment groups and healthy controls (p = 0.23). The PM shear elastic modulus differed between groups (p = 0.002), with Group 1 patients exhibiting a stiffer PM than Group 2 patients (p < 0.001) and healthy controls (p = 0.027). The mean prescribed radiotherapy dose to the PM was significantly correlated with passive shear elastic modulus (p = 0.018). Breast cancer patients undergoing more extensive axillary surgery and nodal radiotherapy did not experience long-term functional deficits to shoulder integrity but did experience long-term mechanical changes of the PM.
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http://dx.doi.org/10.1038/s41598-019-54100-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882786PMC
November 2019

Clinicogenomic Radiotherapy Classifier Predicting the Need for Intensified Locoregional Treatment After Breast-Conserving Surgery for Early-Stage Breast Cancer.

J Clin Oncol 2019 12 16;37(35):3340-3349. Epub 2019 Oct 16.

Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.

Purpose: Most patients with early-stage breast cancer are treated with adjuvant radiotherapy (RT) after breast-conserving surgery (BCS) to prevent locoregional recurrence (LRR). However, no genomic tools are used currently to select the optimal RT strategy.

Methods: We profiled the transcriptome of primary tumors on a clinical grade assay from the SweBCG91-RT trial, in which patients with node-negative breast cancer were randomly assigned to either whole-breast RT after BCS or no RT. We derived a new classifier, Adjuvant Radiotherapy Intensification Classifier (ARTIC), comprising 27 genes and patient age, in three publicly available cohorts, then independently validated ARTIC for LRR in 748 patients in SweBCG91-RT. We also compared previously published genomic signatures for ability to predict benefit from RT in SweBCG91-RT.

Results: ARTIC was highly prognostic for LRR in patients treated with RT (hazard ratio [HR], 3.4; 95% CI, 2.0 to 5.9; < .001) and predictive of RT benefit ( = .005). Patients with low ARTIC scores had a large benefit from RT (HR, 0.33 [95% CI, 0.21 to 0.52], < .001; 10-year cumulative incidence of LRR, 6% 21%), whereas those with high ARTIC scores benefited less from RT (HR, 0.73 [95% CI, 0.44 to 1.2], = .23; 10-year cumulative incidence of LRR, 25% 32%). In contrast, none of the eight previously published signatures were predictive of benefit from RT in SweBCG91-RT.

Conclusion: ARTIC identified women with a substantial benefit from RT as well as women with a particularly elevated LRR risk in whom whole-breast RT was not sufficiently effective and, thus, in whom intensified treatment strategies such as tumor-bed boost, and possibly regional nodal RT, should be considered. To our knowledge, ARTIC is the first classifier validated as predictive of benefit from RT in a phase III clinical trial with patients randomly assigned to receive or not receive RT.
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http://dx.doi.org/10.1200/JCO.19.00761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901281PMC
December 2019

Comprehensive Transcriptomic Profiling Identifies Breast Cancer Patients Who May Be Spared Adjuvant Systemic Therapy.

Clin Cancer Res 2020 01 26;26(1):171-182. Epub 2019 Sep 26.

Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.

Purpose: There is currently no molecular signature in clinical use for adjuvant endocrine therapy omission in breast cancer. Given the unique trial design of SweBCG91-RT, where adjuvant endocrine and chemotherapy were largely unadministered, we sought to evaluate the potential of transcriptomic profiling for identifying patients who may be spared adjuvant endocrine therapy.

Experimental Design: We performed a whole-transcriptome analysis of SweBCG91-RT, a randomized phase III trial of ± radiotherapy after breast-conserving surgery for node-negative stage I-IIA breast cancer. Ninety-two percent of patients were untreated by both adjuvant endocrine therapy and chemotherapy. We calculated 15 transcriptomic signatures from the literature and combined them into an average genomic risk, which was further used to derive a novel 141-gene signature (MET141). All signatures were then independently examined in SweBCG91-RT and in the publicly available METABRIC cohort.

Results: In SweBCG91-RT, 454 patients were node-negative, postmenopausal, and systemically untreated with ER-positive, HER2-negative cancers, which constitutes a low-risk subgroup and potential candidates for therapy omission. Most transcriptomic signatures were highly prognostic for distant metastasis, but considerable discordance was observed on the individual patient level. Within the MET141 low-risk subgroup (lowest 25th percentile of scores), 95% of patients were free of metastasis at 15 years, even in the absence of adjuvant endocrine therapy. In a clinically low-risk subgroup of the METABRIC cohort not treated with systemic therapy, no breast cancer death occurred among the MET141 low-risk patients.

Conclusions: Transcriptomic profiling identifies patients with an excellent outcome without any systemic adjuvant therapy in clinically low-risk patients of the SweBCG91-RT and METABRIC cohorts.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1038DOI Listing
January 2020

PARP1 Inhibition Radiosensitizes Models of Inflammatory Breast Cancer to Ionizing Radiation.

Mol Cancer Ther 2019 11 14;18(11):2063-2073. Epub 2019 Aug 14.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.

Sustained locoregional control of disease is a significant issue in patients with inflammatory breast cancer (IBC), with local control rates of 80% or less at 5 years. Given the unsatisfactory outcomes for these patients, there is a clear need for intensification of local therapy, including radiation. Inhibition of the DNA repair protein PARP1 has had little efficacy as a single agent in breast cancer outside of studies restricted to patients with BRCA mutations; however, PARP1 inhibition (PARPi) may lead to the radiosensitization of aggressive tumor types. Thus, this study investigates inhibition of PARP1 as a novel and promising radiosensitization strategy in IBC. In multiple existing IBC models (SUM-149, SUM-190, MDA-IBC-3), PARPi (AZD2281-olaparib and ABT-888-veliparib) had limited single-agent efficacy (IC > 10 μmol/L) in proliferation assays. Despite limited single-agent efficacy, submicromolar concentrations of AZD2281 in combination with RT led to significant radiosensitization (rER 1.12-1.76). This effect was partially dependent on mutational status. Radiosensitization was due, at least in part, to delayed resolution of double strand DNA breaks as measured by multiple assays. Using a SUM-190 xenograft model , the combination of PARPi and RT significantly delays tumor doubling and tripling times compared with PARPi or RT alone with limited toxicity. This study demonstrates that PARPi improves the effectiveness of radiotherapy in IBC models and provides the preclinical rationale for the opening phase II randomized trial of RT ± PARPi in women with IBC (SWOG 1706, NCT03598257).
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825563PMC
November 2019

Cardiac Dose in Locally Advanced Lung Cancer: Results From a Statewide Consortium.

Pract Radiat Oncol 2020 Jan - Feb;10(1):e27-e36. Epub 2019 Aug 2.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.

Purpose: The heart has been identified as a potential significant organ at risk in patients with locally advanced non-small cell lung cancer treated with radiation. Practice patterns and radiation dose delivered to the heart in routine practice in academic and community settings are unknown.

Methods And Materials: Between 2012 and 2017, 746 patients with stage III non-small cell lung cancer were treated with radiation within the statewide Michigan Radiation Oncology Quality Consortium (MROQC). Cardiac radiation dose was characterized, including mean and those exceeding historical or recently proposed Radiation Therapy Oncology Group and NRG Oncology constraints. Sites were surveyed to determine dose constraints used in practice. Patient-, anatomic-, and treatment-related associations with cardiac dose were analyzed using multivariable regression analysis and inverse probability weighting.

Results: Thirty-eight percent of patients had a left-sided primary, and 80% had N2 or N3 disease. Median prescription was 60 Gy (interquartile range, 60-66 Gy). Twenty-two percent of patients were prescribed 60 Gy in 2012, which increased to 62% by 2017 (P < .001). Median mean heart dose was 12 Gy (interquartile range, 5-19 Gy). The volume receiving 30 Gy (V30 Gy) exceeded 50% in 5% of patients, and V40 Gy was >35% in 3% of cases. No heart dose constraint was uniformly applied. Intensity modulated radiation therapy (IMRT) usage increased from 33% in 2012 to 86% in 2017 (P < .001) and was significantly associated with more complex cases (larger planning target volume, higher stage, and preexisting cardiac disease). In multivariable regression analysis, IMRT was associated with a lower percent of the heart receiving V30 Gy (absolute reduction = 3.0%; 95% confidence interval, 0.5%-5.4%) and V50 Gy (absolute reduction = 3.6%; 95% confidence interval, 2.4%-4.8%) but not mean dose. In inverse probability weighting analysis, IMRT was associated with 29% to 48% relative reduction in percent of the heart receiving V40-V60 Gy without increasing lung or esophageal dose or compromising planning target volume coverage.

Conclusions: Within MROQC, historical cardiac constraints were met in most cases, yet 1 in 4 patients received a mean heart dose exceeding 20 Gy. Future work is required to standardize heart dose constraints and to develop treatment approaches that allow for constraints to be met without compromising other planning goals.
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http://dx.doi.org/10.1016/j.prro.2019.07.013DOI Listing
June 2020

NCCN Guidelines Insights: Breast Cancer, Version 3.2018.

J Natl Compr Canc Netw 2019 02;17(2):118-126

26Huntsman Cancer Institute at the University of Utah.

These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor-positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.
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http://dx.doi.org/10.6004/jnccn.2019.0009DOI Listing
February 2019

Contemporary Statewide Practice Pattern Assessment of the Palliative Treatment of Bone Metastasis.

Int J Radiat Oncol Biol Phys 2018 06 6;101(2):462-467. Epub 2018 Mar 6.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.

Purpose: Palliative radiation therapy for bone metastases is often viewed as a single entity, despite national guidelines providing input principally only for painful uncomplicated bone metastases. Data surrounding the treatment of bone metastases are often gleaned from questionnaires of what providers would theoretically do in practice or from population-based data lacking critical granular information. We investigated the real-world treatment of bone metastases with radiation therapy.

Methods And Materials: Twenty diverse institutions across the state of Michigan had data extracted for their 10 most recent cases of radiation therapy delivered for the treatment of bone metastases at their institution between January and February 2017. Uni- and multivariable binary logistic regression was used to assess the use of single fraction (8 Gy × 1) radiation therapy.

Results: A total of 196 cases were eligible for inclusion. Twenty-eight different fractionation schedules were identified. The most common schedule was 3 Gy × 10 fractions (n = 100; 51.0%), 4 Gy × 5 fractions (n = 32; 16.3%), and 8 Gy × 1 (n = 15; 7.7%). The significant predictors for the use of single fraction radiation therapy were the presence of oligometastatic disease (P = .008), previous overlapping radiation therapy (P = .050), and academic practice type (P = .039). Twenty-nine cases (14.8%) received >10 fractions (median 15, range 11-20). Intensity modulated radiation therapy was used in 14 cases (7.1%), stereotactic body radiation therapy in 11 (5.6%), and image guidance with cone beam computed tomography in 11 (5.6%). Of the cases of simple painful bone metastases (no previous surgery, spinal cord compression, fracture, soft tissue extension, or overlapping previous radiation therapy; n = 70), only 12.9% were treated with 8 Gy × 1.

Conclusions: Bone metastases represent a heterogeneous disease, and radiation therapy for bone metastases is similarly diverse. Future work is needed to understand the barriers to single fraction use, and clinical trials are necessary to establish appropriate guidelines for the breadth of this complex disease.
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http://dx.doi.org/10.1016/j.ijrobp.2018.02.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844366PMC
June 2018

Breast Cancer, Version 4.2017, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2018 Mar;16(3):310-320

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.
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http://dx.doi.org/10.6004/jnccn.2018.0012DOI Listing
March 2018
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