Publications by authors named "Veerle Bossuyt"

37 Publications

Expression of lymphoid enhancer-binding factor 1 in breast fibroepithelial lesions.

Hum Pathol 2021 Feb 24;108:68-75. Epub 2020 Nov 24.

Department of Pathology, Yale School of Medicine, New Haven, CT, 06510, United States. Electronic address:

Phyllodes tumors (PTs) are rare epithelial-mesenchymal tumors of the breast with malignant potential. Here, we evaluate the nuclear expression of lymphoid enhancer-binding factor 1 (LEF-1), a transcription factor downstream of Wnt/β-catenin signaling, in fibroepithelial lesions of the breast. Excised fibroepithelial lesions of the breast were retrospectively reviewed, blinded to the original diagnosis, and classified according to World Health Organization (WHO) criteria. A tissue microarray (TMA) was composed with two representative cores from each case, including 24 benign lesions, 11 borderline phyllodes, and 8 malignant PTs. β-Catenin, LEF-1, p120, and E-cadherin immunohistochemistry was performed on the TMA, and staining was quantified. The malignant/borderline PTs showed higher stromal LEF-1 expression than benign tumors (P < 0.001). Stromal cells expressed LEF-1 in 100% (16/16 of core TMA) of malignant phyllodes, compared with 73% (16/22) borderline and 27% (13/48) benign tumors. The average LEF-1 H-score was 24.9, 6.1, and 1.5 for malignant, borderline, and benign tumors, respectively. Nuclear expression of β-catenin in the stromal component was more often seen in malignant than in borderline and benign tumors (44% versus 32% and 23%, respectively). Nine TMA cores of malignant tumors without nuclear β-catenin staining demonstrated LEF-1 expression. Both LEF-1 and nuclear β-catenin showed expression in the majority of borderline/malignant PTs suggesting a biological progression of Wnt/β-catenin pathway activation in the stromal component from benign to malignant tumors. Inhibitors for the Wnt/β-catenin pathway may provide alternative treatment options in the future for malignant or metastatic PTs.
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http://dx.doi.org/10.1016/j.humpath.2020.11.009DOI Listing
February 2021

The adjuvant use of capecitabine for residual disease following pre-operative chemotherapy for breast cancer: Challenges applying CREATE-X to a US population.

J Oncol Pharm Pract 2020 Nov 5:1078155220971751. Epub 2020 Nov 5.

Massachusetts General Hospital, Boston, MA, USA.

Introduction: The CREATE-X study, conducted in Japan and South Korea, established capecitabine as an adjuvant treatment option for patients with triple negative breast cancer (TNBC) who have residual disease (RD) following neoadjuvant anthracycline or taxane-based chemotherapy. However, there are no reports on the tolerability and outcomes of adjuvant capecitabine in the US setting following publication of the CREATE-X data.

Methods: We retrospectively collected treatment and tolerability data from the medical records of the first 23 TNBC patients who received adjuvant capecitabine for RD post neoadjuvant chemotherapy at our institution. Disease-free survival was assessed using the Kaplan-Meier method.

Results: The median starting dosage of capecitabine was 1871 mg/m/day, most commonly divided into two daily doses on days 1-14 of each 21 day cycle. 34.8% of patients completed the treatment as prescribed. Side effects associated with treatment were common with 69.6% of patients experiencing hand-foot syndrome, 39.1% of patients experiencing diarrhea, and 13.0% of patients requiring hospitalization for side effects. Of 23 patients treated with adjuvant capecitabine, 34.8% completed the planned dose, 30.4% completed with dose reduction, and 34.8% discontinued early. At a median follow-up time of 14 months, the median disease-free survival was 22 months, with 30.4% of patients experiencing recurrence.

Conclusion: Tolerability was poor overall compared to the CREATE-X cohort. Administering adjuvant capecitabine for TNBC patients with residual disease in the United States is challenging given differences in tolerability. More research is needed to understand how poor tolerability will affect the efficacy of this approach in the US population.
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http://dx.doi.org/10.1177/1078155220971751DOI Listing
November 2020

Management of recurrent bilateral multifocal pseudoangiomatous stromal hyperplasia (PASH).

Breast J 2020 09 19;26(9):1814-1817. Epub 2020 Jun 19.

Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.

Pseudoangiomatous stromal hyperplasia (PASH) is a benign hyperplastic condition of the breast that can lead to macromastia. The standard treatment for PASH is focal excision or rarely reduction mammoplasty. We present a rare case of postpartum bilateral rapid breast enlargement and axillary growth that was refractory to reduction mammoplasty. Ultimately, the patient required bilateral mastectomy and two-stage implant-based breast reconstruction. This more extensive form along with its management represents one of the few reported cases in the literature. The decision to pursue bilateral mastectomy was undertaken after exhausting more conservative options. Excellent aesthetic outcome and pain relief was obtained following definitive extirpative and reconstructive surgery.
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http://dx.doi.org/10.1111/tbj.13950DOI Listing
September 2020

Pathologic evaluation of response to neoadjuvant therapy drives treatment changes and improves long-term outcomes for breast cancer patients.

Breast J 2020 06 29;26(6):1189-1198. Epub 2020 May 29.

Massachusetts General Hospital, Boston, Massachusetts, USA.

Systemic therapy for breast cancer may be given before (neoadjuvant) or after (adjuvant) surgery. When neoadjuvant systemic therapy is given, response to treatment can be evaluated. However, some prognostic information (for example, pathologic tumor size pretreatment) is then lost and pathologic evaluation of breast specimens after neoadjuvant therapy is more difficult. Pathologic complete response (pCR), defined as no invasive disease in the breast (ypT0/is or ypT0) and no disease in all sampled lymph nodes (ypN0), identifies patients with a lower risk of recurrence or death compared to those with residual disease. Multidisciplinary collaboration, marking of the tumor site and any lymph node involvement pretreatment, and access to specimen imaging to facilitate correlation of gross and microscopic findings are critical for accurate determination of pCR. For HER2-positive and triple negative tumors requiring systemic therapy, giving the treatment before surgery identifies a high-risk group of patients that can receive additional adjuvant therapy after surgery if a pCR is not achieved. Recent clinical trials have demonstrated that this approach reduced recurrence risk. More than ever, pathologic evaluation of response to neoadjuvant systemic therapy directs treatment received after surgery. Using a single standardized protocol for sampling of the post-neoadjuvant surgical specimen allows pathologists to ensure accurate determination of pCR or residual disease and quantify residual disease. Residual cancer burden (RCB) and AJCC stage provide complementary quantitative information about residual disease and prognosis.
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http://dx.doi.org/10.1111/tbj.13864DOI Listing
June 2020

Prospective multi-institutional evaluation of pathologist assessment of PD-L1 assays for patient selection in triple negative breast cancer.

Mod Pathol 2020 09 16;33(9):1746-1752. Epub 2020 Apr 16.

Yale School of Medicine, New Haven, CT, USA.

The US Food and Drug Administration (FDA) approved the PD-L1 immunohistochemical assay, SP142, as a companion test to determine eligibility for atezolizumab therapy in patients with advanced triple negative breast cancer (TNBC) but data in lung cancer studies suggest the assay suffers from poor reproducibility. We sought to evaluate reproducibility and concordance in PD-L1 scoring across multiple pathologists. Full TNBC sections were stained with SP142 and SP263 assays and interpreted for percentage (%) immune cell (IC) staining by 19 pathologists from 14 academic institutions. Proportion of PD-L1 positive cases (defined as ≥1% IC) was determined for each assay as well as concordance across observers. We utilized a new method we call Observers Needed to Evaluate Subjective Tests (ONEST) to determine the minimum number of evaluators needed to estimate concordance between large numbers of readers, as occurs in the real-world setting. PD-L1 was interpreted as positive with the SP142 assay in an average 58% of cases compared with 78% with SP263 (p < 0.0001). IC positive continuous scores ranged from 1 to 95% (mean = 20%) and 1 to 90% (mean = 10%) for SP263 and SP142, respectively. With SP142, 26 cases (38%) showed complete two category (<1% vs. ≥1%) concordance; with SP263, 38 cases (50%) showed complete agreement. The intraclass correlation coefficient (ICC) for two category scoring of SP263 and SP142 was 0.513 and 0.560. ONEST plots showed decreasing overall percent agreement (OPA) as observer number increased, reaching a low plateau of 0.46 at ten observers for SP263 and 0.41 at eight observers for SP142. IC scoring with both assays showed poor reproducibility across multiple pathologists with ONEST analysis suggesting more than half of pathologists will disagree about IC scores. This could lead to many patients either receiving atezolizumab when they are unlikely to benefit, or not receiving atezolizumab when they may benefit.
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http://dx.doi.org/10.1038/s41379-020-0544-xDOI Listing
September 2020

Interobserver variability in breast carcinoma grading results in prognostic stage differences.

Hum Pathol 2019 12 23;94:51-57. Epub 2019 Oct 23.

Department of Pathology, Yale University School of Medicine New Haven, New Haven, CT. Electronic address:

The AJCC Cancer Staging Manual 8th edition included tumor grade in the pathologic prognostic stage for breast carcinomas. Due to the known subjectivity of tumor grading, we aimed to assess the degree of interobserver agreement for invasive carcinoma grade among pathologists and determine its effect on pathologic prognostic stage. One hundred consecutive cases of invasive stage II carcinomas were independently graded twice, with an 4-week intervening wash-out period, by 6 breast pathologists utilizing established Nottingham grading criteria. Inter- and intra-observer variability was determined for overall grade and for each of the 3 scoring components. Interobserver variability was good to very good (κ range = 0.582-0.850) with even better intra-observer variability (mean κ = 0.766). Tubule score was the most reproducible element (κ = 0.588). Complete concordance was reached in 54 cases and 58 cases in rounds 1 and 2 respectively. In round 1 this resulted in different pathologic prognostic stage in only 25 of discordant cases, 18 of which were stage IA versus IB. In conclusion, grading agreement between pathologists was good to very good and discordant grades resulted in small changes to pathologic prognostic stage.
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http://dx.doi.org/10.1016/j.humpath.2019.09.006DOI Listing
December 2019

Quantitative assessments and clinical outcomes in HER2 equivocal 2018 ASCO/CAP ISH group 4 breast cancer.

NPJ Breast Cancer 2019 29;5:28. Epub 2019 Aug 29.

6Massachusetts General Hospital, Boston, MA USA.

We quantified human epidermal growth factor receptor 2 (HER2) RNA and protein expression in 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) in situ hybridization (ISH) group 4 ( () ratio <2.0, average copy number ≥4.0 and <6.0, and 2013 ASCO/CAP ISH equivocal) breast cancers. Breast cancers in 2018 ASCO/CAP ISH group 4 between 2014 and 2017 were identified from the Yale archives. Sixty-three patients (34 with HER2 immunohistochemistry (IHC) 0/1+ and 29 with HER2 IHC 2+) were included. We compared patient characteristics, systemic treatments, and outcomes. We assessed HER2 by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and quantitative immunofluorescence (QIF). Among ISH group 4 cancers, higher mRNA ( < 0.0001) but similar HER2 protein levels were observed in IHC 2+ compared to IHC 0/1+ cancers. The distribution of RT-qPCR and QIF scores were independent of fluorescence in situ hybridization (FISH) ratio/copy number. Concordance between HER2 RT-qPCR and QIF was 69.8% ( = 0.52). Among 29 patients with IHC2+ results, 16 were HER2 positive by RT-qPCR and 12 were HER2 positive by QIF. Systemic treatment, recurrence, and survival outcomes were comparable among ISH group 4 cancers regardless of IHC 0/1+ or 2+ results. ISH group 4 cancers appear to form a distinct group with intermediate levels of RNA/protein expression, close to positive/negative cut points. Therefore, adjudication into positive or negative categories may not be meaningful. Our results support the 2018 ASCOCAP recommendation to refrain from routine additional testing of these samples. Additional outcome information after trastuzumab treatment for patients in this special group might help to guide treatment decisions in these patients.
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http://dx.doi.org/10.1038/s41523-019-0122-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715641PMC
August 2019

Breast cancer histopathology is predictive of low-risk Oncotype Dx recurrence score.

Breast J 2018 11 19;24(6):976-980. Epub 2018 Sep 19.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.

Background: Oncotype Dx is a genetic test that has been incorporated into the 2017 AJCC breast cancer staging system for ER positive, HER2-negative, lymph node-negative patients to predict the risk of recurrence. Recent data suggest that immunohistochemistry (ER, PR, HER2, and Ki-67) and histologic subtype may identify patients that will not benefit from Oncotype Dx testing.

Methods: A total of 371 patients underwent Oncotype Dx testing at our institution from 2012 to 2016. Oncotype recurrence score was categorized as low- (ORS = 0-10), intermediate- (11-25), or high risk (26-100). Invasive carcinomas were categorized based on histologic subtype as "favorable" (mucinous, tubular, cribriform, tubulolobular, and lobular) and "unfavorable" (ductal, mixed ductal and lobular, and micropapillary carcinoma). All cases were estrogen receptor positive and HER2-negative. Clinical and histologic predictors of low-risk ORS were assessed in univariate and multivariate logistic regression.

Results: A total of 371 patients were categorized by ORS as low risk (n = 85, 22.9%), intermediate risk (n = 244, 65.8%), and high risk (n = 42, 11.3%). The histologic subtypes with the highest percentage of high-risk ORS were invasive micropapillary (n = 4/17, 23.5%), pleomorphic lobular (n = 2/10, 20%), and ductal carcinoma (n = 28/235, 11.9%). Low-grade invasive carcinomas with favorable histology rarely had a high-risk ORS (n = 1/97, 1%). In a simple multivariable model, favorable histologic subtype (OR = 2.39, 95% CI: 1.10 to 5.15, P = 0.026), and histologic grade (OR = 1.76, 95% CI: 1.07 to 2.90, P = 0.025) were the only significant predictors of an ORS less than 11 in estrogen receptor positive, HER2-negative, and lymph node-negative patients.

Conclusion: We question the utility of performing Oncotype Dx in subtypes of invasive carcinoma that are associated with excellent prognosis. We propose that immunohistochemistry for ER, PR, and HER2 is sufficient for patients with low-grade invasive carcinomas and can be used as a surrogate for Oncotype Dx.
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http://dx.doi.org/10.1111/tbj.13117DOI Listing
November 2018

Increased epigenetic age in normal breast tissue from luminal breast cancer patients.

Clin Epigenetics 2018 08 29;10(1):112. Epub 2018 Aug 29.

Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, 300 George Street, Suite 120, New Haven, CT, 06511, USA.

Background: Age is one of the most important risk factors for developing breast cancer. However, age-related changes in normal breast tissue that potentially lead to breast cancer are incompletely understood. Quantifying tissue-level DNA methylation can contribute to understanding these processes. We hypothesized that occurrence of breast cancer should be associated with an acceleration of epigenetic aging in normal breast tissue.

Results: Ninety-six normal breast tissue samples were obtained from 88 subjects (breast cancer = 35 subjects/40 samples, unaffected = 53 subjects/53 samples). Normal tissue samples from breast cancer patients were obtained from distant non-tumor sites of primary mastectomy specimens, while samples from unaffected women were obtained from the Komen Tissue Bank (n = 25) and from non-cancer-related breast surgery specimens (n = 28). Patients were further stratified into four cohorts: age < 50 years with and without breast cancer and age ≥ 50 with and without breast cancer. The Illumina HumanMethylation450k BeadChip microarray was used to generate methylation profiles from extracted DNA samples. Data was analyzed using the "Epigenetic Clock," a published biomarker of aging based on a defined set of 353 CpGs in the human genome. The resulting age estimate, DNA methylation age, was related to chronological age and to breast cancer status. The DNAmAge of normal breast tissue was strongly correlated with chronological age (r = 0.712, p < 0.001). Compared to unaffected peers, breast cancer patients exhibited significant age acceleration in their normal breast tissue (p = 0.002). Multivariate analysis revealed that epigenetic age acceleration in the normal breast tissue of subjects with cancer remained significant after adjusting for clinical and demographic variables. Additionally, smoking was found to be positively correlated with epigenetic aging in normal breast tissue (p = 0.012).

Conclusions: Women with luminal breast cancer exhibit significant epigenetic age acceleration in normal adjacent breast tissue, which is consistent with an analogous finding in malignant breast tissue. Smoking is also associated with epigenetic age acceleration in normal breast tissue. Further studies are needed to determine whether epigenetic age acceleration in normal breast tissue is predictive of incident breast cancer and whether this mediates the risk of chronological age on breast cancer risk.
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http://dx.doi.org/10.1186/s13148-018-0534-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114717PMC
August 2018

Macrodissection prior to closed system RT-qPCR is not necessary for estrogen receptor and HER2 concordance with IHC/FISH in breast cancer.

Lab Invest 2018 08 1;98(8):1076-1083. Epub 2018 Jun 1.

Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.

An on-demand, closed RT-qPCR, the GeneXpert (GX) system, has the potential to provide biomarker information in low-resourced settings and elsewhere. We used this system with a research use only version of the Breast Cancer STRAT4 cartridge that measures the mRNA expression levels of ERBB2, ESR1, PGR, and MKi67. Here we evaluated the impact of non-macrodissected (non m-d) versus macrodissected (m-d) samples using STRAT4 on formalin-fixed, paraffin-embedded (FFPE) core needle biopsies. Two cohorts were assessed: (1) 60 FFPE infiltrating ductal carcinoma (IDCA) cases and (2) 20 FFPE IDCA cases with ductal carcinoma in situ (DCIS) with a range of HER2 expression as determined by clinical immunohistochemistry and fluorescence in situ hybridization (IHC/FISH). We observed about half of the core needle biopsy area as invasive tumor in both IDCA (mean = 51.5%) and IDCA with DCIS (mean = 53.5%) cohorts, but also found the mRNA levels were independent of tumor area. We found excellent agreement of the mRNA transcript level between the paired samples, m-d versus non m-d, for ERBB2, ESR1, PGR, and MKi67 for both the IDCA and IDCA with DCIS cohorts. No significant difference (P > 0.99) was observed when we compared the mRNA transcript level between the paired samples m-d versus non m-d. In addition, we noted a significant concordance (P < 0.001) between RT-qPCR and IHC/FISH for HER2-positivity, ER-positivity, and PR-positivity, independent of specimen dissection. These data suggest that mRNA expression for ERBB2, ESR, and PGR is sufficiently low in surrounding tissue cells such that macrodissection is not required for assessment of key breast cancer mRNA markers and is independent of the amount of input tumor. This approach may be valuable in settings lacking pathology expertise or using specimen types, such as fine-needle aspirates, where it may be challenging to separate non-tumor from tumor tissue.
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http://dx.doi.org/10.1038/s41374-018-0064-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119113PMC
August 2018

Processing and Reporting of Breast Specimens in the Neoadjuvant Setting.

Authors:
Veerle Bossuyt

Surg Pathol Clin 2018 Mar 11;11(1):213-230. Epub 2017 Dec 11.

Department of Pathology, Yale University, PO Box 208023, 310 Cedar Street, New Haven, CT 06520-8023, USA. Electronic address:

Standardization of quantification of residual disease in the breast and lymph nodes with routine pathologic macroscopic and microscopic evaluation leads to accurate and reproducible measures of response to neoadjuvant treatment. Multidisciplinary collaboration and correlation of clinical, imaging, gross and microscopic findings is essential. The processing approach to post-neoadjuvant breast cancer surgical specimens and the elements needed in the pathology report are the same regardless of breast cancer subtype or type of neoadjuvant treatment. The residual cancer burden incorporates response in the breast and in the lymph nodes into a score that can be combined with other emerging prognostic factors.
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http://dx.doi.org/10.1016/j.path.2017.09.010DOI Listing
March 2018

Metastatic serous carcinoma presenting as inflammatory carcinoma over the breast-Report of two cases and literature review.

J Cutan Pathol 2018 Mar 26;45(3):234-239. Epub 2017 Dec 26.

Department of Dermatology, Yale School of Medicine, New Haven, Connecticut.

Non-mammary metastases involving breast are rare and most commonly involve the breast parenchyma. Infrequently, metastasis from an extramammary primary site presents as inflammatory carcinoma over the breast. Diagnosis of such lesions can be challenging, especially in patients with coexisting primary breast carcinoma. Few such cases have been described in literature; however, none of the previously reported cases had a prior history of primary breast carcinoma. We present 2 patients with history of breast carcinoma and serous carcinoma of ovarian/peritoneal origin that presented with inflammatory carcinoma over the breast. Biopsies from breast tissue showed atypical cells in the dermis forming cords and papillary structures. Histopathologic differential diagnosis included infiltrating ductal carcinoma of breast origin and metastatic serous carcinoma. Immunohistochemical studies showed that the tumor cells were positive for markers of ovarian origin such as PAX-8 and CA-125 and negative for breast markers such as GATA-3, thus supporting the diagnosis. In summary, we describe the unusual presentation of metastatic serous carcinoma as inflammatory carcinoma over breast and discuss the diagnostic challenges in patients with coexisting primary breast and ovarian malignancies. We also review the morphologic features of tumors of breast and ovarian origin and the immunohistochemical stains to differentiate these 2 entities.
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http://dx.doi.org/10.1111/cup.13091DOI Listing
March 2018

Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer.

Semin Cancer Biol 2018 10 9;52(Pt 2):16-25. Epub 2017 Oct 9.

Translational Breast Cancer Genomic and Therapeutics Laboratory, Peter Mac Callum Cancer Center, Victoria, Australia; Breast Cancer Translational Research Laboratory, Jules Bordet Institute, Brussels, Belgium; Department of Pathology, GZA, Antwerp, Belgium.

Morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer is gaining momentum as evidence strengthens the clinical relevance of this immunological biomarker. TILs in the post-neoadjuvant residual disease setting are acquiring increasing importance as a stratifying marker in clinical trials, considering the raising interest on immunotherapeutic strategies after neoadjuvant chemotherapy. TILs in ductal carcinoma in situ, with or without invasive carcinoma, represent an emerging area of clinical breast cancer research. The aim of this report is to update pathologists, clinicians and researchers on TIL assessment in both the post-neoadjuvant residual disease and the ductal carcinoma in situ settings. The International Immuno-Oncology Working Group proposes a method for assessing TILs in these settings, based on the previously published International Guidelines on TIL Assessment in Breast Cancer. In this regard, these recommendations represent a consensus guidance for pathologists, aimed to achieve the highest possible consistency among future studies.
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http://dx.doi.org/10.1016/j.semcancer.2017.10.003DOI Listing
October 2018

Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non-Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors.

Authors:
Shona Hendry Roberto Salgado Thomas Gevaert Prudence A Russell Tom John Bibhusal Thapa Michael Christie Koen van de Vijver M V Estrada Paula I Gonzalez-Ericsson Melinda Sanders Benjamin Solomon Cinzia Solinas Gert G G M Van den Eynden Yves Allory Matthias Preusser Johannes Hainfellner Giancarlo Pruneri Andrea Vingiani Sandra Demaria Fraser Symmans Paolo Nuciforo Laura Comerma E A Thompson Sunil Lakhani Seong-Rim Kim Stuart Schnitt Cecile Colpaert Christos Sotiriou Stefan J Scherer Michail Ignatiadis Sunil Badve Robert H Pierce Giuseppe Viale Nicolas Sirtaine Frederique Penault-Llorca Tomohagu Sugie Susan Fineberg Soonmyung Paik Ashok Srinivasan Andrea Richardson Yihong Wang Ewa Chmielik Jane Brock Douglas B Johnson Justin Balko Stephan Wienert Veerle Bossuyt Stefan Michiels Nils Ternes Nicole Burchardi Stephen J Luen Peter Savas Frederick Klauschen Peter H Watson Brad H Nelson Carmen Criscitiello Sandra O'Toole Denis Larsimont Roland de Wind Giuseppe Curigliano Fabrice André Magali Lacroix-Triki Mark van de Vijver Federico Rojo Giuseppe Floris Shahinaz Bedri Joseph Sparano David Rimm Torsten Nielsen Zuzana Kos Stephen Hewitt Baljit Singh Gelareh Farshid Sibylle Loibl Kimberly H Allison Nadine Tung Sylvia Adams Karen Willard-Gallo Hugo M Horlings Leena Gandhi Andre Moreira Fred Hirsch Maria V Dieci Maria Urbanowicz Iva Brcic Konstanty Korski Fabien Gaire Hartmut Koeppen Amy Lo Jennifer Giltnane Marlon C Rebelatto Keith E Steele Jiping Zha Kenneth Emancipator Jonathan W Juco Carsten Denkert Jorge Reis-Filho Sherene Loi Stephen B Fox

Adv Anat Pathol 2017 Nov;24(6):311-335

Departments of *Pathology §§§Medical Oncology, Peter MacCallum Cancer Centre, Melbourne †The Sir Peter MacCallum Department of Oncology Departments of **Pathology ∥∥Medicine, University of Melbourne ¶¶Department of Anatomical Pathology, Royal Melbourne Hospital, Parkville #Department of Anatomical Pathology, St Vincent's Hospital Melbourne, Fitzroy ††Department of Medical Oncology, Austin Health ‡‡Olivia Newton-John Cancer Research Institute, Heidelberg §§School of Cancer Medicine, La Trobe University, Bundoora §§§§§Centre for Clinical Research and School of Medicine, The University of Queensland ∥∥∥∥∥Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane §§§§§§§§§§The Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst ∥∥∥∥∥∥∥∥∥∥Australian Clinical Labs, Bella Vista ‡‡‡‡‡‡‡‡‡‡‡‡Directorate of Surgical Pathology, SA Pathology §§§§§§§§§§§§Discipline of Medicine, Adelaide University, Adelaide, Australia ***********Department of Surgical Oncology, Netherlands Cancer Institute †††††††††††††Department of Pathology ##Divisions of Diagnostic Oncology & Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands ###Université Paris-Est ****INSERM, UMR 955 ††††Département de pathologie, APHP, Hôpital Henri-Mondor, Créteil ∥∥∥∥∥∥∥∥∥Service de Biostatistique et d'Epidémiologie, Gustave Roussy, CESP, Inserm U1018, Université-Paris Sud, Université Paris-Saclay ¶¶¶¶¶¶¶¶¶¶INSERM Unit U981, and Department of Medical Oncology, Gustave Roussy, Villejuif ##########Faculté de Médecine, Université Paris Sud, Kremlin-Bicêtre †††††††Department of Surgical Pathology and Biopathology, Jean Perrin Comprehensive Cancer Centre ‡‡‡‡‡‡‡University of Auvergne UMR1240, Clermont-Ferrand, France ‡‡‡‡Department of Medicine, Clinical Division of Oncology §§§§Institute of Neurology, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna ††††††††††††††Institute of Pathology, Medical University of Graz, Austria ∥∥∥∥European Institute of Oncology ¶¶¶¶School of Medicine ######Department of Pathology, Istituto Europeo di Oncologia, University of Milan, Milan ¶¶¶¶¶¶¶¶¶¶¶¶¶Department of Surgery, Oncology and Gastroenterology, University of Padova #############Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy †††††Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona †††††††††††Pathology Department, IIS-Fundacion Jimenez Diaz, UAM, Madrid, Spain §Department of Pathology and TCRU, GZA ¶¶¶Department of Pathology, GZA Ziekenhuizen, Antwerp ∥Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven ‡‡‡‡‡‡‡‡‡‡‡Department of Pathology, University Hospital Leuven, Leuven, Belgium ¶Department of Pathology, AZ Klina, Brasschaat ††††††Department of Pathology, GZA Ziekenhuizen, Sint-Augustinus, Wilrijk ∥∥∥Molecular Immunology Unit ‡‡‡‡‡‡Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles ‡Breast Cancer Translational Research Laboratory/Breast International Group, Institut Jules Bordet **************European Organisation for Research and Treatment of Cancer (EORTC) Headquarters *******Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium §§§§§§§Department of Surgery, Kansai Medical School, Hirakata, Japan #######Severance Biomedical Science Institute and Department of Medical Oncology, Yonsei University College of Medicine, Seoul, South Korea ∥∥∥∥∥∥∥∥Tumor Pathology Department, Maria Sklodowska-Curie Memorial Cancer Center ¶¶¶¶¶¶¶¶Institute of Oncology, Gliwice Branch, Gliwice, Poland ‡‡‡‡‡‡‡‡‡‡‡‡‡‡Pathology and Tissue Analytics, Roche Innovation Centre Munich, Penzberg †††††††††Institute of Pathology, Charité Universitätsmedizin Berlin ‡‡‡‡‡‡‡‡‡VMscope GmbH, Berlin ¶¶¶¶¶¶¶¶¶German Breast Group GmbH, Neu-Isenburg, Germany **********Trev & Joyce Deeley Research Centre, British Columbia Cancer Agency ††††††††††Department of Biochemistry and Microbiology, University of Victoria, Victoria Departments of ‡‡‡‡‡‡‡‡‡‡Medical Genetics #########Pathology and Laboratory Medicine ¶¶¶¶¶¶¶¶¶¶¶Department of Pathology and Laboratory Medicine, Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC ###########Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada §§§§§§§§§§§Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Doha, Qatar ‡‡‡‡‡‡‡‡Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center §§§§§§§§Warren Alpert Medical School of Brown University, Providence ¶¶¶¶¶National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, PA †††Breast Cancer Research Program, Vanderbilt Ingram Cancer Center, Vanderbilt University Departments of ‡‡‡Pathology, Microbiology and Immunology ########Department of Medicine, Vanderbilt University Medical Centre *********Vanderbilt Ingram Cancer Center, Nashville §§§§§§§§§Department of Pathology, Yale University School of Medicine, New Haven ∥∥∥∥∥∥∥∥∥∥∥Department of Oncology, Montefiore Medical Centre, Albert Einstein College of Medicine ∥∥∥∥∥∥∥Montefiore Medical Center ¶¶¶¶¶¶¶The Albert Einstein College of Medicine, Bronx, NY ********Department of Pathology, Brigham and Women's Hospital #####Cancer Research Institute and Department of Pathology, Beth Israel Deaconess Cancer Center ******Harvard Medical School ¶¶¶¶¶¶¶¶¶¶¶¶Division of Hematology-Oncology, Beth Israel Deaconess Medical Center ††††††††Department of Cancer Biology ‡‡‡‡‡‡‡‡‡‡‡‡‡Dana-Farber Cancer Institute, Boston, MA ∥∥∥∥∥∥∥∥∥∥∥∥∥Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO ‡‡‡‡‡Department of Cancer Biology, Mayo Clinic, Jacksonville, FL ∥∥∥∥∥∥Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN ¶¶¶¶¶¶Cancer Immunotherapy Trials Network, Central Laboratory and Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA ††††††††††††Department of Pathology, New York University Langone Medical Centre ############New York University Medical School *************Perlmutter Cancer Center §§§§§§§§§§§§§Pulmonary Pathology, New York University Center for Biospecimen Research and Development, New York University ***************Department of Pathology, Memorial Sloan-Kettering Cancer Center ####Departments of Radiation Oncology and Pathology, Weill Cornell Medicine, New York, NY *****Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX ∥∥∥∥∥∥∥∥∥∥∥∥Pathology Department, Stanford University Medical Centre, Stanford ∥∥∥∥∥∥∥∥∥∥∥∥∥∥Department of Pathology, Stanford University, Palo Alto ***Department of Pathology, School of Medicine, University of California, San Diego §§§§§§§§§§§§§§Research Pathology, Genentech Inc., South San Francisco, CA *************Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda ¶¶¶¶¶¶¶¶¶¶¶¶¶¶Translational Sciences, MedImmune, Gaithersberg, MD §§§§§§Academic Medical Innovation, Novartis Pharmaceuticals Corporation, East Hanover ##############Translational Medicine, Merck & Co. Inc., Kenilworth, NJ.

Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.
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http://dx.doi.org/10.1097/PAP.0000000000000161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638696PMC
November 2017

Assessing Tumor-infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method From the International Immunooncology Biomarkers Working Group: Part 1: Assessing the Host Immune Response, TILs in Invasive Breast Carcinoma and Ductal Carcinoma In Situ, Metastatic Tumor Deposits and Areas for Further Research.

Authors:
Shona Hendry Roberto Salgado Thomas Gevaert Prudence A Russell Tom John Bibhusal Thapa Michael Christie Koen van de Vijver M V Estrada Paula I Gonzalez-Ericsson Melinda Sanders Benjamin Solomon Cinzia Solinas Gert G G M Van den Eynden Yves Allory Matthias Preusser Johannes Hainfellner Giancarlo Pruneri Andrea Vingiani Sandra Demaria Fraser Symmans Paolo Nuciforo Laura Comerma E A Thompson Sunil Lakhani Seong-Rim Kim Stuart Schnitt Cecile Colpaert Christos Sotiriou Stefan J Scherer Michail Ignatiadis Sunil Badve Robert H Pierce Giuseppe Viale Nicolas Sirtaine Frederique Penault-Llorca Tomohagu Sugie Susan Fineberg Soonmyung Paik Ashok Srinivasan Andrea Richardson Yihong Wang Ewa Chmielik Jane Brock Douglas B Johnson Justin Balko Stephan Wienert Veerle Bossuyt Stefan Michiels Nils Ternes Nicole Burchardi Stephen J Luen Peter Savas Frederick Klauschen Peter H Watson Brad H Nelson Carmen Criscitiello Sandra O'Toole Denis Larsimont Roland de Wind Giuseppe Curigliano Fabrice André Magali Lacroix-Triki Mark van de Vijver Federico Rojo Giuseppe Floris Shahinaz Bedri Joseph Sparano David Rimm Torsten Nielsen Zuzana Kos Stephen Hewitt Baljit Singh Gelareh Farshid Sibylle Loibl Kimberly H Allison Nadine Tung Sylvia Adams Karen Willard-Gallo Hugo M Horlings Leena Gandhi Andre Moreira Fred Hirsch Maria V Dieci Maria Urbanowicz Iva Brcic Konstanty Korski Fabien Gaire Hartmut Koeppen Amy Lo Jennifer Giltnane Marlon C Rebelatto Keith E Steele Jiping Zha Kenneth Emancipator Jonathan W Juco Carsten Denkert Jorge Reis-Filho Sherene Loi Stephen B Fox

Adv Anat Pathol 2017 Sep;24(5):235-251

Departments of *Pathology §§§Medical Oncology, Peter MacCallum Cancer Centre, Melbourne †The Sir Peter MacCallum Department of Oncology Departments of **Pathology ∥∥Medicine, University of Melbourne ¶¶Department of Anatomical Pathology, Royal Melbourne Hospital, Parkville #Department of Anatomical Pathology, St Vincent's Hospital Melbourne, Fitzroy ††Department of Medical Oncology, Austin Health ‡‡Olivia Newton-John Cancer Research Institute, Heidelberg §§School of Cancer Medicine, La Trobe University, Bundoora §§§§§Centre for Clinical Research and School of Medicine, The University of Queensland ∥∥∥∥∥Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane §§§§§§§§§§The Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst ∥∥∥∥∥∥∥∥∥∥Australian Clinical Labs, Bella Vista ‡‡‡‡‡‡‡‡‡‡‡‡Directorate of Surgical Pathology, SA Pathology §§§§§§§§§§§§Discipline of Medicine, Adelaide University, Adelaide, Australia ***********Department of Surgical Oncology, Netherlands Cancer Institute †††††††††††††Department of Pathology ##Divisions of Diagnostic Oncology & Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands ###Université Paris-Est ****INSERM, UMR 955 ††††Département de pathologie, APHP, Hôpital Henri-Mondor, Créteil ∥∥∥∥∥∥∥∥∥Service de Biostatistique et d'Epidémiologie, Gustave Roussy, CESP, Inserm U1018, Université-Paris Sud, Université Paris-Saclay ¶¶¶¶¶¶¶¶¶¶INSERM Unit U981, and Department of Medical Oncology, Gustave Roussy, Villejuif ##########Faculté de Médecine, Université Paris Sud, Kremlin-Bicêtre †††††††Department of Surgical Pathology and Biopathology, Jean Perrin Comprehensive Cancer Centre ‡‡‡‡‡‡‡University of Auvergne UMR1240, Clermont-Ferrand, France ‡‡‡‡Department of Medicine, Clinical Division of Oncology §§§§Institute of Neurology, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna ††††††††††††††Institute of Pathology, Medical University of Graz, Austria ∥∥∥∥European Institute of Oncology ¶¶¶¶School of Medicine ######Department of Pathology, Istituto Europeo di Oncologia, University of Milan, Milan ¶¶¶¶¶¶¶¶¶¶¶¶¶Department of Surgery, Oncology and Gastroenterology, University of Padova #############Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy †††††Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona †††††††††††Pathology Department, IIS-Fundacion Jimenez Diaz, UAM, Madrid, Spain §Department of Pathology and TCRU, GZA ¶¶¶Department of Pathology, GZA Ziekenhuizen, Antwerp ∥Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven ‡‡‡‡‡‡‡‡‡‡‡Department of Pathology, University Hospital Leuven, Leuven, Belgium ¶Department of Pathology, AZ Klina, Brasschaat ††††††Department of Pathology, GZA Ziekenhuizen, Sint-Augustinus, Wilrijk ∥∥∥Molecular Immunology Unit ‡‡‡‡‡‡Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles ‡Breast Cancer Translational Research Laboratory/Breast International Group, Institut Jules Bordet **************European Organisation for Research and Treatment of Cancer (EORTC) Headquarters *******Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium §§§§§§§Department of Surgery, Kansai Medical School, Hirakata, Japan #######Severance Biomedical Science Institute and Department of Medical Oncology, Yonsei University College of Medicine, Seoul, South Korea ∥∥∥∥∥∥∥∥Tumor Pathology Department, Maria Sklodowska-Curie Memorial Cancer Center ¶¶¶¶¶¶¶¶Institute of Oncology, Gliwice Branch, Gliwice, Poland ‡‡‡‡‡‡‡‡‡‡‡‡‡‡Pathology and Tissue Analytics, Roche Innovation Centre Munich, Penzberg †††††††††Institute of Pathology, Charité Universitätsmedizin Berlin ‡‡‡‡‡‡‡‡‡VMscope GmbH, Berlin ¶¶¶¶¶¶¶¶¶German Breast Group GmbH, Neu-Isenburg, Germany **********Trev & Joyce Deeley Research Centre, British Columbia Cancer Agency ††††††††††Department of Biochemistry and Microbiology, University of Victoria, Victoria Departments of ‡‡‡‡‡‡‡‡‡‡Medical Genetics #########Pathology and Laboratory Medicine ¶¶¶¶¶¶¶¶¶¶¶Department of Pathology and Laboratory Medicine, Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC ###########Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada §§§§§§§§§§§Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Doha, Qatar ‡‡‡‡‡‡‡‡Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center §§§§§§§§Warren Alpert Medical School of Brown University, Providence ¶¶¶¶¶National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, PA †††Breast Cancer Research Program, Vanderbilt Ingram Cancer Center, Vanderbilt University Departments of ‡‡‡Pathology, Microbiology and Immunology ########Department of Medicine, Vanderbilt University Medical Centre *********Vanderbilt Ingram Cancer Center, Nashville §§§§§§§§§Department of Pathology, Yale University School of Medicine, New Haven ∥∥∥∥∥∥∥∥∥∥∥Department of Oncology, Montefiore Medical Centre, Albert Einstein College of Medicine ∥∥∥∥∥∥∥Montefiore Medical Center ¶¶¶¶¶¶¶The Albert Einstein College of Medicine, Bronx, NY ********Department of Pathology, Brigham and Women's Hospital #####Cancer Research Institute and Department of Pathology, Beth Israel Deaconess Cancer Center ******Harvard Medical School ¶¶¶¶¶¶¶¶¶¶¶¶Division of Hematology-Oncology, Beth Israel Deaconess Medical Center ††††††††Department of Cancer Biology ‡‡‡‡‡‡‡‡‡‡‡‡‡Dana-Farber Cancer Institute, Boston, MA ∥∥∥∥∥∥∥∥∥∥∥∥∥Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO ‡‡‡‡‡Department of Cancer Biology, Mayo Clinic, Jacksonville, FL ∥∥∥∥∥∥Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN ¶¶¶¶¶¶Cancer Immunotherapy Trials Network, Central Laboratory and Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA ††††††††††††Department of Pathology, New York University Langone Medical Centre ############New York University Medical School *************Perlmutter Cancer Center §§§§§§§§§§§§§Pulmonary Pathology, New York University Center for Biospecimen Research and Development, New York University ***************Department of Pathology, Memorial Sloan-Kettering Cancer Center ####Departments of Radiation Oncology and Pathology, Weill Cornell Medicine, New York, NY *****Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX ∥∥∥∥∥∥∥∥∥∥∥∥Pathology Department, Stanford University Medical Centre, Stanford ∥∥∥∥∥∥∥∥∥∥∥∥∥∥Department of Pathology, Stanford University, Palo Alto ***Department of Pathology, School of Medicine, University of California, San Diego §§§§§§§§§§§§§§Research Pathology, Genentech Inc., South San Francisco, CA *************Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda ¶¶¶¶¶¶¶¶¶¶¶¶¶¶Translational Sciences, MedImmune, Gaithersberg, MD §§§§§§Academic Medical Innovation, Novartis Pharmaceuticals Corporation, East Hanover ##############Translational Medicine, Merck & Co. Inc., Kenilworth, NJ.

Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.
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http://dx.doi.org/10.1097/PAP.0000000000000162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564448PMC
September 2017

Intratumor Heterogeneity of Homologous Recombination Deficiency in Primary Breast Cancer.

Clin Cancer Res 2017 Mar 6;23(5):1193-1199. Epub 2016 Sep 6.

Yale University School of Medicine and Yale Cancer Center, New Haven, Connecticut.

The 3-biomarker homologous recombination deficiency (HRD) assay measures the number of telomeric allelic imbalances, loss of heterozygosity, and large-scale state transitions in tumor DNA and combines these metrics into a single score that reflects DNA repair deficiency. The goal of this study is to assess the consistency of these HRD measures in different biopsies from distinct areas of the same cancer. HRD scores, BRCA mutation status, and promoter methylation were assessed in 99 samples from 33 surgically resected, stage I-III breast cancers; each cancer was biopsied in three distinct areas. Homologous recombination repair (HR) deficiency was defined as either high HRD score (≥42) or tumor BRCA mutation. Eighty-one biopsies from 32 cancers were analyzed. Tumor BRCA status was available for all samples, HRD scores for 70, and methylation values for 76 samples. The mutation and promoter methylation status and HR category showed perfect concordance across all biopsies from the same cancer. All tumors with mutations or promoter methylation had high HRD scores, as did 17% (4/24) of the wild-type and nonmethylated tumors. The HRD scores were also highly consistent between different biopsies from the same tumor with an intraclass correlation coefficient of 0.977, indicating that only 2.3% of the variance is attributed to within-tumor biopsy-to-biopsy variation. These results indicate that within-tumor spatial heterogeneity for HRD metrics and the technical noise in the assay are small and do not influence HRD scores and HR status. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-0889DOI Listing
March 2017

Standardizing of Pathology in Patients Receiving Neoadjuvant Chemotherapy.

Ann Surg Oncol 2016 10 5;23(10):3153-61. Epub 2016 Jul 5.

The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

The use of neoadjuvant systemic therapy for the treatment of breast cancer patients is increasing. Pathologic response in the form of pathologic complete response (pCR) and grading systems of partial response, such as the residual cancer burden (RCB) system, gives valuable prognostic information for patients and is used as a primary endpoint in clinical trials. The breast cancer and pathology communities are responding with efforts to standardize pathology in patients receiving neoadjuvant chemotherapy. In this review, we summarize the challenges that postneoadjuvant systemic therapy surgical specimens pose and how pathologists and the multidisciplinary team can work together to optimize handling of these specimens. Multidisciplinary communication is essential. A single, standardized approach to macroscopic and microscopic pathologic examination makes it possible to provide reliable response information. This approach employs a map of tissue sections to correlate clinical, gross, microscopic, and imaging findings in order to report the presence of pCR (ypT0 ypN0 and ypT0/is ypN0) versus residual disease, the ypT and ypN stage using the current AJCC/UICC staging system, and the RCB.
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http://dx.doi.org/10.1245/s10434-016-5317-xDOI Listing
October 2016

Economic Impact of Routine Cavity Margins Versus Standard Partial Mastectomy in Breast Cancer Patients: Results of a Randomized Controlled Trial.

Ann Surg 2017 01;265(1):39-44

*Department of Surgery, Yale University †Yale Cancer Center ‡Yale Center for Outcomes Public Policy and Effectiveness Research §Department of Surgery, Thomas Jefferson University ¶Yale-New Haven Hospital ||Yale Center for Analytical Sciences **Department of Pathology, Yale University ††Department of Medicine, Yale University.

Objective: The aim of the study was to compare costs associated with excision of routine cavity shave margins (CSM) versus standard partial mastectomy (PM) in patients with breast cancer.

Background: Excision of CSM reduces re-excision rates by more than 50%. The economic implications of this is, however, unclear.

Methods: Between October 21, 2011 and November 25, 2013, 235 women undergoing PM for Stage 0-III breast cancer were randomized to undergo either standard PM ("no shave", n = 116) or have additional CSM taken ("shave", n = 119). Costs from both a payer and a hospital perspective were measured for index surgery and breast cancer surgery-related care through subsequent 90 days.

Results: The 2 groups were well-matched in terms of baseline characteristics. Those in the "shave" group had a longer operative time at the initial surgery (median 76 vs 66 min, P < 0.01), but a lower re-excision rate for positive margins (13/119 = 10.9% vs 32/116 = 27.6%, P < 0.01). Actual direct hospital costs associated with operating room time ($1315 vs. $1137, P = 0.03) and pathology costs ($1195 vs $795, P < 0.01) were greater for the initial surgery in patients in the "shave" group. Taking into account the index surgery and the subsequent 90 days, there was no significant difference in cost from either the payer ($10,476 vs $11,219, P = 0.40) or hospital perspective ($5090 vs $5116, P = 0.37) between the "shave" and "no shave" groups.

Conclusions: Overall costs were not significantly different between the "shave" and "no shave" groups due to significantly fewer reoperative surgeries in the former.
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http://dx.doi.org/10.1097/SLA.0000000000001799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605915PMC
January 2017

Mutation based treatment recommendations from next generation sequencing data: a comparison of web tools.

Oncotarget 2016 Apr;7(16):22064-76

Medical Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA.

Interpretation of complex cancer genome data, generated by tumor target profiling platforms, is key for the success of personalized cancer therapy. How to draw therapeutic conclusions from tumor profiling results is not standardized and may vary among commercial and academically-affiliated recommendation tools. We performed targeted sequencing of 315 genes from 75 metastatic breast cancer biopsies using the FoundationOne assay. Results were run through 4 different web tools including the Drug-Gene Interaction Database (DGidb), My Cancer Genome (MCG), Personalized Cancer Therapy (PCT), and cBioPortal, for drug and clinical trial recommendations. These recommendations were compared amongst each other and to those provided by FoundationOne. The identification of a gene as targetable varied across the different recommendation sources. Only 33% of cases had 4 or more sources recommend the same drug for at least one of the usually several altered genes found in tumor biopsies. These results indicate further development and standardization of broadly applicable software tools that assist in our therapeutic interpretation of genomic data is needed. Existing algorithms for data acquisition, integration and interpretation will likely need to incorporate artificial intelligence tools to improve both content and real-time status.
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http://dx.doi.org/10.18632/oncotarget.8017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008344PMC
April 2016

The Neoadjuvant Model and Complete Pathologic Response in Breast Cancer: All or Nothing?

JAMA Oncol 2016 Jun;2(6):760-1

Department of Internal Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut3Yale Cancer Center, New Haven, Connecticut.

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http://dx.doi.org/10.1001/jamaoncol.2015.6509DOI Listing
June 2016

Immune Signatures Following Single Dose Trastuzumab Predict Pathologic Response to PreoperativeTrastuzumab and Chemotherapy in HER2-Positive Early Breast Cancer.

Clin Cancer Res 2016 07 3;22(13):3249-59. Epub 2016 Feb 3.

Case Western Reserve University School of Medicine, Cleveland, Ohio.

Purpose: Recent data suggest that intrinsic subtype and immune cell infiltration may predict response to trastuzumab-based therapy. We studied the interaction between these factors, changes in immune signatures following brief exposure to trastuzumab, and achievement of pathologic complete response (pCR) to subsequent preoperative trastuzumab and chemotherapy in HER2-positive breast cancer.

Experimental Design: In patients enrolled on two multicenter trials (03-311 and 211B), tumor core biopsies were obtained at baseline and after brief exposure to single-agent trastuzumab or nab-paclitaxel. Gene expression profiles were assessed to assign PAM50 subtypes, measure immune cell activation, and were correlated with response.

Results: The pCR rate was significantly higher in HER2-enriched tumors in the Discovery, 03-311 (36%, P = 0.043) dataset, as compared with other subtypes, which validated in 211B (50%, P = 0.048). Significant increases in a signature of immune cell admixture (Immune Index) were observed only following brief exposure to trastuzumab in HER2-enriched tumors (Discovery/03-311, P = 0.05; Validation/211B, P = 0.02). Increased Immune Index was predictive of response after brief exposure (03-311, P = 0.03; 211B, P = 0.04), but not at baseline, in addition to increased expression of a CD4(+) follicular helper T-cell signature (03-311, P = 0.05; 211B, P = 0.04). Brief exposure to trastuzumab significantly increased gene expression of the T-cell marker PD-1 in HER2-enriched tumors (Discovery/03-311, P = 0.045) and PD-1 positivity by IHC (Validation/211B, P = 0.035).

Conclusions: Correlations between pCR rates, increases in Immune Index and markers of T-cell activity following brief exposure to trastuzumab in HER2-enriched tumors provide novel insights into the interaction between tumor biology, antitumor immunity, and response to treatment, and suggest potential clinically useful biomarkers in HER2(+) breast cancers. Clin Cancer Res; 22(13); 3249-59. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439498PMC
July 2016

Prospective assessment of the decision-making impact of the Breast Cancer Index in recommending extended adjuvant endocrine therapy for patients with early-stage ER-positive breast cancer.

Breast Cancer Res Treat 2015 Dec 14;154(3):533-41. Epub 2015 Nov 14.

Breast Medical Oncology, Yale Cancer Center, Yale School of Medicine, PO Box 208032, 333 Cedar St, New Haven, CT, 06520-8032, USA.

Extended adjuvant endocrine therapy (10 vs. 5 years) trials have demonstrated improved outcomes in early-stage estrogen receptor (ER)-positive breast cancer; however, the absolute benefit is modest, and toxicity and tolerability challenges remain. Predictive and prognostic information from genomic analysis may help inform this clinical decision. The purpose of this study was to assess the impact of the Breast Cancer Index (BCI) on physician recommendations for extended endocrine therapy and on patient anxiety and decision conflict. Patients with stage I-III, ER-positive breast cancer who completed at least 3.5 years of adjuvant endocrine therapy were offered participation. Genomic classification with BCI was performed on archived tumor tissues and the results were reported to the treating physician who discussed results with the patient. Patients and physicians completed pre- and post-test questionnaires regarding preferences for extended endocrine therapy. Patients also completed the validated traditional Decisional Conflict Scale (DCS) and State Trait Anxiety Inventory forms (STAI-Y1) pre- and post-test. 96 patients were enrolled at the Yale Cancer Center [median age 60.5 years (range 45-87), 79% postmenopausal, 60% stage I). BCI predicted a low risk of late recurrence in 59% of patients versus intermediate/high in 24 and 17%, respectively. Physician recommendations for extended endocrine therapy changed for 26% of patients after considering BCI results, with a net decrease in recommendations for extended endocrine therapy from 74 to 54%. After testing, fewer patients wanted to continue extended therapy and decision conflict and anxiety also decreased. Mean STAI and DCS scores were 31.3 versus 29.1 (p = 0.031) and 20.9 versus 10.8 (p < 0.001) pre- and post-test, respectively. Incorporation of BCI into risk/benefit discussions regarding extended endocrine therapy resulted in changes in treatment recommendations and improved patient satisfaction.
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http://dx.doi.org/10.1007/s10549-015-3631-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661200PMC
December 2015

Brief-exposure to preoperative bevacizumab reveals a TGF-β signature predictive of response in HER2-negative breast cancers.

Int J Cancer 2016 Feb 31;138(3):747-57. Epub 2015 Aug 31.

Seidman Cancer Center, University Hospitals, Cleveland, OH.

To best define biomarkers of response, and to shed insight on mechanism of action of certain clinically important agents for early breast cancer, we used a brief-exposure paradigm in the preoperative setting to study transcriptional changes in patient tumors that occur with one dose of therapy prior to combination chemotherapy. Tumor biopsies from breast cancer patients enrolled in two preoperative clinical trials were obtained at baseline and after one dose of bevacizumab (HER2-negative), trastuzumab (HER2-positive) or nab-paclitaxel, followed by treatment with combination chemo-biologic therapy. RNA-Sequencing based PAM50 subtyping at baseline of 46 HER2-negative patients revealed a strong association between the basal-like subtype and pathologic complete response (pCR) to chemotherapy plus bevacizumab (p ≤ 0.0027), but did not provide sufficient specificity to predict response. However, a single dose of bevacizumab resulted in down-regulation of a well-characterized TGF-β activity signature in every single breast tumor that achieved pCR (p ≤ 0.004). The TGF-β signature was confirmed to be a tumor-specific read-out of the canonical TGF-β pathway using pSMAD2 (p ≤ 0.04), with predictive power unique to brief-exposure to bevacizumab (p ≤ 0.016), but not trastuzumab or nab-paclitaxel. Down-regulation of TGF-β activity was associated with reduction in tumor hypoxia by transcription and protein levels, suggesting therapy-induced disruption of an autocrine-loop between tumor stroma and malignant cells. Modulation of the TGF-β pathway upon brief-exposure to bevacizumab may provide an early functional readout of pCR to preoperative anti-angiogenic therapy in HER2-negative breast cancer, thus providing additional avenues for exploration in both preclinical and clinical settings with these agents.
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http://dx.doi.org/10.1002/ijc.29808DOI Listing
February 2016

Standardization of pathologic evaluation and reporting of postneoadjuvant specimens in clinical trials of breast cancer: recommendations from an international working group.

Mod Pathol 2015 Sep 24;28(9):1185-201. Epub 2015 Jul 24.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Neoadjuvant systemic therapy is being used increasingly in the treatment of early-stage breast cancer. Response, in the form of pathological complete response, is a validated and evaluable surrogate end point of survival after neoadjuvant therapy. Thus, pathological complete response has become a primary end point for clinical trials. However, there is a current lack of uniformity in the definition of pathological complete response. A review of standard operating procedures used by 28 major neoadjuvant breast cancer trials and/or 25 sites involved in such trials identified marked variability in specimen handling and histologic reporting. An international working group was convened to develop practical recommendations for the pathologic assessment of residual disease in neoadjuvant clinical trials of breast cancer and information expected from pathology reports. Systematic sampling of areas identified by informed mapping of the specimen and close correlation with radiological findings is preferable to overly exhaustive sampling, and permits taking tissue samples for translational research. Controversial areas are discussed, including measurement of lesion size, reporting of lymphovascular space invasion and the presence of isolated tumor cells in lymph nodes after neoadjuvant therapy, and retesting of markers after treatment. If there has been a pathological complete response, this must be clearly stated, and the presence/absence of residual ductal carcinoma in situ must be described. When there is residual invasive carcinoma, a comment must be made as to the presence/absence of chemotherapy effect in the breast and lymph nodes. The Residual Cancer Burden is the preferred method for quantifying residual disease in neoadjuvant clinical trials in breast cancer; other methods can be included per trial protocols and regional preference. Posttreatment tumor staging using the Tumor-Node-Metastasis system should be included. These recommendations for standardized pathological evaluation and reporting of neoadjuvant breast cancer specimens should improve prognostication for individual patients and allow comparison of treatment outcomes within and across clinical trials.
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http://dx.doi.org/10.1038/modpathol.2015.74DOI Listing
September 2015

A Randomized, Controlled Trial of Cavity Shave Margins in Breast Cancer.

N Engl J Med 2015 Aug 30;373(6):503-10. Epub 2015 May 30.

From the Departments of Surgery (A.B.C., B.K.K., M.B., K.S., D.R.L., N.R.H.), Pathology (V.B., M.H.), and Medicine (L.P.), Yale Cancer Center (A.B.C., B.K.K., M.B., K.S., F.L., X.Y., D.R.L., L.P., N.R.H.), and Yale Center for Analytical Sciences (F.L., X.Y.), Yale University School of Medicine, New Haven, CT; and the Department of Surgery, Thomas Jefferson University, Philadelphia (T.N.T.).

Background: Routine resection of cavity shave margins (additional tissue circumferentially around the cavity left by partial mastectomy) may reduce the rates of positive margins (margins positive for tumor) and reexcision among patients undergoing partial mastectomy for breast cancer.

Methods: In this randomized, controlled trial, we assigned, in a 1:1 ratio, 235 patients with breast cancer of stage 0 to III who were undergoing partial mastectomy, with or without resection of selective margins, to have further cavity shave margins resected (shave group) or not to have further cavity shave margins resected (no-shave group). Randomization occurred intraoperatively after surgeons had completed standard partial mastectomy. Positive margins were defined as tumor touching the edge of the specimen that was removed in the case of invasive cancer and tumor that was within 1 mm of the edge of the specimen removed in the case of ductal carcinoma in situ. The rate of positive margins was the primary outcome measure; secondary outcome measures included cosmesis and the volume of tissue resected.

Results: The median age of the patients was 61 years (range, 33 to 94). On final pathological testing, 54 patients (23%) had invasive cancer, 45 (19%) had ductal carcinoma in situ, and 125 (53%) had both; 11 patients had no further disease. The median size of the tumor in the greatest diameter was 1.1 cm (range, 0 to 6.5) in patients with invasive carcinoma and 1.0 cm (range, 0 to 9.3) in patients with ductal carcinoma in situ. Groups were well matched at baseline with respect to demographic and clinicopathological characteristics. The rate of positive margins after partial mastectomy (before randomization) was similar in the shave group and the no-shave group (36% and 34%, respectively; P=0.69). After randomization, patients in the shave group had a significantly lower rate of positive margins than did those in the no-shave group (19% vs. 34%, P=0.01), as well as a lower rate of second surgery for margin clearance (10% vs. 21%, P=0.02). There was no significant difference in complications between the two groups.

Conclusions: Cavity shaving halved the rates of positive margins and reexcision among patients with partial mastectomy. (Funded by the Yale Cancer Center; ClinicalTrials.gov number, NCT01452399.).
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http://dx.doi.org/10.1056/NEJMoa1504473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584380PMC
August 2015

PD-L1 Expression Correlates with Tumor-Infiltrating Lymphocytes and Response to Neoadjuvant Chemotherapy in Breast Cancer.

Cancer Immunol Res 2015 Apr 19;3(4):326-32. Epub 2014 Dec 19.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.

Programmed death 1 ligand 1 (PD-L1) is an immune regulatory molecule that limits antitumor immune activity. Targeting of PD-L1 and other immune checkpoint proteins has shown therapeutic activity in various tumor types. The expression of PD-L1 and its correlation with response to neoadjuvant chemotherapy in breast cancer has not been studied extensively. Our goal was to assess PD-L1 expression in a cohort of breast cancer patients treated with neoadjuvant chemotherapy. Pretreatment biopsies from 105 patients with breast cancer from Yale New Haven Hospital that subsequently received neoadjuvant chemotherapy were assessed for PD-L1 protein expression by automated quantitative analysis with a rabbit monoclonal antibody (E1L3N) to the cytoplasmic domain of PD-L1. In addition, tumor-infiltrating lymphocytes (TIL) were assessed on hematoxylin and eosin slides. PD-L1 expression was observed in 30% of patients, and it was positively associated with hormone-receptor-negative and triple-negative status and high levels of TILs. Both TILs and PD-L1 measured in the epithelium or stroma predicted pathologic complete response (pCR) to neoadjuvant chemotherapy in univariate and multivariate analyses. However, because they are strongly associated, TILs and PD-L1 cannot both be included in a significant multivariate model. PD-L1 expression is prevalent in breast cancer, particularly hormone-receptor-negative and triple-negative patients, indicating a subset of patients that may benefit from immune therapy. Furthermore, PD-L1 and TILs correlate with pCR, and high PD-L1 predicts pCR in multivariate analysis.
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http://dx.doi.org/10.1158/2326-6066.CIR-14-0133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390454PMC
April 2015

Multiplexed quantitative analysis of CD3, CD8, and CD20 predicts response to neoadjuvant chemotherapy in breast cancer.

Clin Cancer Res 2014 Dec 25;20(23):5995-6005. Epub 2014 Sep 25.

Department of Pathology, Yale University Medical School, New Haven, Connecticut.

Purpose: Although tumor-infiltrating lymphocytes (TIL) have been associated with response to neoadjuvant therapy, measurement typically is subjective, semiquantitative, and unable to differentiate among subpopulations. Here, we describe a quantitative objective method for analyzing lymphocyte subpopulations and assessing their predictive value.

Experimental Design: We developed a quantitative immunofluorescence assay to measure stromal expression of CD3, CD8, and CD20 on one slide. We validated this assay by comparison with flow cytometry on tonsil specimens and assessed predictive value in breast cancer on a neoadjuvant cohort (n = 95). Then, each marker was tested for prediction of pathologic complete response (pCR) compared with pathologist estimation of the percentage of lymphocyte infiltrate.

Results: The lymphocyte percentage and CD3, CD8, and CD20 proportions were similar between flow cytometry and quantitative immunofluorescence on tonsil specimens. Pathologist TIL count predicted pCR [P = 0.043; OR, 4.77; 95% confidence interval (CI), 1.05-21.6] despite fair interobserver reproducibility (κ = 0.393). Stromal AQUA (automated quantitative analysis) scores for CD3 (P = 0.023; OR, 2.51; 95% CI, 1.13-5.57), CD8 (P = 0.029; OR, 2.00; 95% CI, 1.08-3.72), and CD20 (P = 0.005; OR, 1.80; 95% CI, 1.19-2.72) predicted pCR in univariate analysis. CD20 AQUA score predicted pCR (P = 0.019; OR, 5.37; 95% CI, 1.32-21.8) independently of age, size, nuclear grade, nodal status, ER, PR, HER2, and Ki-67, whereas CD3, CD8, and pathologist estimation did not.

Conclusions: We have developed and validated an objective, quantitative assay measuring TILs in breast cancer. Although this work provides analytic validity, future larger studies will be required to prove clinical utility.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-1622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4252785PMC
December 2014

Quantitative measurements of HER2 and phospho-HER2 expression: correlation with pathologic response to neoadjuvant chemotherapy and trastuzumab.

BMC Cancer 2014 May 8;14:326. Epub 2014 May 8.

Department of Pathology, Yale University School of Medicine, 310 Cedar Street, PO Box 208023, New Haven, CT 06520-8023, USA.

Background: Preoperative therapy with chemotherapy and the HER2-targeted monoclonal antibody trastuzumab is valuable for patients with large or locally advanced HER2-positive (HER2+) breast cancers but traditional methods of measuring HER2 expression do not accurately stratify patients for likelihood of response. Quantitative immunofluorescent approaches have the potential to provide a mathematically continuous measure of HER2. Here we seek to determine whether quantitative measurement of HER2 or phospho-HER2 correlates with likelihood of response to trastuzumab- containing neoadjuvant therapy.

Methods: We evaluated core biopsy samples from 27 HER2+ breast cancer patients enrolled in a preoperative clinical trial using trastuzumab, nab-paclitaxel and carboplatin combination therapy (BrUOG BR-211B (NCT00617942)). Tumor core biopsies were taken before initiation of treatment and 9-13 days after patients received "run-in" doses of either single agent trastuzumab or nab-paclitaxel. The AQUA method of quantitative immunofluorescence was used for analysis of in situ protein expression. Patients then received 18 weeks of treatment, followed by surgery to assess pathologic response to the neoadjuvant regimen.

Results: A HER2 score of 2111 by AQUA analysis has been shown to be equivalent to HER2 3+ by immunohistochemical staining in previous studies. Of 20 evaluable patients, 10 cases who achieved a pathologic complete response (pathCR) with neoadjuvant treatment had a mean HER2 level of 10251 compared with 4766 in the patients without pathCR (p = 0.0021). Measurement of phospho-HER2 showed no difference in pathCR vs non-pathCR groups. In 9 patients who had HER2 levels repeated after a single treatment with trastuzumab there was no evidence of a reduction in the HER2 or phospho-HER2 levels following that exposure.

Conclusions: High levels of HER2 are associated with achievement of a pathCR in the preoperative setting, while levels of Phospho-HER2 were not predictive of response. This data suggests that accurate measurement of HER2 may help determine the likelihood of response in the pre-surgical setting. Further validation in larger cohorts is required, but this pilot data shows the feasibility of this approach.
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http://dx.doi.org/10.1186/1471-2407-14-326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4037428PMC
May 2014

Molecular phenotypes in triple negative breast cancer from African American patients suggest targets for therapy.

PLoS One 2013 18;8(11):e71915. Epub 2013 Nov 18.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, United States of America ; Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany.

Triple negative breast cancer (TNBC) is characterized by high proliferation, poor differentiation and a poor prognosis due to high rates of recurrence. Despite lower overall incidence African American (AA) patients suffer from higher breast cancer mortality in part due to the higher proportion of TNBC cases among AA patients compared to European Americans (EA). It was recently shown that the clinical heterogeneity of TNBC is reflected by distinct transcriptional programs with distinct drug response profiles in preclinical models. In this study, gene expression profiling and immunohistochemistry were used to elucidate potential differences between TNBC tumors of EA and AA patients on a molecular level. In a retrospective cohort of 136 TNBC patients, a major transcriptional signature of proliferation was found to be significantly upregulated in samples of AA ethnicity. Furthermore, transcriptional profiles of AA tumors showed differential activation of insulin-like growth factor 1 (IGF1) and a signature of BRCA1 deficiency in this cohort. Using signatures derived from the meta-analysis of TNBC gene expression carried out by Lehmann et al., tumors from AA patients were more likely of basal-like subtypes whereas transcriptional features of many EA samples corresponded to mesenchymal-like or luminal androgen receptor driven subtypes. These results were validated in The Cancer Genome Atlas mRNA and protein expression data, again showing enrichment of a basal-like phenotype in AA tumors and mesenchymal subtypes in EA tumors. In addition, increased expression of VEGF-activated genes together with elevated microvessel area determined by the AQUA method suggest that AA patients exhibit higher tumor vascularization. This study confirms the existence of distinct transcriptional programs in triple negative breast cancer in two separate cohorts and that these programs differ by racial group. Differences in TNBC subtypes and levels of tumor angiogenesis in AA versus EA patients suggest that targeted therapy choices should be considered in the context of race.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071915PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832509PMC
July 2014

Cancerous 'floater': a lesson learned about tissue identity testing, endometrial cancer and microsatellite instability.

Mod Pathol 2013 Sep 5;26(9):1264-9. Epub 2013 Apr 5.

Department of Pathology, Yale University School of Medicine, New Haven, CT06520-8023 , USA.

A 46-year-old woman presented with endometrial cells on a pap smear and underwent endometrial curettage. The specimen revealed secretory endometrium and a possible endometrial polyp. In addition, a single 4 mm fragment of well-differentiated adenocarcinoma was found. Tissue identity DNA genotyping was performed and the adenocarcinoma tissue fragment showed a drastically different allelic pattern from that of the background endometrium. To confirm tissue contamination, genotyping of three other tumor specimens-probable sources for a contaminant-was performed but failed to identify a match. Without confirmation of contamination, a second endometrial curettage was obtained from the patient, in which similar adenocarcinoma tissue was once again found. Further workup demonstrated that the patient had a microsatellite unstable (MSI) endometrial adenocarcinoma by immunohistochemistry and molecular testing. The patient subsequently underwent staging surgery, which revealed an early-stage, well-differentiated endometrioid adenocarcinoma. This case study illustrates an uncommon, yet important caveat of tissue identity testing by DNA genotyping, where MSI instability can significantly alter the allelic pattern of DNA polymorphisms in the tumor genome, leading to erroneous conclusion regarding the tissue identity. Awareness of this phenomenon is crucial for a molecular pathologist to avoid interpretation errors of tissue identity testing in a cancer diagnostic workup.
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http://dx.doi.org/10.1038/modpathol.2013.63DOI Listing
September 2013