Antibody-mediated rejection in the cardiac allograft: diagnosis, treatment and future considerations.

PURPOSE OF REVIEW: This review summarizes the latest publications dealing with antibody-mediated rejection (AMR) and defines areas of controversy and future steps that may improve the outcome for patients with this virulent form of rejection. RECENT FINDINGS: Recent progress includes publication of standardized pathologic criteria for acute AMR by the International Society for Heart and Lung Transplantation (ISHLT) and guidelines for treatment of acute AMR by the American Heart Association, endorsed by ISHLT as well. Recently published review articles emphasize the important role of innate immune mechanisms, clarify the role of viral infection and provide insights into vascular biology and the role of innate effector populations, macrophages and dendritic cells. SUMMARY: Strategies for future studies are discussed in the context of these new findings and similar efforts undertaken by renal and liver allograft investigators.

Evidence of autoinflammation as a principal mechanism of myocardial injury in SARS-CoV-2 PCR-positive medical examiner cases.

BACKGROUND: Disease from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) remains the seventh leading cause of death in the United States. Many patients infected with this virus develop later cardiovascular complications including myocardial infarctions, stroke, arrhythmia, heart failure, and sudden cardiac death (20-28%). The purpose of this study is to understand the primary mechanism of myocardial injury in patients infected with SARS-CoV-2. METHODS: We investigated a consecutive cohort of 48 medical examiner cases who died with PCR-positive SARS-CoV-2 (COVpos) infection in 2020. We compared them to a consecutive cohort of 46 age- and sex-matched controls who were PCR-negative for SARS-CoV-2 (COVneg). Clinical information available at postmortem examination was reviewed on each patient. Formalin-fixed sections were examined using antibodies directed against CD42 (platelets), CD15 (myeloid cells), CD68 (monocytes), C4d, fibrin, CD34 (stem cell antigen), CD56 (natural killer cells), and myeloperoxidase (MPO) (neutrophils and neutrophil extracellular traps(NETs)). We used a Welch 2-sample T-test to determine significance. A cluster analysis of marker distribution was also done. RESULTS: We found a significant difference between COVpos and COVneg samples for CD42, CD15, CD68, C4d, fibrin, and MPO, all of which were significant at p < 0.001. The most prominent features were neutrophils (CD15, MPO) and MPO-positive debris suggestive of NETs. A similar distribution of platelets, monocytes, fibrin and C4d was seen in COVpos cases. Clinical features were similar in COVpos and COVneg cases for age, sex, and body mass index (BMI). CONCLUSION: These findings suggest an autoinflammatory process is likely involved in cardiac damage during SARS-CoV-2 infection. No information about clinical cardiac disease was available.

Donor Age, Sex, and Cause of Death and Their Relationship to Heart Transplant Recipient Cardiac Death.

BACKGROUND: Recent studies indicate that donor innate immune responses participate in initiating and accelerating innate responses and allorecognition in the recipient. These immune responses negatively affect recipient outcomes and predispose recipients to cardiovascular death (CV death). We hypothesized that a donor cause of death (COD) associated with higher levels of innate immune response would predispose recipients to more adverse outcomes post-transplant, including CV death. METHODS: We performed a single-institution retrospective analysis comparing donor characteristics and COD to recipient adverse cardiovascular outcomes. We analyzed the medical records of local adult donors (age 18-64) in a database of donors where adequate data was available. Donor age was available on 706 donors; donor sex was available on 730 donors. We linked donor characteristics (age and sex) and COD to recipient CV death. The data were analyzed using logistic regression, the log-rank test of differences, and Tukey contrast. RESULTS: Donor age, female sex, and COD of intracranial hemorrhage were significantly associated with a higher incidence of recipient CV death. CONCLUSIONS: In this single institution study, we found that recipients with hearts from donors over 40 years, donors who were female, or donors who died with a COD of intracranial hemorrhage had a higher frequency of CV death. Donor monitoring and potential treatment of innate immune activation may decrease subsequent recipient innate responses and allorecognition stimulated by donor-derived inflammatory signaling, which leads to adverse outcomes.

Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer.

PURPOSE.­: To update the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer. An Update Panel is aware that a new generation of antibody-drug conjugates targeting the HER2 protein is active against breast cancers that lack protein overexpression or gene amplification. METHODS.­: The Update Panel conducted a systematic literature review to identify signals for updating recommendations. RESULTS.­: The search identified 173 abstracts. Of 5 potential publications reviewed, none constituted a signal for revising existing recommendations. RECOMMENDATIONS.­: The 2018 ASCO-CAP recommendations for HER2 testing are affirmed. DISCUSSION.­: HER2 testing guidelines have focused on identifying HER2 protein overexpression or gene amplification in breast cancer to identify patients for therapies that disrupt HER2 signaling. This update acknowledges a new indication for trastuzumab deruxtecan when HER2 is not overexpressed or amplified but is immunohistochemistry (IHC) 1+ or 2+ without amplification by in situ hybridization. Clinical trial data on tumors that tested IHC 0 are limited (excluded from DESTINY-Breast04), and evidence is lacking that these cancers behave differently or do not respond similarly to newer HER2 antibody-drug conjugates. Although current data do not support a new IHC 0 versus 1+ prognostic or predictive threshold for response to trastuzumab deruxtecan, this threshold is now relevant because of the trial entry criteria that supported its new regulatory approval. Therefore, although it is premature to create new result categories of HER2 expression (eg, HER2-Low, HER2-Ultra-Low), best practices to distinguish IHC 0 from 1+ are now clinically relevant. This update affirms prior HER2 reporting recommendations and offers a new HER2 testing reporting comment to highlight the current relevance of IHC 0 versus 1+ results and best practice recommendations to distinguish these often subtle differences. Additional information is available at www.asco.org/breast-cancer-guidelines.

Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO-College of American Pathologists Guideline Update.

PURPOSE: To update ASCO-College of American Pathologists (CAP) recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer. The Panel is aware that a new generation of antibody-drug conjugates (ADCs) targeting the HER2 protein is active against breast cancers that lack protein overexpression or gene amplification. METHODS: An Update Panel conducted a systematic literature review to identify signals for updating recommendations. RESULTS: The search identified 173 abstracts. Of five potential publications reviewed, none constituted a signal for revising existing recommendations. RECOMMENDATIONS: The 2018 ASCO-CAP recommendations for HER2 testing are affirmed. DISCUSSION: HER2 testing guidelines have focused on identifying HER2 protein overexpression or gene amplification in breast cancer to identify patients for therapies that disrupt HER2 signaling. This update acknowledges a new indication for trastuzumab deruxtecan when HER2 is not overexpressed or amplified but is immunohistochemistry (IHC) 1+ or 2+ without amplification by in situ hybridization. Clinical trial data on tumors that tested IHC 0 are limited (excluded from DESTINY-Breast04), and evidence is lacking that these cancers behave differently or do not respond similarly to newer HER2 ADCs. Although current data do not support a new IHC 0 versus 1+ prognostic or predictive threshold for response to trastuzumab deruxtecan, this threshold is now relevant because of the trial entry criteria that supported its new regulatory approval. Therefore, while it is premature to create new result categories of HER2 expression (eg, HER2-Low, HER2-Ultra-Low), best practices to distinguish IHC 0 from 1+ are now clinically relevant. This Update affirms prior HER2 reporting recommendations and offers a new HER2 testing reporting comment to highlight the current relevance of IHC 0 versus 1+ results and best practice recommendations to distinguish these often subtle differences.Additional information is available at www.asco.org/breast-cancer-guidelines.

An Overview of Clinical Development of Agents for Metastatic or Advanced Breast Cancer Without ERBB2 Amplification (HER2-Low).

Importance: Erb-b2 receptor tyrosine kinase 2 (ERBB2; formerly HER2 [human epidermal growth factor receptor 2]) is an important prognostic and predictive factor in breast cancer. Anti-ERBB2 therapies have improved outcomes in ERBB2-positive breast cancer. However, based on current definitions, tumors with low ERBB2 expression are included in the ERBB2-negative subtype, and therefore, are ineligible for anti-ERBB2 therapies; patients with ERBB2-low (immunohistochemistry [IHC] 1 positive [+] or IHC 2+/in situ hybridization [ISH] negative [-]) tumors account for up to approximately 50% of breast cancer cases. Although the prognostic role of ERBB2-low needs to be defined, ERBB2 offers a potential therapeutic target in these patients. Observations: Most breast cancer tumors have some ERBB2 expression, with ERBB2-low being more common in hormone receptor-positive than in hormone receptor-negative breast cancer. Although an early clinical study failed to demonstrate benefit of adjuvant trastuzumab for ERBB2-low disease, several novel anti-ERBB2 therapies have shown efficacy in ERBB2-low breast cancer, including the antibody-drug conjugate trastuzumab deruxtecan in a phase 3 trial, and trastuzumab duocarmazine and the bispecific antibody zenocutuzumab in early-phase studies. Although reports are conflicting, some differences in biology and patient outcomes have been found between ERBB2-low and ERBB2 IHC-0 breast cancer. Currently, no established guidelines exist for scoring ERBB2-low expression in breast cancer because the focus has been on binary classification as ERBB2-positive or ERBB2-negative. Additional interpretive cutoffs may be needed to select patients for treatment with effective agents in ERBB2-low breast cancer, along with standardized laboratory quality assurance programs to ensure consistent patient identification for eligibility for ERBB2-low targeting agents. Conclusions and Relevance: This review suggests that ERBB2-low may be a distinct, clinically relevant breast cancer entity warranting reassessment of traditional diagnostic and therapeutic paradigms. Ongoing clinical trials and further investigations may provide optimized strategies for diagnosing and treating ERBB2-low breast cancer, including reproducible, consistent definitions to identify patients in this diagnostic category and demonstration of benefits of emerging therapies.

Bias in Medicine: Lessons Learned and Mitigation Strategies.

Cognitive bias consists of systematic errors in thinking due to human processing limitations or inappropriate mental models. Cognitive bias occurs when intuitive thinking is used to reach conclusions about information rather than analytic (mindful) thinking. Scientific progress is delayed when bias influences the dissemination of new scientific knowledge, as it has with the role of human leucocyte antigen antibodies and antibody-mediated rejection in cardiac transplantation. Mitigating strategies can be successful but involve concerted action by investigators, peer reviewers, and editors to consider how we think as well as what we think.

Estrogen and Progesterone Receptor Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Guideline Update.

PURPOSE.­: To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer guideline. METHODS.­: A multidisciplinary international Expert Panel was convened to update the clinical practice guideline recommendations informed by a systematic review of the medical literature. RECOMMENDATIONS.­: The Expert Panel continues to recommend ER testing of invasive breast cancers by validated immunohistochemistry as the standard for predicting which patients may benefit from endocrine therapy, and no other assays are recommended for this purpose. Breast cancer samples with 1% to 100% of tumor nuclei positive should be interpreted as ER positive. However, the Expert Panel acknowledges that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive. Samples with these results should be reported using a new reporting category, ER Low Positive, with a recommended comment. A sample is considered ER negative if < 1% or 0% of tumor cell nuclei are immunoreactive. Additional strategies recommended to promote optimal performance, interpretation, and reporting of cases with an initial low to no ER staining result include establishing a laboratory-specific standard operating procedure describing additional steps used by the laboratory to confirm/adjudicate results. The status of controls should be reported for cases with 0% to 10% staining. Similar principles apply to PgR testing, which is used primarily for prognostic purposes in the setting of an ER-positive cancer. Testing of ductal carcinoma in situ (DCIS) for ER is recommended to determine potential benefit of endocrine therapies to reduce risk of future breast cancer, while testing DCIS for PgR is considered optional. Additional information can be found at www.asco.org/breast-cancer-guidelines .

Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update.

PURPOSE: To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists estrogen (ER) and progesterone receptor (PgR) testing in breast cancer guideline. METHODS: A multidisciplinary international Expert Panel was convened to update the clinical practice guideline recommendations informed by a systematic review of the medical literature. RECOMMENDATIONS: The Expert Panel continues to recommend ER testing of invasive breast cancers by validated immunohistochemistry as the standard for predicting which patients may benefit from endocrine therapy, and no other assays are recommended for this purpose. Breast cancer samples with 1% to 100% of tumor nuclei positive should be interpreted as ER positive. However, the Expert Panel acknowledges that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive. Samples with these results should be reported using a new reporting category, ER Low Positive, with a recommended comment. A sample is considered ER negative if < 1% or 0% of tumor cell nuclei are immunoreactive. Additional strategies recommended to promote optimal performance, interpretation, and reporting of cases with an initial low to no ER staining result include establishing a laboratory-specific standard operating procedure describing additional steps used by the laboratory to confirm/adjudicate results. The status of controls should be reported for cases with 0% to 10% staining. Similar principles apply to PgR testing, which is used primarily for prognostic purposes in the setting of an ER-positive cancer. Testing of ductal carcinoma in situ (DCIS) for ER is recommended to determine potential benefit of endocrine therapies to reduce risk of future breast cancer, while testing DCIS for PgR is considered optional. Additional information can be found at www.asco.org/breast-cancer-guidelines.

Microvascular Loss and Diastolic Dysfunction in Severe Symptomatic Cardiac Allograft Vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) remains an important source of mortality after heart transplant. The aim of our study was to identify structural and microvasculature changes in severe CAV. METHODS AND RESULTS: The study group included heart transplant recipients with severe CAV who underwent retransplantation (severe CAV, n=20). Control groups included time from transplant matched cardiac transplant recipients without CAV (transplant control, n=20), severe ischemic cardiomyopathy patients requiring left ventricular assist device implantation (ischemic control, n=18), and normal hearts donated for research (donor control, n=10). We collected baseline demographic information, echocardiography data, and performed histopathologic examination of myocardial microvasculature. Echocardiographic features of severe CAV included lack of eccentric remodeling and presence of significant diastolic dysfunction. In contrast, diastolic function was preserved in transplant control subjects. Histopathologic examination showed increased interstitial fibrosis among severe CAV, transplant controls, and ischemic control patients. Compared with transplant controls, severe CAV subjects had reduced capillary density and increased capillary wall thickness ( P<0.05). CONCLUSIONS: Our results suggest that the marked diastolic dysfunction and resultant symptoms in patients with severe CAV may be secondary to the loss of microvasculature and remodeling of remaining microvessels rather than a consequence of interstitial fibrosis. The clinical significance and potential therapeutic implications of these unique microvasculature characteristics warrant further investigation.

Antisense-MDM2 sensitizes LNCaP prostate cancer cells to androgen deprivation, radiation, and the combination in vivo.

PURPOSE: To test the effects of antisense (AS)-MDM2 alone and with androgen deprivation (AD), radiotherapy (RT), and AD + RT on wild-type LNCaP cells in an orthotopic in vivo model. METHODS: Androgen-sensitive LNCaP cells were grown in the prostates of nude mice. Magnetic resonance imaging-based tumor volume and serum prostate-specific antigen (PSA) measurements were used to assess effects on tumor response. Tumor response was measured by biochemical and tumor volume failure definitions and doubling time estimates from fitted PSA and tumor volume growth curves. Expression of MDM2, p53, p21, and Ki-67 was quantified using immunohistochemical staining and image analysis of formalin-fixed tissue, analogous to methods used clinically. RESULTS: Antisense-MDM2 significantly inhibited the growth of LNCaP tumors over the mismatch controls. The most significant increase in tumor growth delay and tumor doubling time was from AS-MDM2 + AD + RT, although the effect of AS-MDM2 + AD was substantial. Expression of MDM2 was significantly reduced by AS-MDM2 in the setting of RT. CONCLUSIONS: This is the first in vivo investigation of the effects of AS-MDM2 in an orthotopic model and the first to demonstrate incremental sensitization when added to AD and AD + RT. The results with AD underscore the potential to affect micrometastatic disease, which is probably responsible for treatment failure in 30-40% of men with high-risk disease.

Bcl-2 and bax expression and prostate cancer outcome in men treated with radiotherapy in Radiation Therapy Oncology Group protocol 86-10.

PURPOSE: Bcl-2 and bax are proteins with opposing roles in apoptosis regulation; yet abnormal expression of either has been associated with failure after radiotherapy (RT). In this study we examined bcl-2 and bax expression as predictive markers in men treated with radiotherapy +/- androgen deprivation on Radiation Therapy Oncology Group (RTOG) protocol 86-10. EXPERIMENTAL DESIGN: Suitable archival diagnostic tissue was obtained from 119 (26%) patients for bcl-2 analysis and 104 (23%) patients for bax analysis. Cox proportional hazards multivariate analysis was used to determine the relationship of abnormal bcl-2 and bax expression to the end points of local failure, distant metastasis, cause-specific mortality, and overall mortality. Bcl-2 overexpression was classified as any tumor cell cytoplasmic staining and altered bax expression was classified as greater or lesser cytoplasmic staining intensity of tumor cells as compared with adjacent normal prostate epithelium. RESULTS: The study cohort exhibited bcl-2 overexpression in 26% (n = 30) of cases and abnormal bax expression in 47% (n = 49) of cases. A borderline significant relationship was observed between abnormal bax expression and higher Gleason score (p = 0.08). In univariate and multivariate analyses, there was no statistically significant relationship seen between abnormal bcl-2 or bax expression and outcome. CONCLUSIONS: Abnormal bcl-2 and bax expression were not related to any of the end points tested. The cohort examined was comprised of patients with locally advanced disease and it is possible that these markers may be of greater value in men with earlier-stage prostate cancer.

ISHLT pathology antibody mediated rejection score correlates with increased risk of cardiovascular mortality: A retrospective validation analysis.

BACKGROUND: Antibody-mediated rejection (AMR) in cardiac transplant recipients is a serious form of rejection with adverse patient outcomes. The International Society of Heart and Lung Transplantation (ISHLT) has published a consensus schema for the pathologic diagnosis of various grades of antibody-mediated rejection (pathology antibody-mediated rejection [pAMR]). We sought to determine whether the ISHLT pAMR grading schema correlates with patient outcomes. METHODS: Using our database, which contains a semi-quantitative scoring of all pathologic descriptors of pAMR, we retrospectively used these descriptors to convert the previous AMR categories to the current ISHLT pAMR categories. Cox proportional hazard models were fit with cardiovascular (CV) death or retransplant as the outcome. The pAMR value was included as a categorical variable, and cellular rejection (CR) values were included in a separate model. RESULTS: There were 13,812 biopsies from 1,014 patients analyzed. The pAMR grades of pAMR1h, pAMR1i, and pAMR2 conferred comparable increased risk for CV mortality. Significantly increased risk of CV mortality was conferred by biopsies graded as severe AMR (pAMR3). CONCLUSIONS: The new ISHLT pAMR grading schema identifies patients at increased risk of CV mortality, consistent with risks published from several programs before 2011. The current schema is validated by this analysis in a large biopsy database. Because pAMR1h, pAMR1i, and pAMR2 have similar CV risks associated with them, the threshold for a positive diagnosis of pAMR should be re-evaluated in future iterations of the ISHLT schema.

Mixed cellular and antibody-mediated rejection in heart transplantation: In-depth pathologic and clinical observations.

BACKGROUND: Little is known about mixed cellular and antibody-mediated rejection (MR) in heart transplantation. It remains unclear whether cardiac MR has distinctive pathologic and clinical features beyond those of simultaneous cellular rejection (CR) and antibody-mediated rejection (AMR). In this study we systematically explore the pathologic and clinical characteristics of MR in heart transplantation. METHODS: The UTAH Cardiac Transplant Program database was queried for transplant recipients who survived long enough to have at least one endomyocardial biopsy (EMB) between 1985 and 2014. Only EMBs with both CR and AMR scores documented were included. In addition to detailed pathologic analyses, we also examined the incidence and prevalence of MR, the likelihood to transition from and to MR, and mortality associated with MR. RESULTS: Patients (n = 1,207) with a total of 28,484 EMBs met the study inclusion criteria. The overall prevalence of MR was 7.8% and it was nearly twice as frequent within the first year post-transplant. Mild MR was by far the most common occurrence and was typically preceded by an immune active state. When CR increased in severity, AMR tended to follow, but the reverse was not true. On pathology, individual features of CR and AMR were more easily separated in cases of mild MR, whereas they substantially overlapped in more severe cases. MR was associated with a significant cardiovascular death risk that was incremental with severity. CONCLUSIONS: MR is not common, usually occurs early after transplant, and is associated with worse outcomes. MR reflects a complex interplay between cellular and humoral processes, which varies with rejection severity.

Issues and barriers to development of clinically useful tumor markers: a development pathway proposal.

There are few tumor markers that are clinically useful in predicting therapeutic responses or patient outcomes despite nearly 20 years of advances in molecular biology. We discuss a variety of issues and barriers that have affected movement of clinical tests from research into clinical practice. Studies of new markers frequently lack clear hypotheses and are generally underpowered to reach statistically valid conclusions. Relevant clinical endpoints may not be possible to evaluate, often leading to suboptimal study designs. Major stumbling blocks exist because studies are rarely comparable. This makes it difficult to determine why results vary from study to study. It also prevents pooling of small datasets for analysis. We propose a tumor marker development pathway that we think will be more efficient and effective. The pathway depends on developing statistically valid study designs, focusing on assay refinement and standardization early in the process, including assay details in publications, and providing data in a format that allows comparison with other studies. The process described should be applicable to development of new technologies that include analysis and interpretation of large, complex datasets. The proposed marker development pathway will require thoughtful refinement and expansion, but it should begin a productive dialog.

Early failure of a tricuspid valve replacement with a mitral valve homograft in a heart transplant recipient.

A 24-year-old woman experienced severe tricuspid valve regurgitation 6 years after heart transplantation. Tricuspid valve replacement was performed using a cryopreserved mitral valve homograft. Severe tricuspid valve regurgitation recurred within 4 months, associated with an increase in the panel reactive antibody titers from zero to 72%. Tricuspid valve replacement was repeated with a porcine bioprosthesis with excellent recovery and function for >2 years. The mitral valve homograft displayed inflammatory features consistent with humoral immune-mediated destruction.

Standard reference material for Her2 testing: report of a National Institute of Standards and Technology-sponsored Consensus Workshop.

A workshop was sponsored by the National Institute of Standards and Technology, the Cancer Diagnosis Program of the National Cancer Institute, the Food and Drug Administration, and the College of American Pathologists to address the need for a reference material for Her2 gene protein testing. It was agreed that such a standard was desirable and necessary to ensure the reliability of Her2 testing to qualify patients for trastuzumab therapy. Two standards consisting of well characterized cell lines will be produced, 1 that will be a National Institute of Standards and Technology-certifiable standard, and 1 that will be a commercially developed standard for use in all Her2 testing. It was also agreed that all Her2 testing must be performed on samples fixed only in 10% buffered formalin, as specified in the Food and Drug Administration-approved testing methods. Participants agreed to plan strategies to educate pathologists, clinicians, and laboratories about the need and use of such a standard. A National Committee for Clinical Laboratory Standards guideline for the use of the standard reference material will be created to facilitate this process.

Margins for breast-conserving surgery with whole-breast irradiation in stage I and II invasive breast cancer: American Society of Clinical Oncology endorsement of the Society of Surgical Oncology/American Society for Radiation Oncology consensus guideline.

PURPOSE: The Society of Surgical Oncology (SSO)/American Society for Radiation Oncology (ASTRO) guideline on surgical margins for breast-conserving surgery with whole-breast irradiation in stage I and II invasive breast cancer was considered for endorsement. METHODS: The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing practice guidelines developed by other organizations. ASCO staff reviewed the SSO/ASTRO guideline for developmental rigor; an ASCO ad hoc review panel of experts reviewed the guideline content. RESULTS: The ASCO ad hoc guideline review panel concurred that the recommendations are clear, thorough, and based on the most relevant scientific evidence in this content area and that they present options acceptable to patients. According to the SSO/ASTRO guideline, the use of no ink on tumor (ie, no cancer cells adjacent to any inked edge/surface of specimen) as the standard for an adequate margin in invasive cancer in the era of multidisciplinary therapy is associated with low rates of ipsilateral breast tumor recurrence and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs. CONCLUSION: The ASCO review panel endorses the SSO/ASTRO recommendations with qualifications, as follows. The panel reinforces and amplifies the guideline authors' call for the monitoring of outcomes of the guideline at the institutional level, as institutions transition to adopting the SSO/ASTRO recommendations; would place greater emphasis on the importance of postlumpectomy mammography for cases involving microcalcifications; and calls for flexibility in the application of the guideline in light of the generally weak evidence supporting the recommendations.

Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update.

PURPOSE: To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer. METHODS: ASCO/CAP convened an Update Committee that included coauthors of the 2007 guideline to conduct a systematic literature review and update recommendations for optimal HER2 testing. RESULTS: The Update Committee identified criteria and areas requiring clarification to improve the accuracy of HER2 testing by immunohistochemistry (IHC) or in situ hybridization (ISH). The guideline was reviewed and approved by both organizations. RECOMMENDATIONS: The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2-positive status when (on observing within an area of tumor that amounts to >10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (revised criteria), reflex testing should be performed using an alternative assay (IHC or ISH). Repeat testing should be considered if results seem discordant with other histopathologic findings. Laboratories should demonstrate high concordance with a validated HER2 test on a sufficiently large and representative set of specimens. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Update Committee urges providers and health systems to cooperate to ensure the highest quality testing.