A comprehensive single-cell breast tumor atlas defines epithelial and immune heterogeneity and interactions predicting anti-PD-1 therapy response.

We present an integrated single-cell RNA sequencing atlas of the primary breast tumor microenvironment (TME) containing 236,363 cells from 119 biopsy samples across eight datasets. In this study, we leverage this resource for multiple analyses of immune and cancer epithelial cell heterogeneity. We define natural killer (NK) cell heterogeneity through six subsets in the breast TME. Because NK cell heterogeneity correlates with epithelial cell heterogeneity, we characterize epithelial cells at the level of single-gene expression, molecular subtype, and 10 categories reflecting intratumoral transcriptional heterogeneity. We develop InteractPrint, which considers how cancer epithelial cell heterogeneity influences cancer-immune interactions. We use T cell InteractPrint to predict response to immune checkpoint inhibition (ICI) in two breast cancer clinical trials testing neoadjuvant anti-PD-1 therapy. T cell InteractPrint was predictive of response in both trials versus PD-L1 (AUC = 0.82, 0.83 vs. 0.50, 0.72). This resource enables additional high-resolution investigations of the breast TME.

The Right Dose: Results of a Patient Advocate-Led Survey of Individuals With Metastatic Breast Cancer Regarding Treatment-Related Side Effects and Views About Dosage Assessment to Optimize Quality of Life.

PURPOSE: Although patients with metastatic breast cancer (MBC) have been living longer with the advent of more effective treatments such as targeted therapy and immunotherapy, the disease remains incurable, and most patients will undergo therapy indefinitely. When beginning therapy, patients are typically prescribed dose often based upon the maximum tolerated dose identified in phase I clinical trials. However, patients' perspectives about tolerability and willingness to discuss individualized dosing of drugs upon initiation of a new regimen and throughout the course of treatment have not been comprehensively evaluated. METHODS: Patient advocates and medical oncologists from the Patient-Centered Dosing Initiative (PCDI) developed a survey to ascertain the prevalence and severity of MBC patients' treatment-related side effects, the level of patient-physician communication, mitigation strategies, perception about the relative efficacy of higher versus lower doses, and willingness to discuss alternative dosing. The PCDI distributed the anonymous confidential online survey in August 2020 to individuals with self-reported MBC. RESULTS: One thousand and two hundred twenty-one patients with MBC completed the survey. 86.1% (n = 1,051) reported experiencing at least one significant treatment-related side effect, and of these, 20.3% (n = 213) visited the emergency room/hospital and 43.2% (n = 454) missed at least one treatment. Nearly all patients with side effects (97.6%, n = 1,026) informed their doctor and 81.7% (n = 838) received assistance. Of the 556 patients given a dose reduction for side-effect mitigation, 82.6% (n = 459) reported relief. Notably, majority of patients (53.3%, n = 651) do not believe that higher dose is always more effective than lower dose, and 92.3% (n = 1,127) would be willing to discuss flexible dosing options with their physicians based upon personal characteristics to optimize quality of life. CONCLUSION: Given that the majority of patients with MBC experienced at least one substantial treatment-related side effect and most patients given a dose reduction reported improvement, innovative dosage-related strategies are warranted to sustain and improve patients' well-being. Patient-physician discussions in which the patient's unique attributes and circumstances are assessed upon initiation of new treatment and throughout the course of therapy may facilitate the identification of the most favorable dose for each patient, and the majority of patients would be receptive to this approach.

Promise and Perils of Large Language Models for Cancer Survivorship and Supportive Care.

A call to action to bring stakeholders together to plan for the future of LLM-enhanced cancer survivorship.

The patient perspective on dose optimization for anticancer treatments: A new era of cancer drug dosing-Challenging the "more is better" dogma.

The Patient-Centered Dosing Initiative, a patient-led effort advocating for a paradigm shift in determining cancer drug dosing strategies, pioneers a departure from traditional oncology drug dosing practices. Historically, oncology drug dosing relies on identifying the maximum tolerated dose through phase 1 dose escalation methodology, favoring higher dosing for greater efficacy, often leading to higher toxicity. However, this approach is not universally applicable, especially for newer treatments like targeted therapies and immunotherapies. Patient-Centered Dosing Initiative challenges this "more is better" ethos, particularly as metastatic breast cancer patients themselves, as they not only seek longevity but also a high quality of life since most metastatic breast cancer patients stay on treatment for the rest of their lives. Surveying 1221 metastatic breast cancer patients and 119 oncologists revealed an evident need for flexible dosing strategies, advocating personalized care discussions based on patient attributes. The survey results also demonstrated an openness toward flexible dosing and a willingness from both patients and clinicians to discuss dosing as part of their care. Patient-centered dosing emphasizes dialogue between clinicians and patients, delving into treatment efficacy-toxicity trade-offs. Similarly, clinical trial advocacy for multiple dosing regimens encourages adaptive strategies, moving away from strict adherence to maximum tolerated dose, supported by recent research in optimizing drug dosages. Recognizing the efficacy-effectiveness gap between clinical trials and real-world practice, Patient-Centered Dosing Initiative underscores the necessity for patient-centered dosing strategies. A focus on individual patient attributes aligns with initiatives like Project Optimus and Project Renewal, aiming to optimize drug dosages for improved treatment outcomes at both the pre- and post-approval phases. Patient-Centered Dosing Initiative's efforts extend to patient education, providing tools to initiate dosage-related conversations with physicians. In addition, it emphasizes physician-patient dialogues and post-marketing studies as essential in determining optimal dosing and refining drug regimens. A dose-finding paradigm prioritizing drug safety, tolerability, and efficacy benefits all stakeholders, reducing emergency care needs and missed treatments for patients, aligning with oncologists' and patients' shared goals. Importantly, it represents a win-win scenario across healthcare sectors. In summary, the Patient-Centered Dosing Initiative drives transformative changes in cancer drug dosing, emphasizing patient well-being and personalized care, aiming to enhance treatment outcomes and optimize oncology drug delivery.

Re-imagining metastatic breast cancer care delivery: a patient-partnered qualitative study.

PURPOSE: While significant progress in metastatic breast cancer (MBC) treatment has prolonged survival and improved prognosis, there remain substantial gaps in providing patient-centered supportive care. The specific care delivery needs for metastatic cancer differ from that of early-stage cancer due to the incurable nature and lifelong duration of the condition. The objective of this study was to assess how patients living with MBC would re-imagine cancer care delivery. METHODS: This qualitative study was conducted in partnership with patient-led organizations Guiding Researchers and Advocates to Scientific Partnerships (GRASP) and Project Life, a nonprofit, online wellness community founded by patients with MBC for patients living with MBC. Virtual semi-structured interviews (n = 36) were conducted with Project Life members purposively sampled from the groups' overall membership. The interview guide contained items surrounding patients' lived experiences of MBC, greatest unmet needs related to care, and perspectives on virtual wellness community involvement. Interviews were coded using two-stage deductive and inductive analysis. RESULTS: Three major themes for re-imagining cancer care delivery were identified, including holistic care, information needs, and conceptual shifts. Within these several subthemes emerged with patients re-imagining referrals to non-oncological services, caregiver support, acceptance of integrative medicine, streamlined clinical trial enrollment, curated quality patient resources, MBC-specific terminology and approaches, long-term life and goal-of-care planning, and patient-centered voice throughout. CONCLUSION: People living with metastatic cancers have specific supportive care needs. These findings highlight patient-driven areas for re-imagination that are most salient for individuals with MBC.

Perspectives on Patient-Reported Outcome Data After Treatment Discontinuation in Cancer Clinical Trials.

OBJECTIVES: Patient-reported outcome (PRO) data are critical in understanding treatments from the patient perspective in cancer clinical trials. The potential benefits and methodological approaches to the collection of PRO data after treatment discontinuation (eg, because of progressive disease or unacceptable drug toxicity) are less clear. The purpose of this article is to describe the Food and Drug Administration's Oncology Center of Excellence and the Critical Path Institute cosponsored 2-hour virtual roundtable, held in 2020, to discuss this specific issue. METHODS: We summarize key points from this discussion with 16 stakeholders representing academia, clinical practice, patients, international regulatory agencies, health technology assessment bodies/payers, industry, and PRO instrument development. RESULTS: Stakeholders recognized that any PRO data collection after treatment discontinuation should have clearly defined objectives to ensure that data can be analyzed and reported. CONCLUSIONS: Data collection after discontinuation without a justification for its use wastes patients' time and effort and is unethical.

A Qualitative Study of the Impact of the COVID-19 Pandemic on Metastatic Breast Cancer Care.

The COVID-19 pandemic substantially impacted the delivery of oncology care, particularly for individuals with metastatic cancers. The objective of this study was to qualitatively evaluate the impacts of COVID-19 on metastatic breast cancer (MBC) care among patients. This study consisted of 36 semi-structured qualitative interviews conducted virtually with people living with MBC, who were members of a patient support organization called Project Life. Project Life is an MBC patient-led, web-based wellness community. Responses were analyzed using Phronetic Iterative Analysis. Interviews were conducted from March 14, 2022, to May 31, 2022. Analysis from 36 individual in-depth qualitative interviews revealed the following themes during COVID-19: (1) variable preferences for telehealth (2) disruptions to care, (3) virtualization of social care. Wide variations existed in preferences surrounding telehealth, centered around ideas of convenience. Disruptions to care included delays to diagnostic care, isolation from caregivers, and interruptions associated with COVID-19 infection. These results call for adaptability in oncology care given wide-ranging preferences on telehealth and the shifting of available support services.

HER2DX ERBB2 mRNA expression in advanced HER2-positive breast cancer treated with T-DM1.

In advanced HER2-positive (HER2+) breast cancer, the new antibody-drug conjugate trastuzumab deruxtecan is more effective compared with trastuzumab emtansine (T-DM1). However, trastuzumab deruxtecan can have considerable toxicities, and the right treatment sequence is unknown. Biomarkers to guide the use of anti-HER2 therapies beyond HER2 status are needed. Here, we evaluated if preestablished levels of ERBB2 mRNA expression according to the HER2DX standardized assay are associated with response and survival following T-DM1. In ERBB2 low, medium, and high groups, the overall response rate was 0%, 29%, and 56%, respectively (P < .001). ERBB2 mRNA was statistically significantly associated with better progression-free survival (P = .002) and overall survival (OS; P = .02). These findings were independent of HER2 immunohistochemistry (IHC) levels, hormone receptor, age, brain metastasis, and line of therapy. The HER2DX risk score (P = .04) and immunoglobulin signature (P = .04) were statistically significantly associated with overall survival since diagnosis. HER2DX provides prognostic and predictive information following T-DM1 in advanced HER2+ breast cancer.

Patient-centered dosing: oncologists' perspectives about treatment-related side effects and individualized dosing for patients with metastatic breast cancer (MBC).

PURPOSE: Although metastatic breast cancer (MBC) is treatable, it is not curable and most patients remain on treatment indefinitely. While oncologists commonly prescribe the recommended starting dose (RSD) from the FDA-approved label, patient tolerance may differ from that seen in clinical trials. We report on a survey of medical oncologists' perspectives about treatment-related toxicity and willingness to discuss flexible dosing with patients. METHODS: We disseminated a confidential survey via social media/email in Spring 2021. Eligible respondents needed to be US-based medical oncologists with experience treating patients with MBC. RESULTS: Of 131 responses, 119 were eligible. Physicians estimated that 47% of their patients reported distressing treatment-related side effects; of these, 15% visited the Emergency Room/hospital and 37% missed treatment. 74% (n = 87) of doctors reported improvement of patient symptoms after dose reduction. 87% (n = 104) indicated that they had ever, if appropriate, initiated treatment at lower doses. Most (85%, n = 101) respondents did not believe that the RSD is always more effective than a lower dose and 97% (n = 115) were willing to discuss individualized dosing with patients. CONCLUSION: Treatment-related side effects are prevalent among patients with MBC, resulting in missed treatments and acute care visits. To help patients tolerate treatment, oncologists may decrease initial and/or subsequent doses. The majority of oncologists reject the premise that a higher dose is always superior and are willing to discuss individualized dosing with patients. Given potential improvements regarding quality of life and clinical care, dose modifications should be part of routine shared decision-making between patients and oncologists.

Improving the odds together: a framework for breast cancer research scientists to include patient advocates in their research.

Including patient advocates in basic cancer research ensures that breast cancer research is intentional, supports effective communication with broader audiences, and directly connects researchers with those who they are striving to help. Despite this utility, many cancer research scientists do not work with patient advocates. To understand barriers to engagement and build a framework for enhanced interactions in the future, we hosted a workshop with patient advocates and researchers who do engage, then discussed findings at an international metastatic breast cancer conference to solicit additional feedback and suggestions. Findings demonstrate that researchers are uncertain about how to initiate and maintain relationships with advocates. We offer actionable steps to support researchers working with patient advocates to improve cancer research and accomplish our collective goal of improving lives of those who have been diagnosed with breast cancer. We hope that this initiative will facilitate such collaborative efforts.

Radiation Therapy for Brain Metastases: ASCO Guideline Endorsement of ASTRO Guideline.

PURPOSE: American Society of Radiation Oncology (ASTRO) has developed a guideline on appropriate radiation therapy for brain metastases. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS: "Radiation Therapy for Brain Metastases: An ASTRO Clinical Practice Guideline"2 was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel subsequently reviewed the content and the recommendations. RESULTS: The ASCO Endorsement Panel determined that the recommendations from the ASTRO guideline, published May 6, 2022, are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorses "Radiation Therapy for Brain Metastases: An ASTRO Clinical Practice Guideline."2. RECOMMENDATIONS: Within the guideline, stereotactic radiosurgery (SRS) is recommended for patients with Eastern Cooperative Oncology Group performance status of 0-2 and up to four intact brain metastases, and conditionally recommended for patients with up to 10 intact brain metastases. The guideline provides detailed dosing and fractionation recommendations on the basis of the size of the metastases. For patients with resected brain metastases, radiation therapy (SRS or whole-brain radiation therapy [WBRT]) is recommended to improve intracranial disease control; if there are limited additional brain metastases, SRS is recommended over WBRT. For patients with favorable prognosis and brain metastases ineligible for surgery and/or SRS, WBRT is recommended with hippocampal avoidance where possible and the addition of memantine is recommended. For patients with brain metastases, limiting the single-fraction V12Gy to brain tissue to ≤ 10 cm3 is conditionally recommended.Additional information is available at www.asco.org/neurooncology-guidelines.

Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline.

PURPOSE: To provide guidance to clinicians regarding therapy for patients with brain metastases from solid tumors. METHODS: ASCO convened an Expert Panel and conducted a systematic review of the literature. RESULTS: Thirty-two randomized trials published in 2008 or later met eligibility criteria and form the primary evidentiary base. RECOMMENDATIONS: Surgery is a reasonable option for patients with brain metastases. Patients with large tumors with mass effect are more likely to benefit than those with multiple brain metastases and/or uncontrolled systemic disease. Patients with symptomatic brain metastases should receive local therapy regardless of the systemic therapy used. For patients with asymptomatic brain metastases, local therapy should not be deferred unless deferral is specifically recommended in this guideline. The decision to defer local therapy should be based on a multidisciplinary discussion of the potential benefits and harms that the patient may experience. Several regimens were recommended for non-small-cell lung cancer, breast cancer, and melanoma. For patients with asymptomatic brain metastases and no systemic therapy options, stereotactic radiosurgery (SRS) alone should be offered to patients with one to four unresected brain metastases, excluding small-cell lung carcinoma. SRS alone to the surgical cavity should be offered to patients with one to two resected brain metastases. SRS, whole brain radiation therapy, or their combination are reasonable options for other patients. Memantine and hippocampal avoidance should be offered to patients who receive whole brain radiation therapy and have no hippocampal lesions and 4 months or more expected survival. Patients with asymptomatic brain metastases with either Karnofsky Performance Status ≤ 50 or Karnofsky Performance Status < 70 with no systemic therapy options do not derive benefit from radiation therapy.Additional information is available at www.asco.org/neurooncology-guidelines.

The Evolution of Clinical Trials in Metastatic Breast Cancer: Design Features and Endpoints That Matter.

The evolution of thought in assessing benefit in clinical trials of systemic therapy for metastatic breast cancer (MBC) is well documented, with most agents garnering regulatory approval based either on an advantage in overall survival (OS), time to progression (TTP), or progression-free survival (PFS) over an existing standard of care or objective response rate (ORR). Previous guidance for industry on clinical trial endpoints for the approval of cancer drugs and biologics was provided by the U.S. Food and Drug Administration (FDA) in 2007 and recently updated in 2018. The more recent FDA guidance recognizes that advances in science are facilitating the development of oncology products, which "may also result in the identification of additional endpoints that may be used to support approval of oncology products." This article critically addressed the evolution of thought on the advancement of clinical trials in MBC, from various stakeholder perspectives. Despite the term "stakeholder," the objective of all co-authors and parties concerned is to promote and inform the optimal design, conduct, and reporting of clinical trials for women with advanced breast cancer toward improving and extending lives. This article provides an overview of the evolving perspectives on this issue from the physician, regulatory agency, and patient and/or advocate points of view.

Anticonvulsant Prophylaxis and Steroid Use in Adults With Metastatic Brain Tumors: ASCO and SNO Endorsement of the Congress of Neurological Surgeons Guidelines.

PURPOSE: The Congress of Neurological Surgeons (CNS) has developed a series of guidelines for the treatment of adults with metastatic brain tumors, including systemic therapy and supportive care topics. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS: Two CNS guidelines were reviewed for developmental rigor by methodologists, and an independent multidisciplinary Expert Panel was formed to review the content and assess agreement with the recommendations. The Expert Panel voted to endorse the two guidelines, and ASCO and Society for Neuro-Oncology (SNO) independently reviewed and approved the ASCO/SNO guideline endorsement. RESULTS: The ASCO/SNO Expert Panel determined that the recommendations from the CNS anticonvulsants and steroids guidelines, published January 9, 2019, are clear, thorough, and based on the most relevant scientific evidence. ASCO/SNO endorsed these two CNS guidelines with minor alterations. RECOMMENDATIONS: Key recommendations include the following: prophylactic antiepileptic drugs were not recommended for routine use; and corticosteroids, specifically dexamethasone, were recommended for temporary symptomatic relief in patients with neurologic symptoms and signs related to mass effect from brain metastases. Additional information is available at www.asco.org/neurooncology-guidelines .

Anticonvulsant prophylaxis and steroid use in adults with metastatic brain tumors: summary of SNO and ASCO endorsement of the Congress of Neurological Surgeons guidelines.

BACKGROUND: The Congress of Neurological Surgeons (CNS) has developed a series of guidelines on the treatment of adults with metastatic brain tumors, including systemic therapy and supportive care topics. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS: Two CNS Guidelines were reviewed for developmental rigor by methodologists and an independent multi-disciplinary Expert Panel was formed to review the content and assess agreement with the recommendations. The expert panel voted to endorse the two guidelines and ASCO and SNO independently reviewed and approved the ASCO/SNO guideline endorsement. RESULTS: The ASCO/SNO Expert Panel determined that the recommendations from the CNS anticonvulsants and steroids guidelines, published January 9, 2019, are clear, thorough, and based upon the most relevant scientific evidence. ASCO/SNO endorsed these two CNS guidelines, with minor alterations. CONCLUSIONS: Key recommendations include: prophylactic anti-epileptic drugs were not recommended for routine use; corticosteroids (specifically dexamethasone) were recommended for temporary symptomatic relief in patients with neurologic symptoms and signs related to mass effect from brain metastases.

Promoting Scientist-Advocate Collaborations in Cancer Research: Why and How.

Advocates bring unique and important viewpoints to the cancer research process, ensuring that scientific and medical advances are patient-centered and relevant. In this article, we discuss the benefits of engaging advocates in cancer research and underscore ways in which both the scientific and patient communities can facilitate this mutually beneficial collaboration. We discuss how to establish and nurture successful scientist-advocate relationships throughout the research process. We review opportunities that are available to advocates who want to obtain training in the evaluation of cancer research. We also suggest practical solutions that can strengthen communication between scientists and advocates, such as introducing scientist-advocate interactions at the trainee level. Finally, we highlight the essential role social media can play in disseminating patient-supported cancer research findings to the patient community and in raising awareness of the importance of promoting cancer research. Our perspective offers a model that Georgetown Breast Cancer Advocates have found effective and which could be one option for those interested in developing productive, successful, and sustainable collaborations between advocates and scientists in cancer research. Cancer Res; 78(20); 5723-8. ©2018 AACR.