Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study.

Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints included the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) is associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.

Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study.

Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints include the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) was associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.

NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2024.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic/likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer, including BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53, and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants. These NCCN Guidelines Insights summarize important updates regarding: (1) a new section for transgender, nonbinary and gender diverse people who have a hereditary predisposition to cancer focused on risk reduction strategies for ovarian cancer, uterine cancer, prostate cancer, and breast cancer; and (2) testing criteria and management associated with TP53 P/LP variants and Li-Fraumeni syndrome.

Disparities in Breast Cancer Associated With African American Identity.

Persistent disparities in the burden of breast cancer between African Americans and White Americans have been documented over many decades. Features characterizing breast cancer in the African American community include a 40% higher mortality rate, younger age distribution, greater advanced-stage distribution, increased risk of biologically aggressive disease such as the triple-negative phenotype, and increased incidence of male breast cancer. Public health experts, genetics researchers, clinical trialists, multidisciplinary oncology teams, and advocates must collaborate to comprehensively address the multifactorial etiology of and remedies for breast cancer disparities. Efforts to achieve breast health equity through improved access to affordable, high-quality care are especially imperative in the context of the COVID-19 pandemic and its disproportionately high economic toll on African Americans.

Long-term follow-up assessment of cardiac safety in SAFE-HEaRt, a clinical trial evaluating the use of HER2-targeted therapies in patients with breast cancer and compromised heart function.

PURPOSE: HER2-targeted therapies are associated with cardiotoxicity which is usually asymptomatic and reversible. We report the updated cardiac safety assessment of patients with compromised heart function receiving HER2-targeted therapy for breast cancer, enrolled in the SAFE-HEaRt trial, at a median follow-up of 3.5 years. METHODS: Thirty patients with stage I-IV HER2-positive breast cancer receiving trastuzumab with or without pertuzumab, or ado-trastuzumab emtansine (T-DM1), with asymptomatic LVEF (left ventricular ejection fraction) 40-49%, were started on cardioprotective medications, with the primary endpoint being completion of HER2-targeted therapy without cardiac events (CE) or protocol-defined asymptomatic worsening of LVEF. IRB-approved follow-up assessment included 23 patients. RESULTS: Median follow-up as of June 2020 is 42 months. The study met its primary endpoint with 27 patients (90%) completing their HER2-targeted therapies without cardiac issues. Of the 23 evaluable patients at long-term f/u, 14 had early stage breast cancer, and 9 had metastatic disease, 8 of whom remained on HER2-targeted therapies. One patient developed symptomatic heart failure with no change in LVEF. There were no cardiac deaths. The mean LVEF improved to 52.1% from 44.9% at study baseline, including patients who remained on HER2-targeted therapy, and those who received prior anthracyclines. CONCLUSIONS: Long-term follow-up of the SAFE-HEaRt study continues to provide safety data of HER2-targeted therapy use in patients with compromised heart function. The late development of cardiac dysfunction is uncommon and continued multi-disciplinary oncologic and cardiac care of patients is vital for improved patient outcomes.

Use of 18F-FDG PET/CT as an Initial Staging Procedure for Stage II-III Breast Cancer: A Multicenter Value Analysis.

BACKGROUND: Metastatic staging imaging is not recommended for asymptomatic patients with stage I-II breast cancer. Greater distant metastatic disease risk may warrant baseline imaging in patients with stage II-III with high-risk biologic subtypes. NCCN Guidelines recommend considering CT of the chest, abdomen, and pelvis (CT CAP) and bone scan in appropriate patients. CT CAP and bone scan are considered standard of care (SoC), although PET/CT is a patient-centered alternative. METHODS: Data were available for 799 high-risk patients with clinical stage II-III disease who initiated screening for the I-SPY2 trial at 4 institutions. A total of 564 complete records were reviewed to compare PET/CT versus SoC. Costs were determined from the payer perspective using the national 2018 Medicare Physician Fee Schedule and representative reimbursements to the University of California, San Francisco (UCSF). Incremental cost-effectiveness ratio (ICER) measured cost of using PET/CT per percent of patients who avoided a false-positive (FP). RESULTS: The de novo metastatic disease rate was 4.6%. Imaging varied across the 4 institutions (P<.0001). The FP rate was higher using SoC versus PET/CT (22.1% vs 11.1%; P=.0009). Mean time between incidental finding on baseline imaging to FP determination was 10.8 days. Mean time from diagnosis to chemotherapy initiation was 44.3 days with SoC versus 37.5 days with PET/CT (P=.0001). Mean cost per patient was $1,132 (SoC) versus $1,477 (PET/CT) using the Medicare Physician Fee Schedule, with an ICER of $31. Using representative reimbursements to UCSF, mean cost per patient was $1,236 (SoC) versus $1,073 (PET/CT) for Medicare, and $3,083 (SoC) versus $1,656 (PET/CT) for a private payer, with ICERs of -$15 and -$130, respectively. CONCLUSIONS: Considerable variation exists in metastatic staging practices. PET/CT reduced FP risk by half and decreased workup of incidental findings, allowing for earlier treatment start. PET/CT may be cost-effective, and at one institution was shown to be cost-saving. Better alignment is needed between hospital pricing strategies and payer coverage policies to deliver high-value care.

Prevalence of Phosphatidylinositol-3-Kinase (PI3K) Pathway Alterations and Co-alteration of Other Molecular Markers in Breast Cancer.

Background: PI3K/AKT signaling pathway is activated in breast cancer and associated with cell survival. We explored the prevalence of PI3K pathway alterations and co-expression with other markers in breast cancer subtypes. Methods: Samples of non-matched primary and metastatic breast cancer submitted to a CLIA-certified genomics laboratory were molecularly profiled to identify pathogenic or presumed pathogenic mutations in the PIK3CA-AKT1-PTEN pathway using next generation sequencing. Cases with loss of PTEN by IHC were also included. The frequency of co-alterations was examined, including DNA damage response pathways and markers of response to immuno-oncology agents. Results: Of 4,895 tumors profiled, 3,558 (72.7%) had at least one alteration in the PIK3CA-AKT1-PTEN pathway: 1,472 (30.1%) harbored a PIK3CA mutation, 174 (3.6%) an AKT1 mutation, 2,682 (54.8%) had PTEN alterations (PTEN mutation in 7.0% and/or PTEN loss by IHC in 51.4% of cases), 81 (1.7%) harbored a PIK3R1 mutation, and 4 (0.08%) a PIK3R2 mutation. Most of the cohort consisted of metastatic sites (n = 2974, 60.8%), with PIK3CA mutation frequency increased in metastatic (32.1%) compared to primary sites (26.9%), p < 0.001. Other PIK3CA mutations were identified in 388 (7.9%) specimens, classified as "off-label," as they were not included in the FDA-approved companion test for PIK3CA mutations. Notable co-alterations included increased PD-L1 expression and high tumor mutational burden in PIK3CA-AKT1-PTEN mutated cohorts. Novel concurrent mutations were identified including CDH1 mutations. Conclusions: Findings from this cohort support further exploration of the clinical benefit of PI3K inhibitors for "off-label" PIK3CA mutations and combination strategies with potential clinical benefit for patients with breast cancer.

Randomized trial of proactive rapid genetic counseling versus usual care for newly diagnosed breast cancer patients.

PURPOSE: Breast cancer patients who carry BRCA1/BRCA2 gene mutations may consider bilateral mastectomy. Having bilateral mastectomy at the time of diagnosis not only reduces risk of a contralateral breast cancer, but can eliminate the need for radiation therapy and yield improved reconstruction options. However, most patients do not receive genetic counseling or testing at the time of their diagnosis. In this trial, we tested proactive rapid genetic counseling and testing (RGCT) in newly diagnosed breast cancer patients in order to facilitate pre-surgical genetic counseling and testing. METHODS: We recruited newly diagnosed breast cancer patients at increased risk for carrying a BRCA1/2 mutation. Of 379 eligible patients who completed a baseline survey, 330 agreed to randomization in a 2:1 ratio to RGCT (n = 220) versus UC (n = 108). Primary outcomes were genetic counseling and testing uptake and breast cancer surgical decisions. RESULTS: RGCT led to higher overall (83.8% vs. 54.6%; p < 0.0001) and pre-surgical (57.8% vs. 38.7%; p = 0.001) genetic counseling uptake compared to UC. Despite higher rates of genetic counseling, RGCT did not differ from UC in overall (54.1% vs. 49.1%, p > 0.10) or pre-surgical (30.6% vs. 27.4%, p > 0.10) receipt of genetic test results nor did they differ in uptake of bilateral mastectomy (26.6% vs. 21.8%, p > 0.10). CONCLUSIONS: Although RGCT yielded increased genetic counseling participation, this did not result in increased rates of pre-surgical genetic testing or impact surgical decisions. These data suggest that those patients most likely to opt for genetic testing at the time of diagnosis are being effectively identified by their surgeons.

Practice and Impact of Multidisciplinary Tumor Boards on Patient Management: A Prospective Study.

PURPOSE: Multidisciplinary tumor boards (MTBs) have become commonplace. The use, attendance, and function of MTBs need continued assessment and improvement. METHODS: We prospectively recorded and assessed all cases presented at MTBs between October 2013 and December 2014. Data were collected before and during each MTB. Data were analyzed using SPSS for Windows version 23 (SPSS, Chicago, IL). RESULTS: Five hundred three cases were presented: 234 cases (46%) at GI cancer MTBs, 149 cases (29.6%) at breast cancer MTBs, 69 cases (13.7%) at thoracic/head and neck cancer MTBs, and 51 cases (10.7%) at neuro-oncology MTBs. A total of 86.7% of MTB cases were presented to make plans for management. Plans for upfront management were made in 67% of the breast cancer cases, 63% of GI cases, 59% of thoracic/head and neck cases, and 49% of neuro-oncology cases. Three hundred ninety-four cases (78.3%) were presented by medical oncologists, whereas only 74 cases (14.7%) were presented by surgeons, and 10 cases (2%) were presented by radiation oncologists. The majority of MTBs, with the exception of the neurosurgery MTBs, were led by medical oncologists. Surgeons presented the least number of cases but attended the most, and their contributions to discussions and decision making were essential. CONCLUSION: MTBs enhance the multidisciplinary management of patients with cancer. Upfront multidisciplinary decision making should be considered as an indicator of benefit from MTBs, in addition to changes in management plans made at MTBs. Increasing the contributions of surgeons to MTBs should include bringing more of their own cases for discussion.

BRCA1 and BRCA2 mutations in ethnic Lebanese Arab women with high hereditary risk breast cancer.

PURPOSE: Breast cancer is the most common malignancy among women in Lebanon and in Arab countries, with 50% of cases presenting before the age of 50 years. METHODS: Between 2009 and 2012, 250 Lebanese women with breast cancer who were considered to be at high risk of carrying BRCA1 or BRCA2 mutations because of presentation at young age and/or positive family history (FH) of breast or ovarian cancer were recruited. Clinical data were analyzed statistically. Coding exons and intron-exon boundaries of BRCA1 and BRCA2 were sequenced from peripheral blood DNA. All patients were tested for BRCA1 rearrangements using multiplex ligation-dependent probe amplification (MLPA). BRCA2 MLPA was done in selected cases. RESULTS: Overall, 14 of 250 patients (5.6%) carried a deleterious BRCA mutation (7 BRCA1, 7 BRCA2) and 31 (12.4%) carried a variant of uncertain significance. Eight of 74 patients (10.8%) aged ≤40 years with positive FH and only 1 of 74 patients (1.4%) aged ≤40 years without FH had a mutated BRCA. Four of 75 patients (5.3%) aged 41-50 years with FH had a deleterious mutation. Only 1 of 27 patients aged >50 years at diagnosis had a BRCA mutation. All seven patients with BRCA1 mutations had grade 3 infiltrating ductal carcinoma and triple-negative breast cancer. Nine BRCA1 and 17 BRCA2 common haplotypes were observed. CONCLUSION: Prevalence of deleterious BRCA mutations is lower than expected and does not support the hypothesis that BRCA mutations alone cause the observed high percentage of breast cancer in young women of Lebanese and Arab descent. Studies to search for other genetic mutations are recommended.

Global Practice and Efficiency of Multidisciplinary Tumor Boards: Results of an American Society of Clinical Oncology International Survey.

PURPOSE: Multidisciplinary tumor boards (MDTBs) are universally recommended, but recent literature has challenged their efficiency. METHODS: The American Society of Clinical Oncology (ASCO) conducted a survey of a randomly selected cohort of international ASCO members. The survey was built on SurveyMonkey and was sent via e-mail to a sample of 5,357 members. RESULTS: In all, 501 ASCO members practicing outside the United States responded, and 86% of them participated in MDTBs at their own institutions. Those who attended represented a variety of disciplines in 70% to 86% of all MDTBs. The majority of MDTBs held weekly specialty and/or general meetings. Eighty-nine percent of 409 respondents attended for advice on treatment decisions. Survey respondents reported changes of 1% to 25% in treatment plans for 44% to 49% of patients with breast cancer and in 47% to 50% of patients with colorectal cancer. They reported 25% to 50% changes in surgery type and/or treatment plans for 14% to 21% of patients with breast cancer and 12% to 18% of patients with colorectal cancer. Of the 430 respondents 96% said overall benefit to patients was worth the time and effort spent at MDTBs, and 96% said that MDTBs have teaching value. Mini tumor boards held with whatever types of specialists were available were considered valid. In all, 94.8% (425 of 448) said that MDTBs should be required in institutions in which patients with cancer are treated. CONCLUSION: MDTBs are commonplace worldwide. A majority of respondents attend them to obtain recommendations, and they report changes in patient management. Change occurred more frequently with nonmedical oncologists and with physicians who had less than 15 years in practice. MDTBs helped practitioners make management decisions. Mini tumor boards may improve time efficiency and are favored when the full team is not available. Suggestions for improving MDTBs included making them more efficient, better selection and preparation of cases, choosing an effective team leader, and improving how time is used, but more research is needed on ways to improve the efficiency of MDTBs.

Enhancing cancer care in areas of limited resources: our next steps.

In-depth knowledge of local conditions is necessary in order to enhance care in low- and middle-income countries. In this review we discuss: improving cancer diagnosis, optimizing patient management, increasing health awareness, prevention, early detection, eradication of causative infectious diseases and agents, tobacco control, healthy diets and lifestyles, availability of diagnostic methods, easy access to care, affordable costs, improving infrastructures, quality care measures, implementing and adapting guidelines, multidisciplinary management, supportive and survivorship care, research and optimization of medical school curriculum and training in oncology. Establishment of national cancer control plans by policy makers, physician societies, medical schools, and patient advocates is recommended. We will review evidence and controversies, and outline the next steps needed to prevent cancer and enhance care of cancer patients in LMICs.

Outcome of Breast Cancer Patients Treated outside of Clinical Trials.

BACKGROUND: Information on outcome of breast cancer patients treated in the community is scarce. Data on outcome of patients treated in real-life clinical practice may provide useful information for performance improvement. METHODS: Study population is from a single institution practice at the American University of Beirut Medical Center. Demographics, clinical characteristics and survival data on patients diagnosed 1997-2010 in two IRB-approved studies were entered and analyzed on SPSS program. Survival was estimated using Kaplan Meier Method. FINDINGS: Total was 519 patients. 23.9% had stage I, 39.7% stage II, 30.4% Stage III and 6% stage IV. ER positive in 74.4% of patients. 30.6% of patients <35 had TNBC compared to 12.3% for the whole group. 45.9% of non-metastatic patients had breast-conserving therapy (BCT). BCT rates increased to 64% during the second half of the study, coinciding with increasing awareness and changing cultural mores. 5-year and 10-year overall survivals for stage I were 98.9% and 80.5%, 89.2% and 70.7% for stage II, 67.6% and 35.5% for stage III, and 39.1% and 26.1% for stage IV respectively. INTERPRETATION: Patients treated outside clinical trials in a multidisciplinary fashion according to guidelines have comparable, and at times better, survival compared to data from trials or population statistics. Locally generated outcome data could be valuable for evaluating results of treatment at individual practices for the purpose of quality assessment and improvement. Our data also provides report of increased rate of breast conserving surgery from Middle East.

Tumor boards: optimizing the structure and improving efficiency of multidisciplinary management of patients with cancer worldwide.

Multidisciplinary management tumor boards are now conducted worldwide for the management of patients with cancer. Studies evaluating their influence on decision making and patient outcome are limited; however, single-center studies have reported significant changes in diagnosis and treatment plans. A survey from Arabic countries showed widespread use and reliance on tumor boards for decision making. A recent multi-institutional survey of veteran affairs (VA) hospitals in the United States found limited association between the presence of tumor boards and care and outcomes. The Cancer Care Outcomes Research and Surveillance Consortium looked at the association between tumor board features and measures of quality of care. Results of overall survival among the patients of these physicians participating in tumor boards is ongoing, but preliminary results are outlined along with a recent ASCO survey of international members on the presence, utilization, and influence of tumor boards in this article. Tumor boards allow for implementation of clinical practice guidelines and may help capture cases for clinical trials. Efforts to improve preparations, structure, and conduct of tumor boards, research methods to monitor their performance, teamwork, and outcomes are outlined also in this article. The concept of mini-tumor boards and more efficient methods for MDM in countries with limited resources are also discussed. In suboptimal settings, such as small community hospitals, rural areas, and areas with limited resources, boundaries in diagnosis and management can be overcome, or at least improved, with tumor boards, especially with the use of video-conferencing facilities. Studies from the United Kingdom showed that special training of multidisciplinary teams (MDT) led to better team dynamics and communication, improved patient satisfaction, and improved clinical outcome. The weight of the benefits versus the time and effort spent to improve efficiency, patient care, and better time management in the United States and in the international oncology community is also reviewed in this article.

Epidemiology and prognosis of breast cancer in young women.

Breast cancer is the most common malignancy in women with 6.6% of cases diagnosed in young women below the age of 40. Despite variances in risk factors, Age Standardized Incidence Rates of breast cancer in young women vary little between different countries. Review of modifiable risk factors shows that long-term use of oral contraceptives, low body mass index (BMI) and high animal fat diet consumption are associated with increased risk of premenopausal breast cancer. Decreased physical activity and obesity increase risks of breast cancer in postmenopausal women, but data on premenopausal women rather shows that high BMI is associated with decreased risk of breast cancer. Non-modifiable risk factors such as family history and genetic mutations do account for increased risks of breast cancer in premenopausal women. Breast cancer in young women is associated with adverse pathological factors, including high grade tumors, hormone receptor negativity, and HER2 overexpression. This has a significant negative impact on the rate of local recurrence and overall survival. Moreover, younger women often tend to present with breast cancer at a later stage than their older counterparts, which further explains worse outcome. Despite these factors, age per se is still being advocated as an independent role player in the prognosis. This entails more aggressive treatment modalities and the need for closer monitoring and follow-up.