Multidisciplinary Management of Breast Cancer During Pregnancy

Although breast cancer during pregnancy (BCDP) is rare (occurring with only 0.4% of all BC diagnoses in female patients aged 16–49 years), management decisions are challenging to both the patient and the multidisciplinary team

FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036

Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy

Germline Genetic Mutations in a Multi-center Contemporary Cohort of 550 Phyllodes Tumors: An Opportunity for Expanded Multi-gene Panel Testing

BackgroundA paucity of data exists regarding inherited mutations associated with phyllodes tumors (PT); however, some are reported (TP53, BRCA1, and RB1). A PT diagnosis does not meet NCCN criteria for testing, including within Li-Fraumeni Syndrome (TP53). We sought to determine the prevalence of mutations associated with PT.MethodsWe performed an 11-institution review of contemporary (2007-2017) PT practice. We recorded multigenerational family history and personal history of genetic testing. We identified patients meeting NCCN criteria for genetic evaluation. Logistic regression estimated the association of select covariates with likelihood of undergoing genetic testing.ResultsOf 550 PT patients, 59.8% (n = 329) had a close family history of cancer, and 34.0% (n = 112) had ≥ 3 family members affected. Only 6.2% (n = 34) underwent genetic testing, 38.2% (n = 13) of whom had only BRCA1/BRCA2 tested. Of 34 patients tested, 8.8% had a deleterious mutation (1 BRCA1, 2 TP53), and 5.9% had a BRCA2 VUS. Of women who had TP53 testing (N = 21), 9.5% had a mutation. Selection for testing was not associated with age (odds ratio [OR] 1.01, p = 0.55) or PT size (p = 0.12) but was associated with grade (malignant vs. benign: OR 9.17, 95% CI 3.97-21.18) and meeting NCCN criteria (OR 3.43, 95% confidence interval 1.70-6.94). Notably, an additional 86 (15.6%) patients met NCCN criteria but had no genetic testing.ConclusionsVery few women with PT undergo germline testing; however, in those selected for testing, a deleterious mutation was identified in ~ 10%. Multigene testing of a PT cohort would present an opportunity to discover the true incidence of germline mutations in PT patients

Contemporary Multi-Institutional Cohort of 550 Cases of Phyllodes Tumors (2007-2017) Demonstrates a Need for More Individualized Margin Guidelines.

PurposePhyllodes tumors (PTs) are rare breast neoplasms, which have little granular data on margins. Current guidelines recommend ≥ 1 cm margins; however, recent data suggest narrower margins are sufficient, and for benign PT, a negative margin may not be necessary.MethodsWe performed an 11-institution contemporary (2007-2017) review of PT practices. Demographics, surgical, and histopathologic data were captured. Logistic regression was used to estimate the association of select covariates with local recurrence (LR).ResultsOf 550 PT patients, the majority underwent excisional biopsy (55.3%, n = 302/546) or lumpectomy (wide excision) (38.5%, n = 210/546). Median tumor size was 30 mm, 68.9% (n = 379) were benign, 19.6% (n = 108) borderline, and 10.5% (n = 58) malignant. Surgical margins were positive in 42% (n = 231) and negative in 57.3% (n = 311). A second operation was performed in 38.0% (n = 209) of the total cohort, including 51 patients with an initial negative margin (82.4% with < 2 mm), and 157 with an initial positive margin, with residual disease only found in six (2.9%). Notably, 32.0% (n = 74) of those with an initial positive margin did not undergo a second operation, among whom only 2.7% (n = 2) recurred. Recurrence occurred in 3.3% (n = 18) of the total cohort (n = 15 LR, n = 3 distant), at median follow-up of 36.7 months. LR (all PT grades) was not reduced with wider negative margin width (≥ 2 mm v < 2 mm: odds ratio [OR] = 0.39; 95% CI, 0.07 to 2.10; P = .27) or final margin status (positive v negative: OR = 0.96; 95% CI, 0.26 to 3.52; P = .96).ConclusionIn current practice, many patients are managed outside of current guidelines. For the entire cohort, a wider margin width was not associated with a reduced risk of LR. We do not recommend re-excision of a negative margin for benign PT, regardless of margin width, as a progressively wider surgical margin is unlikely to reduce LR

Multidisciplinary Management of Breast Cancer During Pregnancy

BACKGROUND. Although breast cancer during pregnancy (BCDP) is rare (occurring with only 0.4% of all BC diagnoses in female patients aged 16–49 years), management decisions are challenging to both the patient and the multidisciplinary team. MATERIALS AND METHODS. Experts in breast cancer at the University of North Carolina conducted a targeted literature search regarding the multidisciplinary treatment approaches to BCDP: medical, surgical, and radiation oncology. Supportive care, including antiemetic agents, and imaging approaches were also reviewed. RESULTS. Review of the literature revealed key points in the management of BCDP. Surgical management is similar to that in nonpregnant patients; pregnant patients may safely undergo breast‐conserving surgery. Recommendations should be tailored to the individual according to the clinical stage, tumor biology, genetic status, gestational age, and personal preferences. Anthracycline‐based chemotherapy can be safely initiated only in the second and third trimesters. The rate of congenital abnormalities in children exposed to chemotherapy is similar to the national average (approximately 3%). Dosing of chemotherapy should be similar to that in the nonpregnant patient (i.e., actual body surface area). Antihuman epidermal growth factor receptor 2 therapy, radiation, and endocrine treatment are contraindicated in pregnancy and lactation. Care should include partnership with obstetricians. The literature regarding prognosis of BCDP is mixed. CONCLUSION. To maximize benefit and minimize risk to the mother and fetus, an informed discussion with the patient and her medical team should result in an individualized treatment plan, taking into account the timing of the pregnancy and the stage and subtype of the breast cancer. Because BCDP is rare, it is essential to collect patient data in international registries. IMPLICATIONS FOR PRACTICE. Breast cancer during pregnancy is a major ethical and professional challenge for both the patient and the multidisciplinary treatment team. Although the oncologic care is based on that of the non‐pregnant breast cancer patient, there are many challenges from regarding the medical, surgical and radiation oncology and obstetrical aspects of care that need to be considered to deliver the safest and best treatment plan to both the mother and developing fetus

Limited Reporting of Histopathologic Details in a Multi-Institutional Academic Cohort of Phyllodes Tumors: Time for Standardization

BackgroundPhyllodes tumors are rare fibroepithelial neoplasms that are classified by tiered histopathologic features. While there are protocols for the reporting of cancer specimens, no standardized reporting protocol exists for phyllodes.MethodsWe performed an 11-institution contemporary review of phyllodes tumors. Granular histopathologic details were recorded, including the features specifically considered for phyllodes grade classification.ResultsOf 550 patients, median tumor size was 3.0 cm, 68.9% (n = 379) of tumors were benign, 19.6% (n = 108) were borderline, and 10.5% (n = 58) were malignant. All cases reported the final tumor size and grade classification. Complete pathologic reporting of all histopathologic features was present in 15.3% (n = 84) of cases, while an additional 35.6% (n = 196) were missing only one or two features in the report. Individual details regarding the degree of stromal cellularity was not reported in 53.5% (n = 294) of cases, degree of stromal atypia in 58.0% (n = 319) of cases, presence of stromal overgrowth in 56.2% (n = 309) of cases, stromal cell mitoses in 37.5% (n = 206) of cases, and tumor border in 54.2% (n = 298) of cases. The final margin status (negative vs. positive) was omitted in only 0.9% of cases, and the final negative margin width was specifically reported in 73.8% of cases. Reporting of details was similar across all sites.ConclusionIn this academic cohort of phyllodes tumors, one or more histopathologic features were frequently omitted from the pathology report. While all features were considered by the pathologist for grading, this limited reporting reflects a lack of reporting consensus. We recommend that standardized reporting in the form of a synoptic-style cancer protocol be implemented for phyllodes tumors, similar to other rare tumors