Approximately 5% to 10% of women diagnosed with breast cancer will have a pathogenic variant (PV) in a hereditary cancer susceptibility gene, and this has significant implications for the management ...of these patients and their relatives. Despite the benefits of genetic testing, many eligible patients with breast cancer never undergo testing because of various barriers, including complicated testing criteria such as those from the National Comprehensive Cancer Network (NCCN). In 2019, the American Society of Breast Surgeons (ASBrS) proposed germline genetic testing for all patients with breast cancer to increase the identification of PV carriers. In 2020, a Mayo Clinic study highlighted the limitations of these 2 genetic testing guidelines (NCCN and ASBrS) and proposed a hybrid approach of testing all women diagnosed with breast cancer by the age of 65 years and using NCCN criteria for older patients. This commentary presents an updated analysis of the Mayo Clinic data and discusses the rationale for using the age of 60 years rather than 65 years as the cutoff for this hybrid approach. Using an age at diagnosis of ≤60 or ≤65 years for the universal testing of patients with breast cancer detected more PVs (11.9% 16 of 134 and 15.7% 21 of 134, respectively) in comparison with using the NCCN criteria. Lowering the age for universal testing from 65 to 60 years maintained the sensitivity of detecting a PV at >90% while sparing testing for an additional 10% of women. Compared with the testing of all patients, the hybrid approach would allow 31% of all women with breast cancer to forgo testing and result in fewer variants of uncertain significance identified and, therefore, would decrease the chance of harm from misinterpretation of these variants.
The identification of pathogenic variants in high‐risk breast cancer genes has a significant impact on the management of patients with breast cancer and their relatives, yet many women do not receive genetic testing because of various barriers, with one of the major reasons being complex genetic testing criteria. Testing every single patient with breast cancer is not cost‐effective and has the potential for harm through the mismanagement of benign or ambiguous genetic testing results. This commentary argues that a hybrid approach of testing all patients below a certain age threshold while restricting testing on the basis of guidelines for an older population is a better approach.
Germline BRCA1/2 mutations may be infrequent in unselected breast cancer population but are concentrated in those with triple‐negative breast cancer or high‐risk family history. Insight into the ...biology of BRCA mutation is now allowing a targeted therapeutic approach to these carriers with breast cancer. Functional BRCA genes play a critical role in DNA damage repair. Agents such as platinum salts and poly (ADP‐ribose) polymerase (PARP) inhibitors exploit this vulnerability of impaired DNA damage repair mechanism in BRCA mutant cancers to leverage therapeutic benefit. Research has demonstrated improved response rates to platinum salts in BRCA‐mutated compared with non‐BRCA‐mutated breast cancer, particularly in the metastatic setting. Additionally, clinical trials of single‐agent PARP inhibitors have shown encouraging response rates and progression‐free survival in patients with BRCA1/2‐mutated breast cancer. In this review, we summarize the medical management of BRCA‐associated breast cancer.
The impact of abbreviated neoadjuvant regimens for HER2+ breast cancer on rates of breast conservation therapy (BCT) is unclear. We aimed to determine BCT rates in a single-arm prospective trial of ...neoadjuvant paclitaxel/trastuzumab/pertuzumab (THP) in patients with stage II or III HER2+ breast cancer.
BCT eligibility was prospectively recorded before and after THP. Pre- and posttreatment mammogram and breast ultrasound were required; breast MRI was encouraged. Patients with a large tumor to breast size ratio were eligible for downsizing. Multifocal/multicentric tumors, extensive calcifications, and contraindications to radiation were considered BCT contraindications.
Overall, 92 patients who received neoadjuvant THP on trial were included. At presentation, 39 (42.4%) were considered eligible for BCT and 53 (57.6%) were not. BCT-eligible patients were older (median 54 vs 47 years, respectively; p = 0.006) and had smaller tumors by palpation (median 2.5 vs 3 cm, respectively; p = 0.004). Of 53 BCT-ineligible patients, 28 were candidates for tumor downsizing, whereas 25 had contraindications to BCT. Overall, 51 (55.4%) patients underwent BCT. Of the 28 patients who were candidates for downsizing, 22 (78.6%) became BCT-eligible after THP and 18 of 22 (81.8%) underwent BCT. In total, 44 of 92 (47.8%) patients experienced breast pathologic complete response (ypT0), including 11 of 25 (44.0%) patients with BCT contraindications at presentation.
De-escalated neoadjuvant systemic therapy led to high BCT rates in this cohort. The impact of de-escalated systemic therapy on local therapy and outcomes in early stage HER2+ breast cancer warrants further investigation.
Immune checkpoint inhibitors (ICIs) and poly (ADP-ribose) polymerase (PARP) inhibitors have transformed the treatment landscape of metastatic triple-negative breast cancer (TNBC). Trial results have ...demonstrated the clinical benefit of these targeted agents in the advanced TNBC setting and have led to their evaluation in the treatment of high-risk, early-stage TNBC and
-mutated breast cancer. We provide a summary of the results that have led to the establishment of the ICI pembrolizumab and the PARP inhibitor olaparib as new standards of care.
Using PubMed, we searched for original articles published in English between 2017 and 2022. Search terms included triple-negative breast cancer, adjuvant, neoadjuvant, immunotherapy, and PARP inhibitors.
Two targeted therapies have been approved by the US Food and Drug Administration for the treatment of TNBC and
-mutated breast cancers in the high-risk, early-stage setting on the basis of clinical trial results demonstrating improved clinical outcomes. For high-risk, early-stage TNBC, pembrolizumab was approved as neoadjuvant therapy in combination with chemotherapy and as a single agent for continued treatment after surgery; this approval was based on results of the KEYNOTE-522 trial. Olaparib was approved for the adjuvant treatment of patients with high-risk, early-stage human epidermal growth factor receptor type 2 (HER2)-negative breast cancer with germline
/
mutations who have been previously treated with neoadjuvant or adjuvant chemotherapy on the basis of the OlympiA trial results.
Clinical trial results demonstrate the pronounced clinical benefits of pembrolizumab combined with chemotherapy for high-risk, early-stage TNBC and adjuvant olaparib for high-risk, early-stage HER2-negative
/
-mutated breast cancer.
The 2013 update of the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) human epidermal growth factor receptor 2 (HER2) testing guidelines recommend using an ...alternative chromosome 17 probe assay to resolve HER2 results determined to be equivocal by immunohistochemistry (IHC) or fluorescence in-situ hybridization (FISH). However, it is unclear if cases considered HER2-positive (HER2
) by the alternative probe method are similar to those classified as HER2
by traditional IHC and FISH criteria and benefit the same from HER2-targeted therapies. We studied the clinical and pathologic features of all 31 breast cancers classified as HER2
by the alternative probe method at our institution since 2013 and determined their PAM50 intrinsic molecular subtypes. For comparison, we analyzed 19 consecutive cases that were classified as HER2
by traditional FISH criteria during the same time period. Thirty (97%) cancers in the alternative probe cohort were estrogen receptor (ER)-positive (ER
), while only 9/19 (47%) of traditional HER2 controls were ER
(p = 0.0002). Sufficient tissue for intrinsic subtype analysis was available for 20/31 cancers in the alternative probe cohort and 9/19 in the traditional HER2
group. None (0%) of the 20 alternative probe-positive cases were of the HER2-enriched intrinsic subtype, while 8/9 (89%) of those HER2
by traditional FISH criteria were HER2-enriched (p = 0.0001). These findings suggest that breast cancers classified as HER2
only by the alternative probe method are biologically distinct from those classified as HER2
by traditional criteria, and raises questions as to whether or not they derive the same benefit from HER2-targeted therapies.
Highlights • EGFR mutations occur in some high-grade neuroendocrine lung cancers. • EGFR protein is not expressed in EGFR mutated neuroendocrine lung cancers. • Patients with neuroendocrine lung ...cancers don’t respond to EGFR inhibitors.
De-escalating adjuvant therapy following pathologic complete response (pCR) to an abbreviated neoadjuvant regimen in human epidermal growth factor receptor 2-positive (HER2+) breast cancer is the ...focus of international research efforts. However, the feasibility of this approach and its appeal to patients and providers had not been formally investigated. We aimed to assess adherence to de-escalated adjuvant antibody doublet therapy (trastuzumab and pertuzumab HP, without chemotherapy) among patients with pCR following neoadjuvant paclitaxel/HP (THP). In this single-arm prospective trial, patients with treatment-naïve stage II-III HER2+ breast cancer received neoadjuvant weekly paclitaxel ×12 and HP every 3 weeks ×4. The primary endpoint was receipt of adjuvant non-HER2-directed cytotoxic chemotherapy. Ninety-eight patients received ≥1 dose of THP on study. Patients had median age of 50 years, 86% had stage II tumors, and 34% were hormone receptor-negative. Five patients had incomplete clinical response following THP and received doxorubicin and cyclophosphamide before surgery; they were classified as non-pCR and censored from further analyses. The overall pCR rate was 56.7%. Among patients with pCR, the adherence rate to de-escalated antibody-only therapy (HP) was 98.2% (95% CI 90.3-100.0%), and the primary feasibility endpoint was reached. The majority of patients felt positive or neutral about their adjuvant treatment plans. With brief follow-up (median 19.1 months), there were no breast cancer recurrences. De-escalation of adjuvant chemotherapy among patients who experience pCR in early-stage HER2+ breast cancer is a practicable approach for both patients and physicians. Planned and ongoing prospective trials will determine the long-term efficacy of this approach.Trial registration clinicaltrials.gov, NCT03716180, https://clinicaltrials.gov/ct2/show/NCT03716180 .
Dysregulation of EGFR expression and signaling is well documented to contribute to disease progression and metastasis in many types of cancer including breast cancer. EGF-stimulated EGFR activation ...leads to receptor internalization and endocytic degradation to control EGFR-mediated signaling. This process is frequently deregulated in cancer cells, leading to increased EGFR expression and mitogenic signaling. Here, we demonstrate that Bif-1, a tumor suppressor, plays a role in EGFR endocytic degradation and chemotactic migration in MDA-MB-231 breast cancer cells. Our data reveal that suppression of Bif-1 expression delays EGFR degradation and sustains Erk1/2 activation in response to EGF stimulation. Mechanistically, loss of Bif-1 sequesters internalized EGF in Rab5-positive endosomes and delays EGFR trafficking to lysosomes. Recruitment of Rab7 to EGF-positive vesicles and the activation of Rab7 are impaired in Bif-1 knockdown cells. Additionally, intracellular pH and the localization of acidic vesicles are altered by suppression of Bif-1. Furthermore, inhibition of Bif-1 increases chemotactic cell migration in response to EGF or serum, which correlates with prolonged cytoskeletal reorganization. Importantly, the effect of Bif-1 on EGF-induced cell migration is abolished by gefitinib, an EGFR-specific inhibitor. Taken together, these data suggest a novel function for Bif-1 as a suppressor of breast cancer cell migration by promoting EGFR degradation through the regulation of endosome maturation.
Among cancer predisposition genes, most direct-to-consumer (DTC) genetic tests evaluate three Ashkenazi Jewish (AJ) founder mutations in
, which represent a small proportion of pathogenic or likely ...pathogenic variants (PLPV) in cancer predisposing genes. In this study, we investigate PLPV in
and other cancer predisposition genes that are missed by testing only AJ founder
mutations.
Individuals were referred to genetic testing for personal diagnoses of breast and/or ovarian cancer (clinical cohort) or were self-referred (nonindication-based cohort). There were 348,692 participants in the clinical cohort and 7,636 participants in the nonindication-based cohort. Both cohorts were analyzed for
AJ founder mutations. Full sequence analysis was done for PLPV in
,
,
,
,
,
,
,
,
,
(truncating variants),
,
,
,
,
,
, and 22 other genes.
AJ founder mutations accounted for 10.8% and 29.7% of
PLPV in the clinical and nonindication-based cohorts, respectively. AJ founder mutations accounted for 89.9% of
PLPV in those of full AJ descent, but only 69.6% of those of partial AJ descent. In total, 0.5% of all individuals had a
AJ founder variant, while 7.7% had PLPV in a high-risk breast/ovarian cancer gene. For non-AJ individuals, limiting evaluation to the AJ founder
mutations missed >90% of mutations in actionable cancer risk genes. Secondary analysis revealed a false-positive rate of 69% for PLPV outside of non-AJ
founder mutations.
DTC genetic testing misses >90% of
PLPV in individuals of non-AJ ancestry and about 10% of
PLPV among AJ individuals. There is a high false-positivity rate for non-AJ
PLPV with DTC genetic testing.
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