Clinical Significance of Background Parenchymal Enhancement in Breast Cancer Risk Stratification.

BACKGROUND: Background parenchymal enhancement (BPE) is an established breast cancer risk factor. However, the relationship between BPE levels and breast cancer risk stratification remains unclear. PURPOSE: To evaluate the clinical relationship between BPE levels and breast cancer risk with covariate adjustments for age, ethnicity, and hormonal status. STUDY TYPE: Retrospective. POPULATION: 954 screening breast MRI datasets representing 721 women divided into four cohorts: women with pathogenic germline breast cancer (BRCA) mutations (Group 1, N = 211), women with non-BRCA germline mutations (Group 2, N = 60), women without high-risk germline mutations but with a lifetime breast cancer risk of ≥20% using the Tyrer-Cuzick model (Group 3, N = 362), and women with <20% lifetime risk (Group 4, N = 88). FIELD STRENGTH/SEQUENCE: 3 T/axial non-fat-saturated T1, short tau inversion recovery, fat-saturated pre-contrast, and post-contrast T1-weighted images. ASSESSMENT: Data on age, body mass index, ethnicity, menopausal status, genetic predisposition, and hormonal therapy use were collected. BPE levels were evaluated by two breast fellowship-trained radiologists independently in accordance with BI-RADS, with a third breast fellowship-trained radiologist resolving any discordance. STATISTICAL TESTS: Propensity score matching (PSM) was utilized to adjust covariates, including age, ethnicity, menopausal status, hormonal treatments, and prior bilateral oophorectomy. The Mann-Whitney U test, chi-squared test, and univariate and multiple logistic regression analysis were performed, with an odds ratio (OR) and corresponding 95% confidence interval. Weighted Kappa statistic was used to assess inter-reader variation. A P value <0.05 indicated a significant result. RESULTS: In the assessment of BPE, there was substantial agreement between the two interpreting radiologists (κ = 0.74). Patient demographics were not significantly different between patient groups after PSM. The BPE of Group 1 was significantly lower than that of Group 4 and Group 3 among premenopausal women. In estimating the BPE level, the OR of gene mutations was 0.35. DATA CONCLUSION: Adjusting for potential confounders, the BPE level of premenopausal women with BRCA mutations was significantly lower than that of non-high-risk women. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 3.

Updates in the treatment of HR+HER2- breast cancer.

PURPOSE OF REVIEW: Breast cancer (BC) is the most common cancer among women in the United States and the second leading cause of cancer death. BC research, diagnostics, drug development, and expansion of therapies for novel indications advances so rapidly that BC treatment standards change month-by-month. Herein we discuss notable advancements in the past year for hormone receptor positive (HR+) HER2 negative (HER2-) BC. RECENT FINDINGS: Radiolabeled estradiol imaging and circulating tumor DNA (ctDNA) have changed our approach to metastatic BC (mBC) detection. Amongst an abundance of therapy options, treatment de-escalation to avoid toxicities is a priority. Promising results with CDK4/6 inhibitors in the curative setting have been demonstrated even as we await final data for use in the metastatic setting. Several novel endocrine therapies are expected to gain FDA-approval in the near future. Antibody-drug conjugates have expanded from other mBC types to HR+HER2- mBC. The PROMISE trial helped define disease recurrence outcomes for premenopausal women seeking pregnancy. SUMMARY: The diagnostic and treatment landscape for HR+HER2- BC continues to rapidly evolve on multiple fronts.

Innovations in targeted therapies for triple negative breast cancer.

PURPOSE OF REVIEW: Triple negative breast cancer (TNBC) is defined by a lack of targets, namely hormone receptor (HR) expression and human epidermal growth factor receptor 2 amplification. Cytotoxic chemotherapy remains the mainstay of treatment. Though TNBC constitutes approximately 10-15% of breast cancer, it is disproportionally lethal, but it is hoped that outcomes will improve as targetable oncogenic drivers are identified. RECENT FINDINGS: Translational work in TNBC has focused on subsets defined by defects in homologous recombination repair, immune cell infiltration, or programmed death ligand receptor 1 expression, an over-active phosphoinositide-3 kinase pathway, or expression of androgen receptors. Though not specific to TNBC, the novel cell surface antigen trophoblast antigen 2 has also been identified and successfully targeted. This work has led to Food and Drug Administration approvals for small molecule poly-ADP-ribosyl polymerase inhibitors in patients with deleterious germline mutations in BRCA1 or BRCA2, the combination of nab-paclitaxel with immune checkpoint inhibitor antibodies in the first-line metastatic setting for programmed death ligand receptor 1+ TNBC, and use of the antibody-drug conjugate sacituzumab govitecan in the later-line metastatic setting. SUMMARY: Identification of targetable oncogenic drivers in TNBC is an area of intense cancer biology research, hopefully translating to new therapies and improved outcomes.

Advances in the use of PARP inhibitors for BRCA1/2-associated breast cancer: talazoparib.

Poly-ADP-ribosyl polymerase (PARP) enzymes PARP-1 and PARP-2 recognize DNA damage and set off a cascade of cellular mechanisms required for multiple types of DNA damage repair. PARP inhibitors are small molecule mimetics of nicotinamide which bind to PARP's catalytic domain to inhibit poly-ADP-ribosylation (PARylation) of target proteins, including PARP-1 itself. PARP inhibitors olaparib, veliparib, talazoparib, niraparib and rucaparib have predominantly been studied in women with breast or ovarian cancers associated with deleterious germline mutations in BRCA1 and BRCA2 (gBRCA1/2+). The BRCA1 and BRCA2 proteins are involved in DNA repair by homologous recombination. This review will focus on talazoparib, a PARP inhibitor approved by the US FDA for the treatment of metastatic gBRCA1/2+ breast cancers in October 2018.

Poly-ADP-ribosyl-polymerase inhibitor resistance mechanisms and their therapeutic implications.

PURPOSE OF REVIEW: Poly-ADP-ribosyl-polymerase (PARP) inhibitors are an increasingly-utilized therapy in women with high-grade serous ovarian carcinoma, but tumor resistance to PARP inhibitor monotherapy is inevitable. RECENT FINDINGS: PARP inhibitors have been most studied in patients with breast and ovarian cancers associated with deleterious germline BRCA1 or BRCA2 mutations, though their role has expanded to include use as maintenance therapy in women with platinum-sensitive high-grade serous ovarian cancer due to the high propensity of such cancers to have defects in DNA repair by homologous recombination. As mechanisms of PARP inhibitor resistance are elucidated, rationale combination strategies can be devised to extend therapeutic benefits and to abrogate resistance. SUMMARY: Mechanisms of resistance include restoration of homologous recombination repair proficiency, loss of cancer cell reliance on PARP, and increased intracellular signaling through cell growth pathways.

Novel poly-ADP-ribose polymerase inhibitor combination strategies in ovarian cancer.

PURPOSE OF REVIEW: The recent United States Food and Drug Administration approvals of niraparib and olaparib as maintenance monotherapy for platinum-sensitive, high-grade ovarian cancers independent of BRCA status reflect a willingness to seek indications for poly-ADP-ribose polymerase (PARP) inhibitors beyond cancers with deleterious breast cancer 1 and breast cancer 2 mutations. In this review, I describe the rationale behind current PARP combination clinical trials with chemotherapies, angiogenesis inhibitors, cell cycle checkpoint inhibitors, and inhibitors of the phosphoinositide 3-kinase/AK thymoma/mechanistic target of rapamycin pathway. RECENT FINDINGS: PARP inhibitors have primarily been studied as monotherapy in cancers with homologous recombination repair defects based on an early understanding of PARP-1 as a base excision repair enzyme and the idea that abrogation of two DNA repair pathways cripples rapidly dividing cancer cells. It is now known that PARP-1 is a DNA damage sensor with much wider reaching roles in DNA repair processes and normal cellular functions, opening possibilities for PARP inhibitor use in other clinical contexts. SUMMARY: PARP inhibitor combination clinical trials are in the early stages, but will deepen our understanding of DNA repair mechanisms, cancer biology, and targeted therapies, thus contributing to the next iteration of therapeutic options for our patients.

Selection of appropriate biomarkers to monitor effectiveness of ovarian function suppression in pre-menopausal patients with ER+ breast cancer.

Use of gonadotropin-releasing hormone (GnRH) agonists has been widely adopted to provide reversible ovarian function suppression for pre-menopausal breast cancer patients who are also receiving aromatase inhibitor or tamoxifen therapy based on results of 25 randomized trials representing almost 15,000 women demonstrating a survival benefit with this approach. Past clinical trials designed to establish the efficacy of GnRH agonists have monitored testosterone in the prostate cancer setting and estradiol in the breast cancer setting. We explore the merits of various biomarkers including estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) and their utility for informing GnRH agonist treatment decisions in breast cancer. Estradiol remains our biomarker of choice in ensuring adequate ovarian function suppression with GnRH agonist therapy among pre-menopausal women with breast cancer. We recommend future trials to continue to focus on estradiol levels as the primary endpoint, as they have in the past.

Preclinical and Clinical Trial Results Using Talazoparib and Low-Dose Chemotherapy.

PURPOSE: On the basis of preclinical data, we hypothesized that low doses of chemotherapy (10% of therapeutic doses) with full dose of a PARP inhibitor could have improved efficacy and tolerability. PATIENTS AND METHODS: In this phase I dose-escalation study, patients with BRCA-normal advanced malignancies were assigned to either talazoparib/temozolomide or talazoparib/irinotecan. Talazoparib was dose-escalated from 500 mcg to 1 mg daily before dose escalation of temozolomide/irinotecan. The starting dose of temozolomide was 25 mg/m2/day orally on days 1 to 5 and irinotecan was 25 mg/m2/day intravenously on days 1 and 15. The primary objectives of this trial were safety and tolerability, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD). RESULTS: Of 40 patients enrolled, 18 (mean: 7 prior therapies) were enrolled in talazoparib + temozolomide and 22 in talazoparib + irinotecan. DLTs were hematologic in both arms, but all hematologic adverse events resolved with either treatment interruption and/or dose reductions of talazoparib. The MTDs were talazoparib 1 mg + temozolomide 37.5 mg/m2 and talazoparib 1 mg + irinotecan 37.5 mg/m2. There were four partial responses in the talazoparib + temozolomide arm and five in the talazoparib + irinotecan arm for a response rate of 23% (9/40). The pharmacokinetic profiles of talazoparib + temozolomide/irinotecan were similar to that of talazoparib monotherapy. Responses were seen independent of homologous recombination (HR) status and HR deficiency score. CONCLUSIONS: These results show that talazoparib with low-dose temozolomide or irinotecan is reasonably well tolerated and demonstrates clinical activity in a wide range of cancers. Randomized trials of talazoparib with or without low-dose chemotherapy are ongoing in small cell lung cancer and ovarian cancer.

Quantitative Predictors of Response to Neoadjuvant Chemotherapy on Dynamic Contrast-enhanced 3T Breast MRI.

OBJECTIVE: To assess whether changes in quantitative parameters on breast MRI better predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in breast cancer than change in volume. METHODS: This IRB-approved retrospective study included women with newly diagnosed breast cancer who underwent 3T MRI before and during NAC from January 2013 to December 2019 and underwent surgery at our institution. Clinical data such as age, histologic diagnosis and grade, biomarker status, clinical stage, maximum index cancer dimension and volume, and surgical pathology (presence or absence of in-breast pCR) were collected. Quantitative parameters were calculated using software. Correlations between clinical features and MRI quantitative measures in pCR and non-pCR groups were assessed using univariate and multivariate logistic regression. RESULTS: A total of 182 women with a mean age of 52 years (range, 26-79 years) and 187 cancers were included. Approximately 45% (85/182) of women had pCR at surgery. Stepwise multivariate regression analysis showed statistical significance for changes in quantitative parameters (increase in time to peak and decreases in peak enhancement, wash out, and Kep [efflux rate constant]) for predicting pCR. These variables in combination predicted pCR with 81.2% accuracy and an area under the curve (AUC) of 0.878. The AUCs of change in index cancer volume and maximum dimension were 0.767 and 0.613, respectively. CONCLUSION: Absolute changes in quantitative MRI parameters between pre-NAC MRI and intra-NAC MRI could help predict pCR with excellent accuracy, which was greater than changes in index cancer volume and maximum dimension.

Advances in Targeted Therapies for Triple-Negative Breast Cancer.

While the outcomes for patients diagnosed with hormone receptor positive (HR+) and/or human epidermal growth factor receptor 2-positive (HER2+) breast cancers have continued to improve with the development of targeted therapies, the same cannot be said yet for those affected with triple-negative breast cancer (TNBC). Currently, the mainstay of treatment for the 10-15% of patients diagnosed with TNBC remains cytotoxic chemotherapy, but it is hoped that through an enhanced characterization of TNBC biology, this disease will be molecularly delineated into subgroups with targetable oncogenic drivers. This review will focus on recent therapeutic innovations for TNBC, including poly-ADP-ribosyl polymerase (PARP) inhibitors, phosphoinositide 3-kinase (PI3K) pathway inhibitors, immune checkpoint inhibitors, and cyclin-dependent kinase (CDK) inhibitors.

Radiosensitization of yeast cells by inhibition of histone h4 acetylation.

Deletion of genes for proteins involved in histone H4 acetylation produces sensitivity to DNA-damaging agents in both Saccharomyces cerevisiae and mammalian cells. In the present studies, we show that treating wild-type yeast cells with histone acetyl transferase (HAT) inhibitors, which are chemicals that cause a global decrease in histone H4 acetylation, sensitizes the cells to ionizing radiation. Using HAT inhibitors, we have placed histone H4 acetylation into the RAD51-mediated homologous recombination repair pathway. We further show that yeast cells with functionally defective HAT proteins have normal phospho-H2A (gamma-H2A) induction after irradiation but a reduced rate of loss of gamma-H2A. This argues that HAT-defective cells are able to detect DNA double-strand breaks normally but have a defect in the repair of these lesions. We also show that cells treated with HAT inhibitors have intact G1 and G2 checkpoints after exposure to ionizing radiation, suggesting that G1 and G2 checkpoint activation is independent of histone H4 acetylation.

Advances in the use of PARP inhibitor therapy for breast cancer.

Poly-ADP-ribose polymerase 1 (PARP-1) and PARP-2 are DNA damage sensors that are most active during S-phase of the cell cycle and that have wider-reaching roles in DNA repair than originally described. BRCA1 and BRCA2 (Breast Cancer) proteins are involved in homologous recombination repair (HRR), which requires a homologous chromosome or sister chromatid as a template to faithfully repair DNA double-strand breaks. The small-molecule NAD+ mimetics, olaparib, niraparib, rucaparib, veliparib, and talazoparib, inhibit the catalytic activity of PARP-1 and PARP-2 and are currently being studied in later-stage clinical trials. PARP inhibitor clinical trials have predominantly focused on patients with breast and ovarian cancer with deleterious germline BRCA1 and BRCA2 mutations (gBRCA1/2+) but are now expanding to include cancers with known, suspected, or more-likely-than-not defects in homologous recombination repair. In ovarian cancer, this group also includes women whose cancers are responsive to platinum therapy. Olaparib was FDA-approved in January 2018 for the treatment of gBRCA1/2+ metastatic breast cancers. gBRCA1+ predisposes women to develop triple-negative breast cancers, while women with gBRCA2+ tend to develop hormone-receptor-positive, human epidermal growth factor receptor 2 negative breast cancers. Although PARP inhibitor monotherapy strategies seem most effective in cancers with homologous recombination repair defects, combination strategies may allow expansion into a wider range of cancers. By interfering with DNA repair, PARP inhibitors essentially sensitize cells to DNA-damaging chemotherapies and radiation therapy. Certainly, one could also consider expanding the utility of PARP inhibitors beyond gBRCA1/2+ cancers by causing DNA damage with cytotoxic agents in the presence of a DNA repair inhibitor. Unfortunately, in numerous phase I clinical trials utilizing a combination of cytotoxic chemotherapy at standard doses with dose-escalation of PARP inhibitors, there has generally been failure to reach monotherapy dosages of PARP inhibitors due to myelosuppressive toxicities. Strategies utilizing angiogenesis inhibitors and immune checkpoint inhibitors are generally not hindered by additive toxicities, though the utility of combining PARP inhibitors with treatments that have not been particularly effective in breast cancers somewhat tempers enthusiasm. Finally, there are combination strategies that may serve to mitigate resistance to PARP inhibitors, namely, upregulation of the intracellular PhosphoInositide-3-kinase, AK thymoma (protein kinase B), mechanistic target of rapamycin (PI3K-AKT-mTOR) pathway, or perhaps are more simply meant to interfere with a cell growth pathway heavily implicated in breast cancers while administering relatively well-tolerated PARP inhibitor therapy.

Harnessing the immune system in the battle against breast cancer.

Breast cancer is the most prevalent malignancy in women and the second most common cause of cancer-related death worldwide. Despite major innovations in early detection and advanced therapeutics, up to 30% of women with node-negative breast cancer and 70% of women with node-positive breast cancer will develop recurrence. The recognition that breast tumors are infiltrated by a complex array of immune cells that influence their development, progression, and metastasis, as well as their responsiveness to systemic therapies has sparked major interest in the development of immunotherapies. In fact, not only the native host immune system can be altered to promote potent antitumor response, but also its components can be manipulated to generate effective therapeutic strategies. We present here a review of the major approaches to immunotherapy in breast cancers, both successes and failures, as well as new therapies on the horizon.

Global analysis of gene function in yeast by quantitative phenotypic profiling.

We present a method for the global analysis of the function of genes in budding yeast based on hierarchical clustering of the quantitative sensitivity profiles of the 4756 strains with individual homozygous deletion of nonessential genes to a broad range of cytotoxic or cytostatic agents. This method is superior to other global methods of identifying the function of genes involved in the various DNA repair and damage checkpoint pathways as well as other interrogated functions. Analysis of the phenotypic profiles of the 51 diverse treatments places a total of 860 genes of unknown function in clusters with genes of known function. We demonstrate that this can not only identify the function of unknown genes but can also suggest the mechanism of action of the agents used. This method will be useful when used alone and in conjunction with other global approaches to identify gene function in yeast.

A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis.

Telomerase is a ribonucleoprotein (RNP) complex that synthesizes telomere repeats in tissue progenitor cells and cancer cells. Active human telomerase consists of at least three principal subunits, including the telomerase reverse transcriptase, the telomerase RNA (TERC), and dyskerin. Here, we identify a holoenzyme subunit, TCAB1 (telomerase Cajal body protein 1), that is notably enriched in Cajal bodies, nuclear sites of RNP processing that are important for telomerase function. TCAB1 associates with active telomerase enzyme, established telomerase components, and small Cajal body RNAs that are involved in modifying splicing RNAs. Depletion of TCAB1 by using RNA interference prevents TERC from associating with Cajal bodies, disrupts telomerase-telomere association, and abrogates telomere synthesis by telomerase. Thus, TCAB1 controls telomerase trafficking and is required for telomere synthesis in human cancer cells.