Research Spotlight

Filho, O.M., Stover, D.G., Asad, S., Ansell, P.J., Watson, M., Loibl, S., Geyer, C.E., Jr., Bae, J., Collier, K., Cherian, M., O’Shaughnessy, J., Untch, M., Rugo, H.S., Huober, J.B., Golshan, M., Sikov, W.M., von Minckwitz, G., Rastogi, P., Maag, D., Wolmark, N., Denkert, C. and Symmans, W.F. (2021). “Association of Immunophenotype With Pathologic Complete Response to Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer: A Secondary Analysis of the BrighTNess Phase 3 Randomized Clinical Trial.” JAMA Oncol Feb 18;e207310. [Epub ahead of print].

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IMPORTANCE: Adding carboplatin to standard neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) likely benefits a subset of patients; however, determinants of benefit are poorly understood. OBJECTIVE: To define the association of molecular subtype, tumor proliferation, and immunophenotype with benefit of carboplatin added to NAC for patients with stages II to III TNBC. DESIGN, SETTING, AND PARTICIPANTS: This was a prespecified secondary analysis of a phase 3, double-blind, randomized clinical trial (BrighTNess) that enrolled 634 women across 145 centers in 15 countries. Women with clinical stages II to III TNBC who had undergone pretreatment biopsy were eligible to participate. Whole transcriptome RNA sequencing was performed on the biopsy specimens. The prespecified end point was association of pathologic complete response (pCR) with gene expression-based molecular subtype, with secondary end points investigating established signatures (proliferation, immune) and exploratory analyses of immunophenotype. Data were collected from April 2014 to March 2016. The study analyses were performed from January 2018 to March 2019. INTERVENTIONS: Neoadjuvant chemotherapy with paclitaxel followed by doxorubicin and cyclophosphamide, or this same regimen with carboplatin or carboplatin plus veliparib. MAIN OUTCOMES AND MEASURES: Association of gene expression-based molecular subtype (PAM50 and TNBC subtypes) with pCR. RESULTS: Of the 634 women (median age, 51 [range, 22-78] years) enrolled in BrighTNess, 482 (76%) patients had evaluable RNA sequencing data, with similar baseline characteristics relative to the overall intention-to-treat population. Pathologic complete response was significantly more frequent in PAM50 basal-like vs nonbasal-like cancers overall (202 of 386 [52.3%] vs 34 of 96 [35.4%]; P = .003). Carboplatin benefit was not significantly different in basal-like vs nonbasal-like subgroups (P = .80 for interaction). In multivariable analysis, proliferation (hazard ratio, 0.36; 95% CI, 0.21-0.61; P < .001) and immune (hazard ratio, 0.62; 95% CI, 0.49-0.79; P < .001) signatures were independently associated with pCR. Tumors above the median for proliferation and immune signatures had the highest pCR rate (84 of 125; 67%), while those below the median for both signatures had the lowest pCR rate (42 of 125; 34%). Exploratory gene expression immune analyses suggested that tumors with higher inferred CD8+ T-cell infiltration may receive greater benefit with addition of carboplatin. CONCLUSIONS AND RELEVANCE: In this secondary analysis of a randomized clinical trial, triple-negative breast cancer subtyping revealed high pCR rates in basal-like and immunomodulatory subsets. Analysis of biological processes related to basal-like and immunomodulatory phenotypes identified tumor cell proliferation and immune scores as independent factors associated with achieving pCR; the benefit of carboplatin on pCR was seen across all molecular subtypes. Further validation of immunophenotype with existing biomarkers may help to escalate or de-escalate therapy for patients with TNBC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02032277.

Desai, C.S., Szempruch, K.R., Vonderau, J.S., Chetboun, M., Pattou, F., Coates, T., De Paep, D.L., Hawthorne, W.J., Khan, K.M., de Koning, E.J.P., Naziruddin, B., Posselt, A., Schrope, B.A., Wijkstrom, M., Witkowski, P. and Shapiro, A.M.J. (2021). “Anticoagulation practices in total pancreatectomy with autologous islet cell transplant patients: an international survey of clinical programs.” Transpl Int 34(3): 593-595.

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Total pancreatectomy with autologous islet cell transplant (TPAIT) is a treatment option for patients suffering from chronic or recurrent acute pancreatitis by providing benefits of pain relief, enhancing quality of life, and preventing brittle type 3c diabetes. While surgical procedure requires extensive dissection and elevates the risk of bleeding, this operation also carries potential risk of portal venous thrombosis (0.9–3.4%) when impure or partially purified autologous islet preparations are infused into the portomesenteric circulation. To mitigate the risk of thrombosis and to assist with islet engraftment by reducing Instant Blood‐Mediated Inflammatory Reaction (IBMIR), anticoagulants are often utilized intra and postoperatively [6]. Through literature review and personal communications, it is clear that centers vary in their anticoagulation practices without any consensus guideline on the type, amount, or duration of anticoagulation, nor on the type and targets for postoperative monitoring. The aim of this study is to gather information about the various anticoagulation strategies utilized by programs internationally. [No abstract; excerpt from article].

Hendrick, R.E., Helvie, M.A. and Monticciolo, D.L. (2021). “Breast Cancer Mortality Rates Have Stopped Declining in U.S. Women Younger than 40 Years.” Radiology Feb 9;203476. [Epub ahead of print].

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Background National Center for Health Statistics (NCHS) data for U.S. women have shown a steady decline in breast cancer mortality rates since 1989. Purpose To analyze U.S. breast cancer mortality rates by age decade in women aged 20-79 years and in women aged 20-39 years and women aged 40-69 years. Materials and Methods The authors conducted a retrospective analysis of (a) female breast cancer mortality rates from NCHS data for 1969-2017 for all races and by race and (b) age- and delay-adjusted invasive breast cancer incidence rates from the Surveillance, Epidemiology, and End Results program. Joinpoint analysis was used to determine trends in breast cancer mortality, invasive breast cancer incidence, and distant-stage (metastatic) breast cancer incidence rates. Results Between 1989 and 2010, breast cancer mortality rates decreased by 1.5%-3.4% per year for each age decade from 20 to 79 years (P < .001 for each). After 2010, breast cancer mortality rates continued to decline by 1.2%-2.2% per year in women in each age decade from 40 to 79 years (P < .001 for each) but stopped declining in women younger than 40 years. After 2010, breast cancer mortality rates demonstrated nonsignificant increases of 2.8% per year in women aged 20-29 years (P = .11) and 0.3% per year in women aged 30-39 years (P = .70), results attributable primarily to changes in mortality rates in White women. A contributing factor is that distant-stage breast cancer incidence rates increased by more than 4% per year after the year 2000 in women aged 20-39 years. Conclusion Female breast cancer mortality rates have stopped declining in women younger than 40 years, ending a trend that existed from 1987 to 2010. Conversely, mortality rates have continued to decline in women aged 40-79 years. Rapidly rising distant-stage breast cancer rates have likely contributed to ending the decline in mortality rates in women younger than 40 years.

Rahimi, G., Tecson, K.M., Elsaid, O. and McCullough, P.A. (2021). “Role of Ischemic Heart Disease in Major Adverse Renal and Cardiac Events Among Individuals With Heart Failure With Preserved Ejection Fraction (from the TOPCAT Trial).” Am J Cardiol 142: 91-96.

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Despite improvements in the prognosis of patients with heart failure with reduced ejection fraction (HFrEF), established therapy for heart failure patients with preserved ejection fraction (HFpEF) is lacking. Additionally, ischemic heart disease adversely impacts the clinical course of HFrEF patients; however, its role in HFpEF is not fully understood. We conducted a post hoc analysis of propensity score matched patients from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial to compare HFpEF patients with versus without myocardial ischemia in terms of major adverse renal and/or cardiac events (MARCE). Of 3,445 participants, the prevalence of ischemia was 59%. For this analysis, we included 1,747 ischemic patients and 1,207 propensity matched nonischemic patients. Ischemia was associated with a 20% increased risk (HR = 1.20, 95% confidence interval [CI] = 1.042 to 1.382, p value = 0.0112) of major adverse renal and/or cardiac events (MARCE) in adjusted analyses. Other important predictors of MARCE were diabetes (hazard ratio [HR] = 1.60, 95% CI = 1.38 to 1.87, p <0.0001), dyslipidemia (HR = 1.30, 95% CI = 1.10 to 1.52, p = 0.001) and smoking (HR = 1.33, 95% CI = 1.04 to 1.69, p = 0.0197). Revascularization was not significantly associated with MARCE in the subgroup of ischemic HFpEF patients. Future work is warranted to develop tailored interventions for patients with both HFpEF and ischemic heart disease to mitigate the risk of MARCE .

Aldujeli, A., Hamadeh, A., Tecson, K.M., Krivickas, Z., Maciulevicius, L., Stiklioraitis, S., Sukys, M., Briedis, K., Aldujeili, M., Briede, K., Braukyliene, R., Pranculis, A., Unikas, R., Zaliaduonyte, D. and McCullough, P.A. (2021). “Six-Month Outcomes for COVID-19 Negative Patients with Acute Myocardial Infarction Before Versus During the COVID-19 Pandemic.” Am J Cardiol Feb 23;S0002-9149(21)00161-2. [Epub ahead of print].

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The Coronavirus disease 2019 (COVID-19) pandemic has changed the way patients seek medical attention and how medical services are provided. We sought to compare characteristics, clinical course, and outcomes of patients presenting with acute myocardial infarction (AMI) during the pandemic compared with before it. This is a multicenter, retrospective cohort study of consecutive COVID-19 negative patients with AMI in Lithuania from March 11, 2020 to April 20, 2020 compared with patients admitted with the same diagnosis during the same period in 2019. All patients underwent angiography. Six-month follow-up was obtained for all patients. A total of 269 patients were included in this study, 107 (40.8%) of whom presented during the pandemic. Median pain-to-door times were significantly longer (858 [quartile 1=360, quartile 3 = 2,600] vs 385.5 [200, 745] minutes, p <0.0001) and post-revascularization ejection fractions were significantly lower (35 [30, 45] vs 45 [40, 50], p <0.0001) for patients presenting during vs. prior to the pandemic. While the in-hospital mortality rate did not differ, we observed a higher rate of six-month major adverse cardiovascular events for patients who presented during versus prior to the pandemic (30.8% vs 13.6%, p = 0.0006). In conclusion, 34% fewer patients with AMI presented to the hospital during the COVID-19 pandemic, and those who did waited longer to present and experienced more 6-month major adverse cardiovascular events compared with patients admitted before the pandemic.