bluuebunny/crossref_metadata_2025 huggingface dataset:
Successful management of Australian patients with extensive skin field cancerization (ESFC) with widefield volumetric arc radiation therapy (VMAT): Report with 12-month follow-up.
Authors: Curran Walter J , Potter Andrew , Baker Christopher , Shumack Stephen , Sinclair Robert , Christie David , Wong Bradley , Foley Peter , Spelman Lynda , O'Brien Peter
Published: June 2022

9582

Background: Non-melanomatous skin cancer (NMSC) diagnoses are associated with a high risk of developing new skin cancers in adjacent areas. Patients with extensive skin field cancerization (ESFC) have large areas (generally ≥50cm2) of compromised skin characterized by pre-cancerous actinic keratoses often requiring repeated interventions. Lesion-directed therapies have excellent cure rates, but therapies targeting a wider region have limited durability, including topical agents such as 5-flurouracil. The development of volumetric modulated arc radiation therapy (VMAT) to precisely target large, curved skin surfaces has generated interest in its application to ESFC. This is a report on the efficacy, safety, and cosmetic outcomes of VMAT in the management of patients with ESFC at facilities across five Australian states. Methods: Sixty-three ESFC zones on 60 patients were prescribed widefield VMAT and prospectively enrolled in the National (Australian) Dermatology Radiation Oncology Registry (NDROR). Over 80% of patients had received up to 4 prior non-radiotherapy interventions. Fields included lower and upper limb, face, scalp, or trunk regions. Total widefield VMAT RT doses ranged from 45-50 Gy delivered in 25-30 daily fractions across 5-7 weeks. 3-, 6-, and 12-month follow-up assessments rated the percentage of disease clearance, cosmesis using the Lovett’s scale, and toxicity based on CTCAE. Results: At 12-month follow-up, 97% of treated zones had achieved and maintained clinical success, defined as > 90% field clearance. Five percent of patients exhibited recurrence of original disease, whereas 10% of patients developed a new actinic keratosis or NMSC. Cosmesis was rated as excellent or good in 98% of patients. Most patients exhibited grade 1-2 radiation-induced dermatitis during therapy, which resolved by 3-month follow-up. Grade 3 dermatitis at end of treatment was exhibited in 7% of the patients, which also resolved. Eight percent of patients discontinued treatment due to acute toxicities. The most common persistent toxicity at 12-month follow-up was localized grade 1 xerosis (dryness) at 43% and/or alopecia at 33%. Conclusions: Widefield VMAT achieved very promising clinical success in patients with ESFC for whom other therapies had failed. VMAT yielded favorable cosmetic outcomes, and treatment-related toxicity was manageable and transient in most patients. While additional follow up is necessary, these results demonstrate that widefield VMAT may be an excellent option for some patients with increasingly unmanageable presentations of ESFC.
The association between mediators of the receptor for advanced glycation end product (RAGE) axis and immune checkpoint inhibitor (ICI)–induced colitis in patients with melanoma.
Authors: Simons Morgan , Manigrasso Michaele , Li Xiaochun , Goldberg Judith , Osman Iman , Schmidt Ann Marie
Published: June 2022

9587

Background: Colitis and other gastrointestinal (GI) toxicity are a frequent and occasionally severe form of immune-related adverse events (irAEs) in patients treated with ICIs. To date, no definitive mechanism has been identified, and this area remains an active field of investigation. We hypothesized that activation of the RAGE axis, known to be implicated in inflammatory bowel disease through stimulation of signal transduction targeted by pro-inflammatory RAGE ligands, members of the S100 family and High Mobility Group Box 1 (HMGB1), might be associated with irAE- colitis. Methods: We examined sera from 111 advanced melanoma patients prospectively accrued and followed up at NYULH (treated with anti-PD-L1, n = 44; antiCTL4, n = 23; and combination, n = 44). 24 (22%) developed GI toxicity grade >2. Serum biomarkers of the ligand-RAGE pathways, soluble (s)RAGE, endogenous secretory (es)RAGE, S100B, and HMGB1, were measured in the patients’ sera during ICI treatment. Multivariable ordinal logistic regression analyses with all grades of GI toxicity as the primary outcome for all the recorded covariates (including serum biomarkers, clinical covariates) were performed. We then used ordinal multivariable logistic regression with stepwise variable selection. Similar analyses with GI toxicity as a binary outcome ((≥grade 1 vs no toxicity) were also conducted. Only those variables that jointly contributed to the odds of developing toxicity were included in the final stepwise model. No adjustments for multiplicity were included. As sRAGE and esRAGE are highly correlated (r = 0.86), esRAGE concentrations were not used in the joint models. Results: A significant association between GI toxicity and concentrations of sRAGE and S100B was identified. The final stepwise multivariable logistic model includes only sRAGE and S100B. The odds of having a one level increase in GI toxicity grade increase 1.100 times (95% CI: 1.008, 1.199; p = 0.029) for each unit decrease of sRAGE ( = sRAGE/100). The odds of a one level increase in GI toxicity increase 1.059 times (95% CI: 1.004, 1.116; p = 0.035) for each unit increase of S100B ( = s100B/100). All other analyses yielded comparable results. In contrast, concentrations of HMGB1 and other clinical covariates, including response and treatment category, were not associated with GI toxicity. Conclusions: Mediators of the RAGE axis, specifically sRAGE and S100B, might have a role in GI toxicity in patients receiving ICIs. The ligand-RAGE axis may be a novel target for irAE therapies for patients receiving ICIs to mitigate the severity of GI toxicity.
Breast cancer: Online education’s effect on clinician ability to assess risk of recurrence and understanding the latest data.
Authors: Patel Urvi , Dorkhom Nabil , Abair Tristin , Cameron Davecia Ragoonath , Cohen Jacob
Published: June 2022

e12509

Background: Hormone receptor positive breast cancer (HR+ BC) is often diagnosed in the early, curable, stage. Emerging treatment options make it important to educate clinicians on how to identify patients eligible for these options and increase their understanding of the clinical data associated with therapies in HR+/HER2- early breast cancer (EBC). The study objective was to assess the impact of 2 educational activities on HR+/HER2- EBC on oncologists’ knowledge, competence, and confidence related to risk of recurrence and clinical data. Methods: Two online continuing medical education activities were launched in 2021 covering a range of topics focused on identification of patients at high risk of recurrence and the latest clinical trial data for CDK4/6 inhibitors (CDK4/6i) in HR+/HER2- EBC. Educational impact was assessed using a repeated pair design, with knowledge/competence and confidence questions pre- and post-education. Confidence was assessed on a Likert-type scale ranging from not confident to very confident. Questions were designed to assess if certain learning objectives (LOs), covering identified educational gaps, were met. Data was collected from 06/14/2021 to 01/31/2022. Statistical significance was assessed using McNemar’s test ( P < .05 level). Results: 5,544 learners participated in these 2 activities, including 727 oncologists. The LOs were grouped in 3 themes that assessed oncologists’ knowledge/competence and confidence related to identifying patients with HR+/HER2- EBC at high risk of recurrence and understanding the clinical trial data investigating CDK4/6i in this setting. Two themes showed a significant improvement. The number of oncologist learners assessed per theme differed from 228 to 260. Conclusions: Participation in text- and video-based activities resulted in a significant improvement of oncologists’ knowledge, competence, and confidence related to CDK4/6i clinical data and treatment eligibility for patients with HR+/HER2- EBC. Baseline knowledge regarding the identification of high risk of recurrence in HR+/HER2-EBC was high (89% correct responses pre-education) in comparison that of clinical trial data and confidence in identification of patients eligible for adjuvant therapy (54% and 21% respectively). This finding could be reflective of clinicians having a high-level knowledge and competence related to risk stratification prior to the developments that occurred secondary to the approval of CDK4/6i in the adjuvant setting. With these new developments additional education around this topic will be required.[Table: see text]
Assessing association of heavy metal levels in urine and sera with neurotoxicity in breast cancer(BC) patients undergoing adjuvant/neoadjuvant chemotherapy.
Authors: Whitaker Kristen Danielle , Ross Eric A. , Klaunig James E. , Singh Tanu , Veggeberg Rosanna , Alpaugh Katherine , Goldstein Lori J.
Published: June 2022

e12510

Background: Standard adjuvant chemotherapy for early stage BC includes taxane therapy with paclitaxel or docetaxel. Taxanes are associated with peripheral neuropathy in some patients, which can impact appropriate dosing and quality of life. In this study, we investigated whether there is an association between the levels of heavy metals in serum or urine and the development of high-grade peripheral neuropathy, defined as grade ≥2 (utilizing CTCAE v.4.0) in a cohort of BC patients undergoing neo/adjuvant taxane chemotherapy. Methods: BC patients undergoing treatment with taxanes were identified in the clinic. Patient eligibility included: histologically confirmed invasive mammary carcinoma, Stage I-III BC, undergoing neo/adjuvant treatment with taxane chemotherapy. Patients previously treated with chemotherapy or who had pre-existing neuropathy were not eligible. Patients were consented and prior to study enrollment, study participants provided blood and urine samples to assess for heavy metals. Neurotoxicity was measured using the NCI CTCAE v.4 criteria throughout patient’s taxane treatment. Serum and urine samples collected at baseline were analyzed for heavy metals by inductively coupled plasma mass spectrometry (ICP-MS). Results: 115 female patients were enrolled. 111 patients were included in the analysis; 4 patients were excluded due to withdrawal from study prior to receiving any taxane treatment. Participants were 78% White (6% of Hispanic origin), 19% Black and 3% Asian with an average age of 51 years (range 26-72). ICP-MS was used for the analysis of Aluminum (Al), Manganese (Mn), Cobalt (Cu), Zinc (Zn), Arsenic (As), Cadmium (Cd), Mercury (Hg), Thallium (Tl), and Lead (Pb) levels in patients’ serum and urine. Patients with neurotoxicity grade >=2 had significantly lower serum Arsenic levels (mean=0.37 [SD=1.08], n=89] than subjects with toxicity grades 0-1 [mean=1.21 (SD=2.33), n=22] (p=0.037; Wilcoxon test). Other than Arsenic no relationship of the other heavy metals and neurotoxicity was found in the serum. We did not observe significant associations between heavy metal levels in urine and neurotoxicity grade. Conclusions: Taxane treatment is an effective BC therapy but its utility is limited by its associated toxicity of peripheral neuropathy. The source of the higher arsenic levels is unclear. We conclude that there is no evidence that high levels of heavy metals were associated with taxane induced neurotoxicity in our study.
Physicians’ acceptance of extended or intermittent adjuvant endocrine therapy (AET): A survey on breast cancer (BC) physicians.
Authors: Chow Louis Wing-Cheong ,   Asian Institute of Clinical Oncology (AICO) Expert Panel
Published: June 2022

e12515

Background: The results from the GIM4, SALSA, and SOLE trials are potentially practice-changing, but it was unknown whether physicians would accept these trial results and adjust their AET prescriptions for postmenopausal women with BC. Methods: A cross-sectional survey involving 77 BC physicians in China was conducted. The survey questions were developed based on the GIM4, SALSA, and SOLE trial results, as well as referred to the latest NCCN guidelines. Statistical analyses were performed using SPSS version 28.0. Results: Almost half (48%) of the respondents were breast surgeons, 19% were breast specialists, 8% were medical oncologists, and 2% were general surgeons. Forty-five percent of the respondents had a clinical experience of ≥15 years, and the mean ± SD number of BC patients managed annually was 762.10 ± 1,254.50. For pN0, tumor size ≤0.5cm, postmenopausal patients, respondents with ≥15 years of clinical experience were more likely to prescribe a longer duration of AET as compared to those with <15 of clinical experience (p=0.025 and p=0.038 for patients receiving prior 4-5 years of tamoxifen [TAM] and prior 5 years of aromatase inhibitor [AI], respectively). More than half (57.1%) did not agree with the hypothesis that AI resistance can be reversed by intermittent letrozole treatment (the SOLE trial hypothesis), but 50.6% considered intermittent letrozole as an acceptable option, especially for patients with ≤3 positive nodes (79.5%), tumor grade 1 (84.6%), tumor size ≤2cm (82.1%), HER2 negative disease (74.4%). Conclusions: A high proportion of the BC physician respondents would prescribe extended AET with AI beyond 5 years for postmenopausal women with BC, especially for those with higher risk. Intermittent letrozole was considered as an acceptable option for low-risk patients.[Table: see text]
Automated H&E image-based detection and prognostic evaluation of HER2 heterogeneity in ER+ breast cancers.
Authors: Mukhopadhyay Satabhisa , Dasgupta Tathagata , Berwick Angelene , Walsh Elizabeth , Cummings Michele , Orsi Nicolas M.
Published: June 2022

e12517

Background: HER2 amplification or overexpression is negative prognostic factor that occurs in circa 15% of primary invasive breast cancers, with positive results opening up eligibility for HER2 targeted (e.g. trastuzumab) combination therapy. However, HER2 intratumoral heterogeneity has been proposed as an explanation for the development of resistance to anti-HER2 targeted therapy. The aim of this retrospective study was to test the prognostic value of a HER2 heterogeneity index on ER+ breast cancer H&E whole slide images (WSIs). Methods: ER+ breast cancers slides ( n=60 cases) of known HER2 status (immunohistochemically assessed over the 0 to 3+ range, with HER2 2+ borderline cases validated by fluorescence in situ hybridization) were digitized on an Aperio AT3 scanner. A subset of these patients ( n=29) was accounted for by HER2 amplified/borderline cases. A HER2 heterogeneity index was tested and compared to standard clinical HER2 status in these cases and related to progression free survival (PFS). Survival analyses were performed using Kaplan-Meier (KM; with median cut-off) and Cox Proportional Hazards (as a continuous variable) models. Results: The HER2 heterogeneity index performed better in terms of prognostication than clinical HER2 status alone in relation to PFS (KM P=0.019; HR 8.06, P=0.01 vs. KM P=0.02; HR 6.75, P=0.048). These differences were more pronounced in the HER2 amplified/borderline tumor subset, where the HER2 heterogeneity index outperformed clinical HER2 status (KM P=0.04; HR 6.38, P=0.001 vs. KM P=0.10; HR 0.64, P=0.20). Conclusions: These findings highlight the merit of identifying HER2 heterogeneity from H&E slides alone and establish this index as a robust prognostic factor in determining PFS in ER+ breast tumors. Future work will extend this investigation into ER- tumors and evaluate patient-specific tumor responses to anti-HER2 targeted therapy.
Analysis of prognostic factors and survival outcomes for patients with T1N0 HER2-positive infiltrating ductal carcinoma of the breast: A real-world study with long-term follow-up.
Authors: Gao Song-lin , Wang Ding-yuan , Wang Xi , Xu Binghe , Yuan Peng , Zhang Bo
Published: June 2022

e12530

Background: The optimal adjuvant systemic treatment and prognostic factors for patients with T1N0 HER2-positive infiltrating ductal carcinoma (IDC) of the breast are still unclear. We conducted a real-world study in China to identify potential prognostic factors in this low-risk population, and to characterize survival outcomes of patients treated with different adjuvant strategies. Methods: We included patients with T1N0 HER2-positive IDC of the breast who were treated at the Cancer Hospital, Chinese Academy of Medical Sciences from April 2010 to April 2017. We performed Cox multivariate analysis to identify potential prognostic factors for invasive disease-free survival (IDFS). We also compared survival outcomes of 1) patients treated with adjuvant chemotherapy alone, or chemotherapy plus trastuzumab (Chemo+T), or observation only; 2) patients receiving adjuvant anthracycline (AC)-based and non-AC regimens, both combined with trastuzumab. Inverse probability of treatment weighting (IPTW) propensity score was used to reduce the selection bias. Results: Overall, 692 consecutive patients with pT1N0 HER2-positive IDC of the breast were included. The median follow-up was 78.0 months. Cox multivariate analysis demonstrated that age≤40 (HR = 2.62, 95%CI 1.39-4.92, P = 0.003) and T1c (HR = 2.35, 95%CI 1.17-4.74, P = 0.017) were associated with inferior IDFS, whereas ER+PR+ (HR = 0.44, 95%CI 0.26-0.77, P = 0.004) and adjuvant trastuzumab (HR = 0.21, 95%CI 0.12-0.35, P< 0.001) were associated with favorable IDFS. For adjuvant treatment, 104, 195, and 373 patients were identified for observation, chemotherapy alone, and Chemo+T, respectively. The IPTW-adjusted Kaplan-Meier analysis demonstrated that compared with observation and chemotherapy alone, the IDFS was significantly longer in the Chemo+T group ( P = 0.034 and < 0.001, respectively). Meanwhile, compared with observation, chemotherapy alone did not significantly prolong IDFS ( P = 0.424). For the comparison of AC-based vs. non-AC regimens, 141 patients were identified in the AC-based group and 227 in the non-AC group. The Kaplan-Meier analysis indicated that patients in both groups had similar IDFS ( P = 0.242). Conclusions: For patients with T1N0 HER2-positive IDC of breast, age≤40, T1c, ER+PR+, adjuvant trastuzumab are independent prognostic factors. We recommend adjuvant chemotherapy plus trastuzumab, especially for patients with T1c tumors. When used in combination with trastuzumab, non-AC regimens may have similar efficacy with AC-based regimens.
Low-dose tamoxifen for breast cancer prevention in patients with ductal carcinoma in situ (DCIS) and atypical lesions: A real-world experience.
Authors: Patel Rima , Jin Cao , Tiersten Amy
Published: June 2022

e12537

Background: Patients diagnosed with non-invasive breast lesions such as DCIS and lobular carcinoma in situ (LCIS) and atypical breast lesions such as atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH) are at increased risk of developing invasive breast cancer (BC). Tamoxifen 20mg daily for 5 years has shown to be effective for BC prevention in these at-risk patients but its use can be limited by its adverse effects. The recent Tam01 study found that low dose tamoxifen (5mg daily for 3 years) in patients with DCIS, ALH, and ADH resulted in an approximate 50% risk reduction in BC events compared to placebo with a slight increase in hot flashes but no increases in uterine cancer or venous thromboembolism within the tamoxifen group (PMID: 30973790). The objective of this study was to evaluate the use of low dose tamoxifen at our institution and determine how many patients preferred this option. Methods: We performed a retrospective chart review of women who were diagnosed with DCIS, LCIS, ADH, and/or ALH at our institution from January 2019 to December 2021 and subsequently started adjuvant tamoxifen. Patients with history of invasive BC were excluded. Patients were categorized as being on standard dose (20mg daily) or low dose (5mg daily or 10mg every other day) tamoxifen. Fisher’s exact test was used to compare rates of standard and low dose tamoxifen use in the entire cohort as well as in pathology-based subgroups. Results: We included 130 women diagnosed with DCIS, LCIS, ADH and/or ALH and who started adjuvant tamoxifen. The median age at diagnosis was 50 years and 68% were premenopausal. Overall, 62% (n = 80) of women started standard dose tamoxifen and 38% (n = 50) low dose tamoxifen. Among 63 patients who were offered both standard and low dose options, 76% (n = 48) initiated low dose tamoxifen (p < 0.0001). Twenty women were noted to be hesitant to start standard dose tamoxifen due to concern for side effects or preexisting menopausal symptoms but were agreeable to the low dose option. Of the 86 patients with DCIS, a preference for standard dose tamoxifen was observed (74% vs 26%, p = 0.0016). Among 44 patients with LCIS, ADH, and/or ALH, more patients were on low dose tamoxifen (64% vs 36%, p = 0.282). Nine percent (n = 7) of patients on standard dose tamoxifen switched to low dose due to adverse effects including hot flashes, mood changes, and insomnia. Conclusions: At our institution, in patients offered both low dose and standard dose tamoxifen, more than 75% started low dose tamoxifen. The low dose option was more frequently used for atypical lesions such as ADH, ALH and LCIS. In women at higher risk of invasive BC who may be reluctant to start standard dose tamoxifen or intolerant of it, low dose tamoxifen should be considered and offered.
The case for simul-omics: Identifying IO biomarkers of ganitumab-metformin pathological complete response (pCR).
Authors: Pfeiffer John R. , Zhang Yuhan , Antony Anu K. , Team The SimBioSys , Cole John A.
Published: June 2022

e12551

Background: During the I-SPY2 clinical trial, ganitumab (G) immunotherapy (IO) was co-administered with metformin (GM) to counteract G-induced hyperglycemia. The GM + standard of care (SOC) combination showed promising results but did not meet the statistical threshold for phase III. Predicting individual patient response to IO is a key limitation for clinical use and a reason why IO phase II to III oncology trial transitions fail. Thus, we used SimBioSys TumorScope (TS), a 4D spatiotemporal multiscale biophysical model, to identify predictive IO biomarkers of pCR in response to GM+SOC. Methods: Patients that received GM+SOC therapy (n=41) and SOC (n=41) matched controls from the I-SPY2 trial were included in analyses. Using SOC clinical data and DCE MRIs, we generated biophysical simulations of each individual patient’s response to SOC therapy. Derived from the TS simulation object of each patient, our “simul-omics” data represent tumor morphology, breast tissue proportions, drug response and delivery, and microvasculature-related feature sets. We also had access to the pre-treatment tumor biopsy-derived transcriptome microarray data. Predictive modeling was performed in a modular 3-step fashion: 1. clinical-only data to predict pCR, 2. clinical data plus candidate simul-omics data to predict pCR, and 3. available feature space for features that interact with treatment to provide the strongest predictive model of pCR. Results: The SOC data model (HR status, grade, treatment, age, race) predicted pCR with an accuracy (acc) of 0.67, sensitivity (sens)=0.71, specificity (spec)=0.66, and Cohen’s kappa=0.27. Simul-omic features median tumoral Kt at sim week 1 (acc=0.73), and tumoral pre-contrast small area emphasis (acc=0.77) improved model performance over SOC. When included in the same model, they increased predictive acc of the model to 0.79 (sens=0.64, spec=0.82, kappa=0.41). Simulation-derived features improved predictive power beyond SOC data. Exploratory search of the feature-space identified simul-omic features that would generate the most predictive models with a significant treatment interaction effect. Two simul-omics features added predictive strength to the model, with near-nominal interaction effects: phi_quant_90_regimen_wk22 (late timepoint mv density) (acc=0.84, kappa=0.58), and slopemap_tumor_glcm_clustershade (acc=0.86, kappa=0.60). We tested transcript expression as interaction terms in the model. The best performing model with an interaction effect was SHISA4 (acc=0.88, sens=0.86, spec=0.88, kappa=0.67). Conclusions: Our results show value in: 1. predicting pCR, the additive value of TS simulation data over just clinical/SOC data, 2. identification of potentially mechanistic drug targets facilitating GM response, and 3. potential to stratify patient populations into responder vs. non-responder categories prior to treatment.
The use of sentinel lymph node biopsy in patients undergoing mastectomy for DCIS.
Authors: Johnson Morgan K. , Cortina Chandler Scott , Aldakkak Mohammed , Kong Amanda L.
Published: June 2022

e12572

Background: Current NCCN guidelines do not recommend sentinel node biopsy (SLNB) for the treatment of DCIS, except in the setting of a mastectomy. The extent of utilization of SLNB in patients undergoing mastectomy for DCIS and which factors are associated with a higher likelihood of SLNB use is unknown. The objective of this study is to evaluate the use of SLNB in patients undergoing mastectomy for DCIS and determine predictors of SLNB utilization. Methods: A retrospective cohort analysis was performed using the NCDB. Women diagnosed with DCIS who underwent a unilateral or bilateral mastectomy from 2012-2017 were included. Patient, tumor, and treatment variables were compared between patients who received a SLNB and those who did not. A multivariate logistic regression model was then used to identify factors predictive of SLNB utilization. Results: A total of 29,962 patients met inclusion criteria. Of these, 25,734 (85.9%) underwent SLNB and 4,228 (14.1%) had no surgical axillary staging. Most patients were age 50-69 (52.0%), non-Hispanic white (71.7%), and had private insurance (65.9%). In those who underwent SLNB, only 10 (<0.01%) were found to have nodal involvement. On multivariate analysis, older patients were less likely to receive SLNB ( p<0.05), while those with grade 2 and 3 DCIS were more likely to undergo SLNB (OR 1.4 and 2.2, respectively, p<0.001) (Table). Patients who were treated from 2014-2017 were also more likely to undergo SLNB (OR 1.2, p<0.01) as were patients treated in the Atlantic and West Central United States ( p<0.05). Treatment at a comprehensive community program, academic/research program, or integrated network program were also more likely to undergo SLNB (OR 1.5, 2.1, 2.3 respectively, p<0.001) compared to community programs. Conclusions: Patterns of SLNB utilization in DCIS varied in clinical practice. Given the low rate of nodal involvement in DCIS patients (<0.01%), and with a 5-10% rate of upper extremity lymphedema after SLNB alone, it may be reasonable to omit SLNB in the setting of a mastectomy for DCIS.[Table: see text]
A nomogram to predict pathological complete response of neoadjuvant systemic therapy in HER2-positive breast cancer based on clinicopathologic characteristics and pretreatment systemic inflammation response index: A dual-center study.
Authors: Wu Hong-Yu , Yang Jie-Ru , Hung Chih-Chiang , Yin Chun-Hao , Tzeng Yen-Dun Tony
Published: June 2022

e12590

Background: Patients with human epidermal growth factor receptor 2 (HER2) positive breast cancer (BC) who achieve a pathologic complete response (pCR) after neoadjuvant systemic therapy (NST) have favorable prognoses. Multiple pretreatment systemic inflammatory markers (SIMs), based on peripheral blood cell counts, have been reported as predictors of pCR in BC patients. The markers include neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, lymphocyte-monocyte ratio, and systemic inflammation response index (SIRI= neutrophil × monocyte / lymphocyte count), etc. However, the most significant SIM remains controversial among studies and the variations among different molecular subtypes remain unknown. Methods: We retrospectively reviewed 233 patients with stage I–III HER2-positive BC who received NST and subsequently underwent surgery in Kaohsiung and Taichung Veterans General Hospital from 2011 to 2021. Data on multiple pretreatment SIMs were collected. The most significant SIM were analyzed for predictive significance with other clinicopathologic factors by using stepwise logistic regression with forward selection. The data was conducted to illustrate a nomogram plot for determining pCR probability. Results: Among the pretreatment SIMs, only SIRI was significantly related to pCR by optimal cut-off value of 1.7 ×109/L. Stepwise logistic analyses indicated that the clinical T and N stage, HER2 immunohistochemistry (IHC) score, PR expression, and targeted therapy regimen were independent predictors of pCR, with an area under the curve (AUC) of 0.74. Sub-analysis was performed after stratifying into T stage subgroups (T1-2 vs. T3-4). Significant predictors In the T1-2 subgroup were clinical N stage, HER2 IHC score, PR, and targeted therapy regimen (AUC=0.722). Significant predictors in the T3-4 subgroup were SIRI and ER (AUC=0.824). The Hosmer–Lemeshow test revealed the predictive ability was a good fit to actual observation. A T-stage-stratified nomogram based on the logistic model was built. Conclusions: In HER2 positive BC patients receiving NST, low pretreatment SIRI is predictive of pCR in T3-4 subgroup. Our nomogram served as an efficient tool to predict pCR and to assist clinical decision support before neoadjuvant treatment.
Impact of capecitabine maintenance on survival outcomes in triple-negative breast cancer patients not attaining pathological complete response following neoadjuvant chemotherapy: Real-world data from a tertiary care center from India.
Authors: Sharma Rakesh Kumar , Gogia Ajay , Sagiraju Hari Krishna Raju , Deo S V Suryanarayana , Sharma Dayanand , Mathur Sandeep
Published: June 2022

e12593

Background: Capecitabine maintenance has demonstrated a survival benefit in triple-negative breast cancer (TNBC) patients not achieving pathological complete response (pCR) following neo-adjuvant chemotherapy (NACT). However, there is scarcity of data from Indian sub-continent corroborating the benefit of capecitabine maintenance. Methods: This retrospective study comprised of 161 TNBC patients registered at our institute between a period of May 2013 to Dec 2020, who received NACT (sequential anthracycline and taxane) but did not achieve pCR. Capecitabine was added to the institutional protocol since 2017 for maintenance therapy of TNBC patients who didn’t achieve pCR post NACT. Using Kaplan-Meir survival analysis and multivariate cox-proportional hazard models, we analysed differences in the relapse-free survival (RFS) and overall survival (OS) among those who received capecitabine maintenance therapy (n=80) versus those who did not receive it (n=81). Results: Distribution of age, family history, baseline performance score, tumor size, node positivity and clinical stage at time of presentation were comparable between the study groups, except for menopausal status (50% in control vs 33% in capecitabine group). Median(IQR) follow up time was 22.2 (16.2-27.4) months in capecitabine groups vs 19.3 (11.7-35.1) in control group. Twenty-three (28.8%) women in the capecitabine group had a disease-relapse while 45.7% (n=37) had relapsed in control group (p=0.026). Median RFS was 20.4 (17.8-25.9) months in control group while it was not reached in capecitabine group (log rank p=0.007). Adjusted for other baseline clinical characteristics, hazard of disease-relapse was significantly lower in the capecitabine group compared to controls [adjusted Hazard Ratio (aHR), 95% CI: 0.57 (0.34-0.96), p=0.035]. Median OS was not achieved in both the study groups, however, the hazard of death was lower in capecitabine group compared to control [aHR(95%CI): 0.44 (0.20-1.01), p-0.053]. Stratified by menopausal status, effect of capecitabine maintenance on disease relapse and RFS was only significant among the post-menopausal women [aHR (95%CI): 0.24 (0.10-0.59)]. Conclusions: This is the first study from our country, demonstrating a survival benefit with capecitabine maintenance in patients with TNBC not achieving pCR following NACT, particularly in post-menopausal women. It is an important observation as most of our patients present with locally advanced disease where pCR rate is low.
Outcomes of neoadjuvant combination chemotherapy with and without targeted therapy in HER2-positive breast cancer: A real-world experience from tertiary care center in North India.
Authors: Gupta Anshul , Gogia Ajay , Sagiraju Hari Krishna Raju , Deo S.V.S. , Sharma Dayanand , Mathur Sandeep , Gupta Ritu
Published: June 2022

e12601

Background: Neoadjuvant chemotherapy (NACT) with HER2 blockade is preferred approach for treatment of early and locally advanced HER2 positive breast cancer. However, there is a lack of survival data with respect to pathological complete response (pCR) from India. Methods: We retrospectively evaluated 211 HER2 positive female breast cancer patients registered between years 2014 and 2021, who received three different NACT regimens (i) Anthracycline free TCH (n=116) [docetaxel (75mg/m2), carboplatin (AUC = 6) and trastuzumab (8mg/kg loading followed by 6mg/kg) with G-CSF q 21 days], (ii) EC-TH (n=52) [epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) for 4 cycles followed by 4 cycles of docetaxel (85mg/m2)] and (iii) EC-T (n=43, without trastuzumab due to financial constraints). Primary end point was pCR. Secondary end points were disease free survival (DFS), Overall Survival (OS) and safety profile. Results: Median age was 45 years (24-71), 88 (41.7%) were postmenopausal and 104 (49.3%) were ER/PR positive. Twenty-two (10.4%) patients were stage II, 164 (77.7.%) were stage III and 25 (11.9%) were oligometastatic stage IV. Distribution of age, performance status, tumor size and nodal positivity were comparable across the study groups. Pathological CR in trastuzumab containing groups, was higher compared to non-trastuzumab containing group (35.8% vs 20%, p=0.045) and was similar between, TCH and EC-TH groups. Median follow-up was 32.9 months (5.7-108), 3-year DFS and OS were 54.8% and 92.1% respectively. Pathological CR rates and survival outcomes of the three groups are given in table 1. When stratified by pCR status, in the trastuzumab containing groups, achievement of pCR translated to improved DFS (log rank p=0.01). This survival advantage of pCR was not seen in non-trastuzumab containing group. The outcome of trastuzumab containing both regimens were similar. Grade 3/4 toxicities were recorded in 21.6% of TCH, 26.7% of EC-TH and in 25.2% of EC-T groups. Most common toxicities were anemia (16.3%), thrombocytopenia (14.2%) and vomiting (10.2%). Conclusions: Trastuzumab containing regimens impact pCR rates and in turn the survival outcomes among Indian women with HER2 positive breast cancer. Safety and efficacy of anthracycline free TCH regimen is comparable with EC-TH.[Table: see text]
Comprehensive profiling of cancer associated cells in the blood of breast cancer patients to predict pathological complete response.
Authors: Pore Adity A. , Dhanasekara Chathurika S. , Navaid Hunaiz Bin , Vanapalli Siva A. , Layeequr Rahman Rakhshanda
Published: June 2022

e12603

Background: Goal of neoadjuvant chemotherapy (NAC) has expanded from increasing the rate of breast conservation to in vivo assessment of response for use of second line therapies that increase survival. Pathological complete response (pCR) is a desirable goal of NAC; however, prediction of pCR for individualized therapeutic decisions remains a vexing problem. Cancer associated cells in the blood provide a promising venue to research response to therapy. Circulating tumor cells (CTCs) are of epithelial origin [CTCs (E+)] that undergo epithelial to mesenchymal transition [CTCs (E+M+)] to become motile and invasive; leading to fully invasive mesenchymal [CTCs (M+)] cells that seed in distant organs, causing metastasis. In addition, cancer associated macrophage-like cells (CAMLs) in the blood of cancer patients are reported to either engulf or aid the transport of cancer cells to distant organs. A comprehensive evaluation of these cancer associated circulating cells through liquid biopsy has a potential to provide a much needed biomarker to predict pCR. Methods: Patients treated with NAC with an intention to cure were enrolled in the study. Blood was collected at 3 time points: pre, mid and post NAC. Microfluidics-based label-free Labyrinth technology was used to isolate CTCs and CAMLs from the blood. Data was collected for patient demographics, biological tumor markers, and treatment response from medical records including pathology reports. Residual Cancer Burden Index (RCBI) and class (pCR vs. residual disease) were analyzed as dependent variables. Independent variables included CTCs, CAMLs and tumor receptor status for univariate and multivariate models to assess the combined effects using R. Results: A total of 57 samples from 19 patients were analyzed. Univariate regression models predicting RCBI or pCR using CTCs and CAML did not show any significant associations. However, in multivariate regression analysis predicting RCBI, an increase in post-NAC CAML and a decrease in post-NAC CTCs were associated with a decrease in RCBI (p=0.005, p=0.035, respectively). In a multivariate logistic regression model predicting pCR, CAML was positively associated with the log-odds of pCR (OR=1.60 [1.01, 2.54]; p=0.047), while CTCs showed a trend in negatively predicting pCR (OR=0.33 [0.10, 1.06]; p=0.063). When controlled for each other, increased CAML and decreased CTCs were associated with increased pCR. While increased M+ was associated with the decreasing log-odds of pCR (OR=0.27 [0.08, 0.99]; p=0.049), neither E+ nor E+M+ was associated with pCR. Conclusions: Increased CAMLs in circulation after treatment combined with lowered CTCs are associated with pCR and lower RCBI. M+ cells could be a factor governing association between CTCs and pCR.
Impact of race on treatment outcomes in triple-negative breast cancer at an academic medical center.
Authors: Patterson Jasmine , Meisel Jane Lowe , Yi Sha , Liu Yuan , Cao Yichun , Li Xiaoxian
Published: June 2022

e12616

Background: Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and in all but the smallest tumors, neoadjuvant chemotherapy (NACT) is part of the standard of care. Black women (BW) suffer a poorer prognosis than white women (WW) with TNBC, and whether this is due to differences in treatment, disease biology, or socioeconomic variables is not fully known. This study, conducted at a racially diverse academic medical center, aimed to investigate factors associated with unfavorable outcomes in BW with TNBC. Methods: 131 patients with TNBC received NACT from 2008-2017 at Winship Cancer Institute were included in this retrospective study. Descriptive statistics were applied to delineate the relationship with racial disparity. Clinical outcomes include progression free survival (PFS) and distance metastasis free survival (DMFS) and were analysis using Cox proportional hazard model. Results: Among 131 patients with TNBC treated with NACT, 58.5% were BW and median age was 55. BW and WW had similar disease staging at diagnosis and similar pathologic responses to treatment. Yet, BW were less likely to complete NACT compared with WW (80.8% BW completed NACT vs 98.0% WW, p=0.005). BW were more likely to either not complete NACT or to require dose reduction or dose delay (42.5% BW vs. 23.1% WW, p=0.024). Coexisting hypertension (65.8% BW vs. 35.2% WW), elevated BMI (31.7% BW vs. 27.5% WW), or covered by Medicaid (29.3% BW vs. 13.0% WW) were more common among BW. Medicaid insurance was associated with worse progression-free survival (HR 2.49, p=0.015) and distant metastasis free survival (DMFS, HR 2.73, p=0.018). Dose delays were associated with worse DMFS (HR 3.02, p=0.017). Discussion: In this study, we found that BW were less likely to complete NACT than WW, more likely to suffer dose delays, and more likely to require dose reductions. BW were also more likely to have Medicaid insurance, another factor that correlated with inferior outcomes; perhaps because patients with Medicaid insurance are also more likely to suffer from reduced access to transportation, childcare, and other infrastructure critical to maintaining a schedule for NACT. More research is needed to understand the reasons for the dose delays, dose reductions, and failures to complete NACT so that interventions can be designed to address them. Conclusions: As we move into the era of chemoimmunotherapy for TNBC, where drug combinations and treatment schedules are becoming even more complex, a better understanding of the reasons for dose delays, dose reductions, and treatment discontinuations will be key to maintaining optimal outcomes for TNBC patients, regardless of race.
Real-world data on outcomes using taxane, trastuzumab, and pertuzumab (THP) in patients with early stage HER2+ breast cancer.
Authors: Sharma Harsh , Kreutzfeldt Jordyn , Mehta Tej , Farr Kiah , Brown-Glaberman Ursa , Chalasani Pavani , Nemunaitis Jacklyn , Segar Jennifer Margaret
Published: June 2022

e12630

Background: In HER2+ early breast cancer, dual HER2 targeted combination of trastuzumab and pertuzumab with chemotherapy achieved higher rates of pathologic complete response (pCR) and improved long term outcomes. However, the optimal chemotherapy backbone is still under investigation. While neoadjuvant taxane in combination with trastuzumab and pertuzumab (THP) has been investigated in NEOSPHERE, patients received anthracycline-based regimen in the adjuvant setting. We report real-world data on long-term patient outcomes after neoadjuvant THP. Methods: An IRB-approved retrospective chart review at 2 academic centers was conducted using EMR to identify women with stage I-III HER2+ breast cancer who exclusively received neoadjuvant THP between 2013-2020. Clinicopathological characteristics and follow up information were extracted from surgical pathology and medical records. Results: 71 patients met criteria (median, 55 years). At presentation, 56 (79%) patients had stage II - III disease and 45 (63%) were lymph node negative. The majority of tumors were ER+ (43 patients, 61%) and received paclitaxel (46 patients, 65%) as their taxane backbone. pCR was achieved in 40 (56%) patients (Table); 38 (95%) continued with adjuvant HER2 therapy alone; 1 received adjuvant endocrine therapy only and 1 received no further treatment. Of the 31 (44%) patients without pCR, 9 received additional adjuvant chemotherapy in addition to HER2 directed therapy while 18 continued with HER2 therapy alone. During the follow-up period (median 34.7 mo, range 6.8-98.9 mo), 3 patients with lymph node positive disease on presentation had disease relapse. Two of the patients with pCR had local recurrence and one without pCR had distant metastasis (brain, lung). The 2 patients with local recurrence were successfully treated with salvage therapy and remain in remission. The patient with metastatic disease remains alive and on treatment. Conclusions: We showed that a real world HER2+ patient population treated with neoadjuvant THP achieved pCR rates consistent with what has been previously reported. In addition, with a median follow up of ̃ 3 years, only 3 patients had relapse supporting the utility of THP as potential de-escalation treatment in the neoadjuvant setting. Ongoing prospective trials, like NCT03716180, will further confirm the efficacy of this regimen in a prospective setting.[Table: see text]
Importance of accurate clinical staging in patients with early stage HER2+ and triple negative breast cancer.
Authors: Sidda Adarsh , Biglow Layana Roslyn , Manu Gurusidda , Abdallah Mahmoud , Tirona Maria R.B. Tria
Published: June 2022

e12631

Background: Comprehensive radiological evaluation in early-stage breast cancer is essential for accurate staging and subsequent therapeutic decisions. This is especially important in early-stage human epidermal receptor -2 (HER2) positive and triple negative breast cancer (TNBC). For these tumors, current guidelines suggest a neoadjuvant approach for ≥cT2 disease. Standard diagnostic modalities have oftentimes failed to confirm the correct size of these tumors. Misrepresentation of their true size may lead to patients being treated with upfront surgery and potentially missing the added benefits of residual treatment if they were later found to have >T2 disease. Methods: We conducted a retrospective analysis via electronic medical record review of a large institutional database from 2008 to 2020. We reviewed all patients with a diagnosis of early-stage breast cancer (Stage I - III) with triple negative or HER2 positive tumors. Patients who received neoadjuvant chemotherapy were excluded. Data on demographics, comorbidities, receptor status, clinical staging, pathological staging, and mortality were collected. Results: Electronic charts from 448 patients were reviewed. 153 patients had ≤cT1 disease. 33 (21.6%) of the 153 patients were upstaged from cT1 to ≥pT2 tumors. Combined imaging modality with mammogram + ultrasound (US) yielded a statistically significant accuracy in clinical staging compared to US alone (82.6 vs. 44.4%; p = 0.02). Comparisons between other imaging methods were not statistically significant (mammogram + US vs. mammogram only, 74.1 vs. 82.6%, p = 0.41 and mammogram only vs. US only, 74.1 vs. 44.4%, p = 0.13). Magnetic Resonance Imaging (MRI) was only utilized on 2 patients with 50% accuracy. Conclusions: Significant discordance (> 20%) exists between radiological staging and pathological staging of T1 TNBC and HER2 positive breast cancers at our institution. This data has considerable therapeutic implications as landmark studies such as the CREATE-X and KATHERINE trials have provided better survival data with the use of drugs such as capecitabine and trastuzumab emtansine (T-DM1), respectively, in patients with residual disease who have undergone neoadjuvant chemotherapy followed by surgery. Combined imaging with mammography and US yielded the most accurate staging. MRI was utilized on only two patients. MRI has shown to be helpful in evaluation of patients for preoperative systemic therapy, defining the extent of disease, assessing response to treatment and the potential for breast conserving surgery. Several studies have also demonstrated the accuracy of MRI for staging breast cancer. Given the significant discordance seen at our institution, one possible solution may be to employ MRI for staging on patients with inherently aggressive early-stage tumors such as TNBC and HER2+ breast cancers. Further prospective studies are required to validate our findings.