bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of checkpoint inhibitor toxicity and survival in patients with advanced melanoma.
Authors: van Not Olivier Jules , Verheijden Rik Jasper , van den Eertwegh Alfonsus Johannes Maria , Haanen John B. A. G. , Blank Christian U. , Aarts Maureen J.B. , Van Den Berkmortel Franchette , de Groot Jan Willem , Hospers Geke , Kapiteijn Ellen , de Meza Melissa Melanie , Piersma Djura , Van Rijn Rozemarijn , Stevense - den Boer Marion , Van Der Veldt Astrid Aplonia Maria , Vreugdenhil Gerard , Boers-Sonderen Marye J. , Blokx Willeke , Wouters Michel W.J.M. , Suijkerbuijk Karijn
Published: June 2022

9546

Background: Management of checkpoint-inhibitor-induced immune-related adverse events (irAEs) is primarily based on expert opinion. Recent studies have suggested detrimental effects of immunosuppressive treatment with anti-TNF on checkpoint-inhibitor efficacy. Methods: Advanced melanoma patients experiencing grade ≥3 irAEs after treatment with first-line ipilimumab-nivolumab between 2015 and 2021 were included from the Dutch Melanoma Treatment Registry. Progression-free survival (PFS), overall survival (OS) and melanoma-specific survival (MSS) were analyzed according to toxicity management regimen. A cox proportional hazards model was used to account for the confounders age, sex, performance status, lactate dehydrogenase, site of metastases and type of irAE. Results: Out of 771 ipilimumab-nivolumab treated patients, 350 were treated with immunosuppression for severe irAEs. Of these patients, 235 received steroids only and 115 received steroids with second-line immunosuppressants consisting of anti-TNF, mycophenolic acid, tacrolimus and other immunosuppressants. Median PFS was significantly longer for patients treated with steroids (11.3 months) than for patients treated with steroids and second-line immunosuppressants (5.4 months; HR 1.43; 95%CI 1.07-1.90; p = 0.01). Median OS was also significantly longer for the steroids group (46.1 months) than for the steroids and second-line immunosuppressants group (22.5 months; HR 1.64; 95%CI 1.16-2.32; p = 0.005). Results for MSS were similar (not reached versus 28.8 months; HR 1.70; 95%CI 1.16-2.49; p = 0.006). Median PFS, OS and MSS are shown in Table 1. After adjustment for potential confounders, patients treated with steroids + second-line immunosuppressants showed a non-significant trend towards a higher risk of progression (HRadj 1.40; 95%CI 1.00-1.97; p = 0.05), a higher risk of death (HRadj 1.54; 95%CI 1.03-2.30; p = 0.04) and of melanoma-specific death (HRadj 1.62; 95%CI 1.04-2.51; p = 0.032) compared to the steroids group. Conclusions: Second-line immunosuppression for irAEs is associated with impaired PFS, OS, and MSS in advanced melanoma patients treated with first-line ipilimumab-nivolumab, irrespective of being anti-TNF or other second-line immunosuppressants. These findings stress the importance of assessing the effects of differential irAE management strategies, not only in melanoma but also in other tumor types. [Table: see text]
Prophylactic lymphaticovenous bypass performed during complete lymphadenectomy is oncologically safe.
Authors: Cakmakoglu Cagri , Gastman Brian , Xia Thomas , Kwiecien Gregorz
Published: June 2022

9557

Background: Lymphaticovenous anastomosis (LVA) is a physiologic surgery indicated for secondary lymphedema of the extremities, particularly for disease refractory to conservative management. Immediate lymphatic reconstruction (ILR) is prophylactic LVA concurrently performed with CLND. After the transected lymphatics are mapped through a dye injection, they are anastomosed to a nearby venous outflow tract. Though prophylactic LVA is increasingly being performed, its risk on cancer recurrence and distant metastasis is currently unknown. The purpose of this study was to compare the distant-metastasis free survival (DMFS) and relapse-free survival (RFS) times in melanoma patients who underwent prophylactic LVA during CLND versus those who underwent conventional CLND for grossly metastatic disease. Our study is the first prospective evaluation of the impact of prophylactic LVA on DMFS in patients undergoing CLND. Methods: This was a prospective study of patients with cutaneous melanoma who underwent CLND with concurrent LVA (LVA group) or CLND alone (comparison group) between 2012 and 2021. Patients were excluded if they had non-melanoma skin cancers, stage IV cancers before CLND, microscopic lymphatic disease only or follow-up time of less than 12 months who did not die from melanoma-related causes. The comparison group consisted of all consecutive patients that underwent CLND alone and met inclusion criteria. To reduce surgical technique variability, all cases were performed by a single, high-volume surgeon at a tertiary care center. Results: A total of 46 melanoma patients underwent prophylactic LVA during this time period. Twenty-three of these patients met all inclusion criteria and were included in the LVA group. Twenty-two consecutive patients that underwent CLND alone were included in the comparison group. All patients underwent either axillary or inguinal CLND. Average number of lymph nodes removed during CLND were 18.20 ± 9.61 and 17.04 ± 9.97 for the LVA and comparison groups, respectively (p = 0.69). Size of largest metastatic tumor in lymph nodes was 45.91 ± 35.03 mm and 44.54 ± 23.32 mm, respectively (p = 0.99). Average time to first recurrence diagnoses was 6.75 ± 3.54 months vs 8.28 ± 5.66 months. For distant metastases only, the average time to first recurrence diagnoses was 6.16 ± 3.79 months and 9.39 ± 6.19 months, respectively (p = 0.25). There was no significant difference in recurrence type between the two groups (p = 0.66). There were no differences in DMFS and RFS times between the LVA and comparison groups. Conclusions: Prophylactic LVA performed for grossly metastatic melanoma does not negatively impact DMFS nor RFS. Considering the extremely aggressive nature of melanoma, our finding is potentially applicable to other cancers that are amenable to CLND and LVA.
A real-world experience of TCH (docetaxel/carboplatin/trastuzumab) regimen in early, locally advanced and oligometastatic HER2 positive breast cancer from tertiary care center in North India.
Authors: Gupta Anshul , Gogia Ajay , Sagiraju Hari Krishna Raju , Deo S.V.S. , Gupta Ritu , Mathur Sandeep , Sharma Dayanand
Published: June 2022

e12505

Background: In HER2 positive breast cancer, TCH is a safe and efficacious anthracycline free regimen used as both adjuvant and neoadjuvant modality. Three is scarcity of data regarding its long term safety and efficacy from India. Methods: This retrospective study comprised of 210HER2 positive breast cancer female patients treated with TCH [docetaxel (75mg/m2), carboplatin (AUC=6) and trastuzumab (8mg/kg loading followed by 6mg/kg) q 21 days with GSF prophylaxis] protocol for 6 cycles at our centre between Jan 2014 and Dec 2021. All eligible patients received maintenance trastuzumab, hormonal therapy and radiotherapy as per institutional protocol. The information regarding baseline clinico-demographic characteristics, treatment details, outcomes and toxicities were collected and evaluated. Results: The median age was 49 years (23-72), 113 (53.8%) were post-menopausal and 100 (47.6%) were Estrogen receptor/Progesterone receptor positive. Sixty-eight (32.4%) patients were stage I and II, 112 (53.3%) stage III and 30 (14.3%) were oligometastatic. TCH regimen was given as neoadjuvant chemotherapy (NACT) in 130 (61.9%) patients and as adjuvant chemotherapy in 80 (38.1%) patients. Of the patients receiving NACT, 114 (87.6%) patients underwent surgery. Twenty-two (19.3%) patients underwent breast conservation surgery and 92 (80.7%) underwent modified radical mastectomy. Over the study period, 62 (29.5%) patients had progression of the disease and 22 (10.5%) patients died. With a median follow up of 31.9 months, 3-year disease free survival (DFS) was 63.5% and overall survival (OS) was 90.8%. Median DFS was 31 months in patients with node positive disease and was not reached in patients with node positive disease. Of the patients who received NACT, pathologic complete response (pCR) was recorded in 42 (36.8%) patients. Three-year DFS was 59.1% in patients who achieved pCR and 44.8% in those who did not achieve pCR. Any grade 3/4 toxicity was seen in 26.7% patients which caused dose modification in 13.9% patients. The most common grade 3/4 hematological toxicity was anemia (15.1%) and thrombocytopenia (10.4%), while non-hematological toxicity was diarrhea (11.6%). Febrile neutropenia was seen in 4 (1.9%) patients. Four patients (1.9%) had reversible decrease in cardiac left ventricular ejection fraction. Conclusions: Anthracycline free TCH regimen is an effective and safe regimen for use in curative (adjuvant and neoadjuvant) setting for HER2 positive breast cancer in Indian women with outcomes comparable to the anthracycline based regimens reported in literature.
Are we overtreating stage I triple negative breast cancer in Ontario? A population-based study using the ICES database.
Authors: Shum Kathryn , Hussein Abdulkadir , Hamm Caroline M.
Published: June 2022

e12511

Background: Triple-negative breast cancer (TNBC) has been associated with poorer long-term outcomes compared to other breast cancer subtypes. Due to the lack of targeted therapies, the use of adjuvant chemotherapy is the mainstay of treatment, and its efficacy has demonstrated to be correlated with tumor size. Currently, different national guidelines exist regarding chemotherapy in early stage I TNBC. This study aims to examine the outcomes of the use of adjuvant chemotherapy in stage I TNBC stratified by tumor size and treated in Ontario, using the ICES database. Methods: Records of stage I TNBC patients diagnosed in 2012 to 2014 were collected from the ICES database and analysed. Kaplan-Meier curves and log-rank tests were used to compared differences in overall survival (OS) between groups. Stage I TNBC cancer patients were analyzed by tumor size: T1a (< 0.5 cm), T1b (> 0.5 cm and < 1.0 cm) and T1c (>1.0 cm and < 2.0 cm). A Cox proportional hazard model was used to determine significance of variables. Results: Of the 610 stage I TNBC patients, 183 had tumor sizes ≤ 1cm, representing stages T1aN0M0 and T1bN0M0, and 427 had tumor sizes > 1cm to 2cm, representing stage T1cN0M0. Patients with tumor sizes ≤ 1cm who received adjuvant chemotherapy did not have a significant difference in OS compared to those who did not receive adjuvant chemotherapy (p = 0.41, hazard ratio (HR) = 0.40, 95% confidence interval (CI) 0.021-2.5). However, patients with tumor sizes > 1cm to 2cm who received adjuvant chemotherapy demonstrated a significantly better OS compared to those without (p = 0.023, HR = 0.40, 95% CI 0.16-0.86). Conclusions: Patients with TNBC stage T1cN0M0 should receive adjuvant chemotherapy for better OS. For stages T1aN0M0 and T1bN0M0, patients may be overtreated and avoidance of adjuvant chemotherapy can be considered at this time. Prospective studies should investigate the efficacy of adjuvant chemotherapy in TNBC patients with stage T1aN0M0 and T1bN0M0.
Melatonin effect on sleep disorders in breast cancer patients receiving adjuvant chemotherapy.
Authors: Shahrasbi Abdolali , Einei Nasrin , Esfandbod Mohsen , Derakhshan Kamran
Published: June 2022

e12512

Background: Sleep disturbances in breast cancer patients who have received chemotherapy are among the most common causes of decreased quality of life during breast cancer treatment. Melatonin is an endogenous hormone and its secretion level is directly related to sleep quality. Melatonin supplements may help with certain conditions, such as delayed sleep-wake phase disorder. In this study, we investigated the effect of melatonin pills in treating sleep disorders in patients diagnosed with invasive breast cancer and who were received adjuvant chemotherapy. Methods: In this randomized clinical trial (before and after), 25 breast cancer patients aged 40 to 60 years who were under adjuvant chemotherapy drugs and had sleep disorders Pittsburg sleep quality index (PSQI) < 5, were enrolled. All the patients were interviewed by a psychiatrist and learned about the Pittsburg questionnaire and filled it out personally. They were evaluated in three phases before starting chemotherapy, one month and three months later. Melatonin was administered orally at a dose of 6mg per night. Then, the effects of melatonin on sleep disorders were determined by the questionnaire and compared by analysis of variance (ANOVA tool) and required statistical analysis. Results: In our study, all cases were women with a mean age of 48.4 ± 6.3 years. In general, all the different domains of sleep components except the “sleeping pills” section were significantly improved during the study period. Over the first 30-days, total score, sleep quality, sleep duration, sleep delay, and daily performance improved considerably. By the end of day 90, sleep efficiency and sleep disorders also became better (table). Conclusions: Melatonin well affects the sleep condition of breast cancer patients who received adjuvant chemotherapy, and this effect persists with the continuation of the treatment plan.[Table: see text]
Automated H&E whole slide image surrogate Ki67 index prediction and prognostic value across breast cancer subtypes.
Authors: Mukhopadhyay Satabhisa , Dasgupta Tathagata , Berwick Angelene , Walsh Elizabeth , Hanby Andrew , Millican-Slater Rebecca , Cummings Michele , Orsi Nicolas M.
Published: June 2022

e12518

Background: Despite its purported prognostic significance in breast cancer, Ki67 index assessment remains poorly standardized and features high discordance rates amongst pathologists. Moreover, its clinical utility is presently confined to low stage, ER+/HER2- tumors in determining the advisability of adjuvant chemotherapy. Unfortunately, established cut-offs limit its utility to tumors with either high or low Ki67 index extremes. While Ki67 is a marker of actively dividing cells, it fails to capture the detail of cell cycle phase and dynamics which could be informative in terms of prognosis and tumor sensitivity to specific therapies (e.g. CDK4/6 inhibitors). This study therefore developed two novel indices as surrogates of (i) Ki67 index and (ii) quiescent cell population load (QPL). Methods: Breast cancer (comprising evenly distributed hormone receptor/HER2 status cases) H&E slides ( n = 79 cases/108 slides) were digitized on an Aperio DT3 scanner, and used to extract surrogate Ki67 and QPL indices. Sections were also stained for Ki67 by immunohistochemistry (IHC) using a clinically validated assay and digitized. Whole slide image (WSI) tumor Ki67 counts were performed on QuPath and used to validate the surrogate Ki67 index (Cohen’s kappa score). Indices (i) and (ii) were 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 surrogate Ki67 index showed good concordance with IHC scores (kappa = 0.76; 95%CI 0.61-0.91; P< 0.00001). However, this surrogate index performed better as a prognostic indicator of PFS compared to conventional Ki67 IHC (KM P = 0.048; HR = 1.35, P = 0.015 vs. KM P = 0.70; HR = 1.23, P = 0.08). Prognostically, the QPL index outperformed both Ki67 indices (KM P = 0.03; HR = 3.22, P = 0.001). Conclusions: We have developed two novel surrogate indices of Ki67 and QPL that can be readily automated to analyze H&E breast cancer WSIs. Our results show that both outperformed conventional Ki67 IHC evaluation in terms of prognostication, applied across molecular subtypes, improved informativeness of mid-range Ki67 index calls, and could potentially have predictive merit in selecting patients for cell cycle targeted therapies such as CDK4/6 inhibitors.
Effectiveness of chemotherapy on prognosis of elderly breast cancer: A retrospective cohort study based on SEER database.
Authors: Wu Yunhao , Qi Yana , Yang Jiqiao , Yang Ruoning , Chen Ruixian , Huang Ya , Liu Weijing , Zhao Xin , He Tao , Lu Shan , Fu Zhoukai , Wang Zhu , Li Qintong , Sun Xin , Chen Jie
Published: June 2022

e12525

Background: The estimated population of breast cancer older than 70 years is over 80,000 new onset cases in 2019 and keep increasing. Currently, the proportion of standard chemotherapy for elderly patients was much lower than that for young patients, due to shorter life expectancy, more comorbidities, and concerns over increased toxicities and reduced tolerance. Till now, few evidences from clinical trials could support the use of chemotherapy for elderly patients, as also indicated by current guidelines for adjuvant chemotherapy. The effectiveness of chemotherapy for elderly breast cancer remains to be further verified. Methods: We identified 75,525 female breast cancer patients aged 70 years and older in the Surveillance, Epidemiology, and End Results (SEER) database from January 1, 2010, to December 31, 2016, and excluded those patients with secondary, metastatic, or bilateral breast cancer, not confirmed by pathology, lacking of key information, dead or loss to follow-up in 6 months after diagnosis. Propensity score matching (PSM) (PSM ratio: 1:1, caliper: 0.2* standard deviation of propensity score) was applied to construct balanced cohorts with or without chemotherapy based on demographic and pathophysiological characteristics. Kaplan-Meier analysis, multivariable Cox proportional model, and subgroup analysis were performed to evaluate the effectiveness of chemotherapy on overall survival (OS) and breast cancer-specific survival (BCSS). Results: A total of 33,177 eligible patients were included, of them, 5273 (15.89%) received chemotherapy. Through PSM, 8360 patients were successfully matched and almost reached balances between groups. In matched dataset, patients receiving chemotherapy exhibited a better prognosis on OS and BCSS (the 5-year survival rate, OS: 0.80 [0.78-0.82] with chemotherapy vs. 0.71[0.69-0.73] control; BCSS: 0.88 [0.87-0.89] with chemotherapy vs. 0.85 [0.84-0.86]; both log-rank test, P < 0.001); in multivariable Cox analysis, chemotherapy was associated with a 35% and 21% risk reduction on OS (HR [95%CI]: 0.65[0.59-0.72]) and BCSS (0.79[0.69-0.91]), respectively. Furthermore, subgroups with HER-2 positive, or more lymph nodes involved, were inclined to benefit more from chemotherapy. Conclusions: Our study provided additional evidences that chemotherapy may improve the prognosis of elderly breast cancer, especially for those subpopulations benefit more from chemotherapy treatment.
Describing U.S. real-world patients (pts) with hormone receptor-positive early breast cancer (HR+ EBC) by risk status.
Authors: Downer Mary K. , Yakubu Amin , Pérez-Moreno Pablo Diego , Steenrod Anna , Badovinac Crnjevic Tanja , Machackova Zuzana
Published: June 2022

e12548

Background: Despite high endocrine therapy (ET) efficacy in HR+ EBC, there is an unmet need to improve outcomes across risk statuses. We describe HR+ EBC demographic and tumor characteristics, treatment, and outcomes by risk status, to inform trial design, outcomes, and care. Methods: Pts from the de-identified, nationwide US, Flatiron Health electronic health record-derived database had HR+ EBC diagnosed from January 1, 2011 to November 30, 2020. We grouped pts into EBC with clinically relevant, high risk (stage T4 or ≥N2; or N1 with ≥1 of ≥T3, grade 3, Ki67 ≥20%, Oncotype DX ≥26), medium risk (N1, not high risk; or N0 with ≥1 of grade 3, Ki67 ≥20%, Oncotype DX ≥26), or low risk (N0, not medium risk) of recurrence. Chi-square and Kruskal–Wallis tests compared characteristics and treatments; Kaplan–Meier methods estimated event-free/overall survival (EFS/OS). Results: Of 7924 pts, 3908 (49.3%), 2477 (31.3%), and 1213 (15.3%) were classified as low-, medium-, and high-risk EBC, respectively (326 missing). Pts with medium-/high-risk EBC vs low-risk were less likely to be non-Hispanic white (p < 0.001), more likely to receive BRCA, MammaPrint, or next-generation sequencing testing (p < 0.001), be slightly younger (p < 0.001), pre-menopausal at diagnosis (p < 0.001), diagnosed in earlier calendar years (p = 0.01), and have invasive lobular carcinoma (p < 0.001). Pts with high-risk EBC were more likely to receive neoadjuvant chemotherapy (NACT) ± ACT vs lower risk. High-risk EBC had significantly lower 3-year EFS/OS vs medium-/low-risk (EFS 0.85 [95% CI = 0.82, 0.87] vs 0.95 [0.94, 0.96]/0.98 [0.98, 0.99], p < 0.0001; OS 0.9 [0.88, 0.92] vs 0.97 [0.96, 0.97]/0.97 [0.96, 0.97], p < 0.0001). Conclusions: Real-world differences in US characteristics, treatments, and outcomes by risk status exist in HR+ EBC. As expected, pts with higher risk EBC were more likely to receive NACT ± ACT. Despite missing risk factors and limited follow-up, and potential misclassification of risk status/treatment and overestimation of time-to-events, US treatment patterns are guideline-aligned. Inferior outcomes in high-risk HR+ EBC show a continued need for improved treatments.[Table: see text]
Survival outcomes after omission of surgery for ductal carcinoma in situ: A National Cancer Database (NCDB) analysis.
Authors: Poli Elizabeth C , Dong Wenli , Shaitelman Simona Flora , Tamirisa Nina , Babiera Gildy , Shen Yu , Bedrosian Isabelle
Published: June 2022

e12574

Background: Clinical trials of active surveillance (AS) for Ductal Carcinoma in Situ (DCIS) are underway. We sought to understand the historical management of biologically favorable DCIS and to determine the long-term outcomes of patients who did not have surgery at time of diagnosis. We hypothesized that women who had biologically favorable DCIS and underwent AS would have excellent long-term outcomes. Methods: The NCDB was queried from 2004 to 2017 for women diagnosed with DCIS. This cohort was further refined to identify those with biologically favorable DCIS defined as grade 1 or 2 and hormone receptor (HR) positive. Women under age 40 were excluded. AS was defined as either no surgery or surgery >12 months from diagnosis. A Cochran-Armitage test was used to assess the trend of surgery omission over year of diagnosis. Multivariable logistic regression was used to assess association between baseline factors and AS. Kaplan-Meier curves were estimated to show overall survival (OS) in this biologically favorable DCIS group that underwent AS, stratified by age (<50, 50-65, >65). Univariate and multivariable Cox proportional hazard models were used to determine the effects of prognostic factors on survival distributions. Results: There were 74,868 women with grade 1 or 2, HR positive DCIS, of whom 2,384 (3.2%) were treated with AS. The proportion of patients with biologically favorable DCIS who underwent AS increased over time, peaking in 2017 with 4.2% of DCIS cases diagnosed that year treated with observation (p<0.001). Only 17% of the patients in the AS group received hormonal therapy. On multivariable analysis, increasing age (OR 1.02, p<0.001), black race (OR 1.7, p<0.001), and being uninsured (OR 2.2, p<0.001) were all associated with increased likelihood of AS. In an unadjusted analysis, receipt of surgery was associated with improved OS in the entire cohort. However, the OS benefit from surgery differed when stratified by age. In women <50 years of age, OS outcomes were similar, with 10-year OS of 97.4% in the immediate surgery cohort vs 99.1% in AS cohort (p=0.43). In contrast, in women >50 years of age, 10-year OS was higher for women undergoing surgery (85.3% vs 70.0% in AS group, p <0.001). This association with OS in this older cohort persisted even after adjusting for age, race and comorbidity as well as facility demographics. Conclusions: The proportion of patients with low or intermediate grade, hormone receptor positive DCIS not treated with surgery has remained small but is increasing over time. AS of biologically favorable DCIS in younger, healthier women is not associated with adverse survival. In older women, the finding of benefit of surgery over AS is very likely confounded by underlying health factors that are not fully captured with co-morbidity scores.
Second primary malignancy in stage I and II breast cancer survivor: A United States population-based study.
Authors: Abdulhaleem Mohammed
Published: June 2022

e12579

Background: In United States, breast cancer accounts for over 260,000 cases each year and is responsible for over 40,000 deaths. Survival primarily depends on the stage at time of diagnosis. 5-year survival among early breast cancer is more than 50%. It is known that patients with cancer undergoing treatment have a significant risk of developing a second primary malignancy (SPM); we aimed to focus our study at the incidence of various SPM among patients surviving stage I and II breast cancer, which can help in their targeted surveillance. Methods: We utilized Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute to select adult patients (18 and above) diagnosed with stage I and II breast cancer as their first malignancy between January 2000 and December 2015. This is one of the largest cancer registries worldwide. SPM is metachronous cancer which develops six months after an index localized breast cancer diagnosis based on Warren and Gates criteria. Multiple primary standardized incidence ratios (MP-SIR) and absolute excess risk (AER) for an occurrence of SPM were obtained utilizing SEER. SIR is observed to expected incidence ratio (O/E) of SPM and AER, it is an actual number of excess SPMs in patients with early breast cancer per 10,000 person-years at risk. Statistical significance was defined as a p-value ≤ 0.05. Results: We localized 513,408 patients with a diagnosis of stage I and II breast cancer from 2000 - 2015. Patients were followed for a median duration of 8.92 years (range 0.5 to 15.92). Of these patients, 81.5% were white. About 8.6% (43938) of patients developed 47708 primary malignancies. These malignancies were significantly higher than the general population with O/E ratio of 1.15 and AER of 17.12. The median age of diagnosis of SPM was 69.8 years (range 22.8 – 105.08 years). The average latency to develop SPM was 5.28 years (range 0.5 – 15.92 years). Among solid tumors, a statistically significant increased risk was observed with salivary gland, tongue, gastric, colon, lung cancer, and genitourinary cancers. Among hematological malignancies, statistically significant risk was seen for ALL, AML and CML. The risk of hepatobiliary, CNS cancers and lymphoma were significantly lower among our cohort included in current study. The SPM was found significantly increased after the latency of 24 months, and the risk of SPM was greater across all age groups. Conclusions: Due to robust breast cancer screening strategies, a significantly higher proportion of the patients are diagnosed early in the course of the disease which tends to be curative and this group of patients has better survival rates. Our study recognizes that the risk of certain SPM is higher in stage I and II breast cancer survivals compared to general population; and they would benefit from guidelines that can identify cancer with increased risk in these patients population.
Axillary surgery after neoadjuvant chemotherapy in breast cancer patients downstaging from cN+ to ycN0.
Authors: Krivorotko Petr , Emelyanov Alexander , Komyahov Alexander , Zhiltsova Elena , Gigolaeva Larisa , Tabagua Tengiz , Nikolaev Kirill , Pesotskiy Roman , Gukova Viktoriia , Amirov Nikolay , Channov Valentin , Yerechshenko Sergey , Zernov Konstantin , Semiglazov Vladimir
Published: June 2022

e12580

Background: Axillary lymph node dissection is a redundant method of surgical treatment and axillary staging for a large number of patients receiving neoadjuvant therapy with positive lymph nodes before NCT. Methods: The study included 212 patients with breast cancer (cT1-3N1M0) who received treatment at the breast tumors department of the N.N. Petrov NMRC of Oncology from 2019 to 2021 All patients included in the study had the cN1 initial status of the axillary lymph nodes. All patients underwent neoadjuvant systemic therapy and subsequent sentinel lymph node biopsy (SLNB). In patients with pathomorphologically proven metastatic lymph nodes (cN1) even at the initial diagnosis, lymph node marking was performed before the start of NCT and targeted axillary lymph node dissection after the completion of neoadjuvant systemic therapy. In the same patients, after SLNB and targeted axillary lymph node dissection, a complete (standard) axillary lymph node dissection was performed to determine the false-negative rate and the oncological safety of the procedure. Results: The identification rate of only one sentinel lymph node was 21% (40 out of 193 patients), two sentinel lymph nodes - 30% (58 out of 193 patients), more than 3 - 49% (95 out of 193 patients). When only 1 sentinel lymph node was found, the false-negative rate of SLNB was 20.0% (4 of 20) (95% CI, 5.7 to 43.7). When two sentinel lymph nodes were found, the false-negative rate of SLNB was 20.0% (6 of 30) (95% CI, 7.7 to 38.6). When three sentinel lymph nodes were found, the false negative rate of SLNB was 4.7% (2 of 43) (95% CI, 0 to 15.8). Among 45 patients who had a microseed with the iodine-125 radioisotope installed before the start of treatment, the frequency of identifying a marked node was 100%. In 19 patients, tumor cells were found in the lymph nodes. The false-negative rate of targeted axillary dissection in combination with SLNB was 5.3% (1 of 19) (95% CI, 0 to 26.0). Conclusions: Targeted axillary dissection and sentinel lymph nodes biopsy, provided that 3 SLNs are removed, are reliable methods for identifying patients in whom systemic therapy is guaranteed to achieve complete response of regional lymph nodes (ypN0), thereby relieving patients of the need to perform a crippling complete axillary lymph node dissection. Clinical trial information: 3/198.
Sentinel node biopsy and regional recurrence following neoadjuvant chemotherapy in patients with isolated tumor cells: A rare event.
Authors: Moody Alison , Jutla Jaswinder , Chung Alice P. , Basho Reva K , Giuliano Armando E.
Published: June 2022

e12581

Background: Lack of consensus exists regarding the optimal surgical axillary management of breast cancer patients treated with neoadjuvant therapy followed by sentinel node biopsy (SNB) with only isolated tumor cells (ITCs) identified in the sentinel node (SN). Few studies with limited patients have addressed this. A prospectively maintained database was reviewed to identify residual nodal metastatic burden and outcomes for patients with SN ITCs. Methods: Operable breast cancer patients treated with neoadjuvant therapy followed by breast surgery with SNB were identified who had only ITCs in the SN. Patients were excluded who had recurrent breast cancer, metastatic disease at time of operation, or who had an operation performed at another institution. Residual burden of axillary metastatic disease in patients who underwent completion axillary dissection and locoregional recurrence were examined. All SNs were examined with both hematoxylin and eosin stains as well as well as immunohistochemical stains. Results: 875 patients underwent neoadjuvant therapy followed by breast surgery and SNB from July 2007 to November 2021. Seventeen patients (1.9%) had only ITCs in the SN. The mean patient age of these 17 patients was 55.6 years (range 31-83 years). The majority had invasive ductal carcinoma (n = 15, 88.2%). Fourteen patients (82.4%) had ER+ tumors, 11 (64.7%) PR+ tumors, 2 patients (11.7%) had HER2+, and 3 patients (17.6%) had triple negative cancers. All patients had clinical T1 to T3 tumors and clinical N0 (n = 11, 64.7%), N1 (n = 5, 29.4%), or N2 (n = 1, 5.9%) disease. Two patients had isolated tumor cells identified on frozen section. Both of these patients underwent axillary dissection during the index operation and had further nodal disease identified (1 patient with ITCs only and 1 patient with macrometastasis). Fourteen patients had SN tumor free frozen sections but ultimately had ITCs identified with H&E. Five of these patients underwent a completion axillary dissection. Three of the 5 patients (60%) had additional ITCs identified after completion ALND. Fourteen patients had nodal irradiation. The three patients who did not receive irradiation did not undergo ALND. All patients with ER+ tumors received adjuvant endocrine therapy, the 2 patients with HER2+ cancers received adjuvant targeted HER2 therapy, and 4 patients received adjuvant chemotherapy. At a mean follow-up of 21.8 months (range 2-63 months), no locoregional recurrences occurred in any patient. Conclusions: ITCs in the SN after neoadjuvant therapy is a rare finding and are unlikely to be associated with regional recurrence.
Axillary dissection 10 years after Z0011.
Authors: Palka-Kotlowska Magda , Custodio-Cabello Sara , Cabezon-Gutierrez Luis , Oliveros-Acebes Eduardo , Khosravi-Shahi Parham , Rabadan-Ruiz Lorenzo
Published: June 2022

e12582

Background: Axillary involvement is one of the strongest prognostic factors in breast cancer. Axillary lymphadenectomy (AL) has been considered one of the milestones to reduce relapse risk of local breast carcinoma. Z0011 trial, demonstrated that axillary dissection was not necessary in cases with one or two nodes involved. The authors proposed 3 sentinel nodes to decide if AL should be done. Since in the trials that explored the omission of lymphadenectomy obtained between one and six nodes, there is no consensus about how many lymph nodes should be obtained in the axillary sampling. The objective of this study is to obtain real data about axillary staging in real practice after Z0011 trial. Methods: 197 patients were selected from clinical records of Hospital Universitario de Torrejon. All patients were diagnosed with localized infiltrating breast carcinoma between 2016 and 2021. All were candidates for sentinel node biopsy (SNB) analyzed by OSNA or histopathology analysis. Patients with in situ tumors, those who underwent neoadjuvant chemotherapy We retrospectively reviewed the number of axillary nodes obtained in SNB and if axillary dissection was performed or not. Results: From 197 patients, 150 were included in the study (47 were excluded because were diagnosed with in situ carcinoma, received neoadjuvant chemotherapy or followup was lost). All 150 women were patients with infiltrating breast cancer who underwent conservative surgery or mastectomy and SNB. After surgical treatment, all patients received subsequent therapies indicated in each case (chemotherapy, radiotherapy or hormone therapy). Medium age at diagnosis was 57 years (range 30-87). Median number of sentinel nodes obtained in SNB was 2 (range 1 to 5). 40 patients had tumor infiltration in SNB, but only 15 underwent axillary dissection,10 of them had one node involved, 4 had 2 nodes involved and one had 3 nodes involved, from up to four extracted. 5 patients had more node involved than those found on the sentinel node biopsy, and all had macrometastasis. Capsular rupture was identified in 7 cases. None of the patients had relapse until the time of follow up was closed. Conclusions: Rate of axillary dissection after Z0011 has decreased without increasing risk of loco-regional or distant relapse. During the time of surgery, not always is possible to obtain 3 sentinel nodes, which could involve more aggressive surgery and comorbidities. Techniques of sentinel node identification are needed and further investigation to resolve in which cases axillary dissection is unavoidable.
Low-dose apatinib combined with neoadjuvant chemotherapy in the treatment of early-stage triple-negative breast cancer (LANCET): A single-center, single-arm, phase II trial.
Authors: Yang Ciqiu , Zhang Junsheng , Wang Kun
Published: June 2022

e12613

Background: Anti-angiogenic therapy combined with chemotherapy could improve pathologic complete response for breast cancer. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits VEGF receptor 2. We assessed the efficacy and safety of the combination therapy of apatinib and standard chemotherapy in patients with triple negative breast cancer (TNBC). Methods: This single-arm, phase II study enrolled patients aged 18-70 years with previously untreated stage IIA-IIIB TNBC. Patients received oral apatinib at a dose of 250 mg once daily and intravenously docetaxel every three weeks for four cycles, followed by epirubicin plus cyclophosphamide every three weeks for four cycles. The primary endpoint was the pathological complete response (pCR) rate in the breast and lymph nodes. Secondary endpoints included objective response rate, event-free survival (EFS), overall survival (OS), and safety. Results: Between August 1, 2018 and March 10, 2021, we screened 34 patients and enrolled 31 patients. At the date of cut-off on December 31, 2021, the median follow-up time was 22.9 months (range: 10.1-41.6 months). The pCR in both breast and lymph nodes were achieved in 17 (54.8%; 95%CI: 36.0–72.7) of 31 patients. Objective responses were achieved in 29 patients (93.5%; 95%CI: 78.6-99.2), and disease control was achieved in 31 patients (100%; 95%CI: 88.8–100.0). The 2-year EFS and 2-year OS were 90.9% and 94.4%, respectively. The five most common treatment-related adverse events were fatigue (51%), hypertension (41%), anorexia (39%), hand-foot syndrome (35%), and diarrhea (32%). Few grade 3 or more adverse events were observed. Conclusions: The combination of apatinib with docetaxel followed by the epirubicin plus cyclophosphamide showed excellent efficacy and manageable toxicities; further randomized controlled phase III trials are warranted. Clinical trial information: NCT03243838.
A novel immune cell signature predicts pathological complete response to neoadjuvant chemotherapy in triple negative breast cancer patients in the Q-CROC3 trial.
Authors: Basik Mark , Zeng Yixiao , Aguilar Adriana , Milne Katy , Lafleur Josiane , Florianova Livia , Aleynikova Olga , Ferrario Cristiano , Boileau Jean-Francois , Marcus Elizabeth A. , Pilon Yohann , Ranjbari Dorsai , Discepola Federico , Greenwood Celia
Published: June 2022

e12614

Background: Tumor infiltrating lymphocytes (TILs) have been associated with good prognosis and response to neoadjuvant chemotherapy. Several reports have shown that the heterogeneity of tumor infiltrating immune cells affects the response to chemotherapy, with for example low levels of FOXP3 expressing T cells associated with good prognosis and pathological complete response (pCR) to chemotherapy. Methods: We examined different immune cell markers on 52 pre-chemotherapy biopsy specimens obtained from triple negative breast cancer patients undergoing neo-adjuvant chemotherapy from the Q-CROC-03 trial. Slides were stained for CD8, CD3,PD-1, PDL-1, FOXP-3 and Granzyme B using multi-colour immunohistochemistry and automated cell counting of stroma and epithelial counts was conducted using the Vectra/inForm image analysis platform. We had total of 39 variables for analysis and we performed Penalized logistic regression for variable selection. Results: Nine variables were found statistically significant to predict response to chemotherapy, PD1+ stroma counts being the one with the highest probability of association with response. A tree algorithm was then used on all 9 variables to identify the best variable and threshold combination to identify patients who respond to chemotherapy. We separated our cohort in test (25% of samples n = 13) and training (75% of samples n = 39) sets for this analysis. Restricting the tree depth to 2 variables for clinical interpretability identified the combination of average counts of stromal PD1+ and average density of stromal FOXP3+ as predictors of chemo response (accuracy 0.82). Both stromal average PD1+ counts and average stromal FOXP3+ density positively correlated with the levels of TILS. Conclusions: Combining FOXP3 and PD1 protein expression in the stroma of pre-treatment biopsies of triple negative breast cancers receiving neoadjuvant chemotherapy is highly predictive of pCR.
Short-term preoperative endocrine therapy allows to estimate and revert patient prognosis with further treatment plan correction in HR+ HER2- early breast cancer patients.
Authors: Zhukova Lyudmila , Ganshina Inna , Ignatieva Maria , Ivanyuk Maria , Kolyadina Irina Vladimirovna , Kvetenadze Gurami , Valeeva Alexandra , Sorokina Irina
Published: June 2022

e12628

Background: The anomaly function of ER/PR-dependent molecular cascade is a key driver of ER-positive HER2-negative breast cancer (HR+ HER2- BC) progression. Ki67>10% and/or grade 3 (G3) determine the initial poor patient (pts) prognosis in this group. The short-term pre-operative endocrine therapy (P-ET) simply allows to look ahead to properly the further adjuvant therapy (AT) and to estimate the endocrine therapy (ET) sensibility of each pts in the routine clinical practice. The existing diagnostic methods weaknesses for the baseline lymph nodes invasion, high BC heterogeneity do not allow to accurately estimate the disease stage and tumor phenotype, respectively, with 100% accuracy before surgery. In addition to pre-ET the post-operative IHC is a base method for further pts treatment plan especially for high heterogenicity breast tumors. Our study is focused on pts proportion estimation with P-ET benefit or tumor phenotype reversion in patients with early HR+ HER2- BC. Methods: HR+ HER2- BC pts stages I-II any level of Ki67 independent from grade have received P-ET (letrozole (L)/anastrozole (A)/tamoxifen (TAM)) no less than 2 weeks until surgery in MCSC named after A.S. Loginov. Enrollment period runs from Jun’21 and will end with 1,000 pts. The primary goal of the study was pts’s proportion evaluation with baseline Ki67>10% who experienced suppression of the proliferation marker to 10% or less and/or phenotype change during P-ET followed by AT strategy amendment. Results: At the data cut-off (Jan’22) 832 pts (5 pts were men) with HR+ HER2- BC were enrolled (IIT population) with median age 61 (range:26-85) and ECOG 0-2. 736 (89%) pts have baseline Ki67>10% of whom 100 (14%) pts - with G3, 291 (35%) pts - with baseline Ki67≥30%. Tumors of the 398 (54%) pts suppressed proliferation marker Ki67≤ 10% and 352 (88%) pts among them avoid planned adjuvant chemotherapy followed by ET prolongation independent of ET type (L/A/TAM). The median time of P-ET amounted to 39,5 days (range: 14-90) in focused group. Post-operative evaluation of specimens in 20 (2,4%) pts have resulted in the identification of phenotype change to HER2+ BC and TNBC with subsequent modification of AT decisions (including anti-HER2-based and/or dose dense regimens). Conclusions: In HR+ HER2- early BC pts short-term P-ET simply allows to estimate pts prognosis and further AT strategy proper planning: to identify the pts population of whom CT can be avoided while maintaining treatment efficacy with a better quality of life (42% pts of IIT) (1), to radically change the planned AT to achieve optimal treatment results (2,4% pts of IIT) (2).
Demonstration of the value of liquid biopsy to identify metastatic breast cancer: Comparison and combination of cell and cell-free platforms.
Authors: Di Caro Giuseppe , Bourdon David , Byun Jiyun , Singer Tatjana , Anderson Amanda , Tubbs Alisa , Blankfard Martin , Wenstrup Rick
Published: June 2022

e13004

Background: Liquid biopsy analysis detecting circulating tumor cells (CTC) or circulating tumor DNA (ctDNA) is a non-invasive approach that may provide clinically actionable information for patients’ (pts) treatment decisions when conventional biopsy is otherwise inaccessible or infeasible. Here we report a liquid biopsy analysis method including CTC characterization and ctDNA alterations in late-stage metastatic breast cancers (MBC). Methods: Blood samples were collected for cell and cell-free DNA analysis from 57 pts with MBC. 44 pts were progressing on treatment and 13 were responding to treatment. Blood was also collected from 25 blood donors (HD) with no known cancer history. After plasma isolation, nucleated cells were plated, and slides were bio-banked. Immunofluorescent staining and subsequent imaging were performed on replicate slides. CTCs were identified using Epic Sciences digital imaging and machine learning algorithms trained to identify breast cancer cells. Single-cell (sc) isolation for genomic quantification of large-scale transitions (scLST) was used to further characterize individual CTCs. cfDNA from bio-banked plasma was analyzed using a validated NGS panel to detect class 1A ctDNA alterations. Results: Within this cohort of 57 MBC pts, CTCs, scLST+CTCs and ctDNA alterations were detected in (77%, 49% and 33%, respectively). All MBC pts on active therapy (23%) had no CTC detected. No CTCs, scLST+CTCs or ctDNA were detected in the HD cohort, suggesting high specificity (100%, 100% and 100%, respectively). The presence of CTCs or of scLST+CTCs had low concordance with the presence of ctDNA+ alterations in MBC pts, suggesting that these platforms provide independent and complementary value when identifying MBC. To test this hypothesis, we designed combination models which added ctDNA to cell analysis methods ([CTC+][ctDNA+] and [scLST+CTC+][ctDNA+]). Adding ctDNA to either cell analysis method increased sensitivity by 5% and 12%, respectively, over the individual methods and retained 100% specificity. Conclusions: Here we demonstrate the value of comprehensive cell and cell-free liquid biopsy analysis for the detection of MBC pts. Our data suggest there may be clinical utility of adding cell-free to cell analysis for the identification of MBC. Analysis of the comparative and combined utility of these liquid biopsy methods in earlier settings is ongoing.
Whole genome sequencing of HER2+ metastatic breast cancer and CNA comparison between long term survivor and short-term survivor.
Authors: Andrieu Charlotte , Goldrick Caoimhe , Skrobo Darko , Eustace Alex , Ballot Jo , Quinn Cecily , Gullo Giuseppe , Walsh Naomi , Crown John
Published: June 2022

e13019

Background: The introduction of anti-HER2 therapies such as trastuzumab for HER2+ metastatic breast cancer (MBC) has led to significant improvements to disease progression. We and others have reported long-term durable complete response to trastuzumab in patients with HER2+ MBC. We hypothesise that genomic copy number alteration (CNA) and tumour mutational burden (TMB) may act as a prognostic measure of predicting response to trastuzumab in long-term survivors (LTS) compared to short-term survivors (STS). Using whole-genome sequencing (WGS) to detect these alterations, we aim to identify the molecular characteristics of primary and metastatic lesions in patients with metastatic HER2+ breast cancer. Methods: WGS was performed on samples from two patients from a HER2+ MBC cohort; a of long-term survivor (PFS 27 months; OS > 60 months) and a short-term survivor (PFS 4 months; OS < 14 months). Primary tumours, adjacent normal tissue and metastases were sequenced at a mean depth of 60X. Reads were aligned on the hg38 reference genome using Burrows-Wheeler Aligner (bwa), CNA were detected using Control-FREEC to evaluate total CNA burden. Single nucleotide variants were detected using GATK Mutect2 to calculate TMB. Results: Analysis of DNA chromosome disruption (fraction of the genome amplified/deleted) revealed a higher overall fraction of disrupted genome in the LTS primary tumour and metastasis compared with the STS (0.061 and 0.064 vs 0.031 and 0.047, respectively). Further delineation of the distribution of CNA burden in all genomes identified chr1 as the most altered in the STS samples whereas chr17 was the most disrupted in the LTS samples. HER2 and CDK12 were amplified in both LTS and STS samples (4 copies in LTS primary tumour and metastasis, 18 and 14 copies in STS primary tumour and metastasis respectively). A high TMB was estimated in both samples but was higher in the STS primary tumour than in the LTS one (161 vs 142, respectively). TMB was increased in LTS metastatic lesions. NRAS mutation was found in LTS primary tumour but was lost in the metastasis. Conclusions: This pilot study highlights the potential for whole-genome sequencing to identify CNA and TMB in HER2+ MBC in patients who display long-term and short-term survival. Further samples from this cohort need to be studied to investigate the relationship between CNA burden and HER2+ MBC patient survival.