The recognition that axillary surgery in early breast cancer primarily serves as a staging tool rather than a curative treatment, along with the shift from axillary lymph node dissection (ALND) to sentinel lymph node biopsy (SLNB) as the standard procedure for clinically node-negative patients, has paved the way for further de-escalation of axillary treatment. This strategy aims to reduce treatment-related morbidity while preserving survival outcomes. Multiple studies have provided compelling evidence that ALND can be safely omitted in cases of limited SLN involvement. Moreover, even the omission of SLNB in selected low-risk cohorts has been shown not to increase recurrence rates. On the other side, from the oncological perspective, research has moved toward an escalation of adjuvant treatments, aiming to reduce recurrence rates and improve overall survival. Thus, while residual axillary disease does not affect patient outcomes, limited axillary staging may hinder access to certain adjuvant therapies. Here, we aim to critically assess the potential impact of recent advances in axillary surgical de-escalation on adjuvant systemic therapy decision-making especially in hormone receptor positive/HER2 negative early breast cancer, with a particular focus on the appropriate selection of patients for adjuvant chemotherapy, CDK4/6 inhibitors, and PARP inhibitors. We argue that decisions on surgical de-escalation should be carefully tailored, balancing its potential benefits with the need for accurate staging to guide adjuvant therapies. A patient-centered, multidisciplinary approach remains essential to ensure that de-escalation does not impact negatively on adjuvant treatment decision making and long-term survival.

Purpose: Trastuzumab deruxtecan (T-DXd) has significantly improved outcomes in patients with HER2-positive and HER2-low/ultralow metastatic breast cancer (MBC). However, most patients eventually discontinue treatment. In clinical trials, discontinuation without disease progression occurred in 30–60% of cases, but real-world data on the reasons for discontinuation and subsequent treatment strategies remain limited. This study aimed to describe T-DXd discontinuation patterns and post-discontinuation treatments in a real-world setting. Methods: We conducted a single-center retrospective observational study including consecutive patients with MBC treated with T-DXd between July 2018 and December 2025. Patients who discontinued T-DXd for any reason were included. Reasons for discontinuation, treatment duration, response outcomes, and subsequent systemic therapies were analyzed using descriptive statistics. Results: Overall, 93 patients were included: 71.0% had HER2-positive, 26.9% HER2-low, and 2.1% HER2 0 tumors. The primary reason for discontinuation was progressive disease (82.8%). Other reasons included adverse events (14.0%), non-treatment-related causes (2.2%) and patient decision (1.1%). Interstitial lung disease represented the most common toxicity leading to discontinuation (10.8%). The median treatment duration was 7.9 months overall and was longer in patients with HER2-positive than in thosewith HER2-low and HER2 0 disease. Among evaluable patients, overall response rate was 83.1% in HER2-positive tumors and 52% in HER2-low tumors. After discontinuation, 80.6% of patients received subsequent therapy. Patients discontinuing for reasons other than progression had longer treatment exposure. Conclusions: In this real-world cohort, most T-DXd discontinuations were due to disease progression, while adverse event-related discontinuations were less frequent than in clinical trials. Several factors may influence treatment persistence, including toxicity management. Further evaluation in larger, multicenter cohorts is warranted to better characterize their contribution.

Background Breast cancer (BC) in women aged <= 40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset. Methods Women aged <= 40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival. Statistical significance was considered for p <= .05. Results Of 3547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p < .001), hormone receptor-positive (p < .001), and node-positive (p = .003). BRCA2 PVs were more often associated with HER2-low than BRCA1 PVs (p < .001). HER2-low versus HER2-0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76-0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64-0.95) and overall survival (HR, 0.65; 95% CI, 0.46-0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p = .014) and TN and luminal A-like in HER2-0 (p = .019) showed the worst DFS. Conclusions In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis.

BackgroundNausea and vomiting are common side effects of Trastuzumab Deruxtecan (T-DXd), but guidelines for optimal management were not initially available. This retrospective single-center study aimed at evaluating the efficacy of two antiemetic regimens in patients receiving T-DXd.MethodsData from metastatic breast cancer patients receiving T-DXd were collected. Two groups were defined: patients treated with 5-HT3 receptor antagonists (RA) ± dexamethasone (5-HT3-group) and patients treated with a fixed oral combination of netupitant (NK1RA) and palonosetron ± dexamethasone (NK1 group). Physicians preferentially offered the NK1 regimen to patients at higher risk of nausea and vomiting based on internal recommendations. Only nausea and vomiting during cycles 1 and 2 were considered. Comparisons of nausea and vomiting by the antiemetic prophylaxis group were assessed using chi-square.ResultsA total of 53 patients were included in the analysis. At cycle 1, 72% and 28% of patients received the 5-HT3 and NK1 prophylaxis, respectively. Overall, 58% reported nausea, with no differences between groups (58% vs. 60%; p = 0.832), but with a trend for lower grade in the NK1 group (33.3% G1; 26.7% G2) compared to the 5-HT3 group (23.7% G1; 31.6% G2; 2.6% G3). Vomiting was reported by 21% and 0% of patients in the 5-HT3 and the NK1 group, respectively (p = 0.054). Among the 15 patients in the 5-HT3 group with nausea at cycle 1 who escalated to NK1 at cycle 2, nausea decreased from 100% to 53% (p = 0.022) and vomiting decreased from 47% to 13% (p = 0.046).ConclusionsThe NK1 regimen improved vomiting control at cycle 1 and, when introduced at cycle 2, significantly improved both nausea and vomiting. The biased NK1 selection for higher-risk patients may have dampened the differences between groups at cycle 1. These findings support enhanced control of T-DXd-related nausea and vomiting with NK1RA.

Adjuvant chemotherapy recommendations for ER+/HER2− early-stage breast cancers (eBC) involve integrating prognostic and predictive information which rely on physician judgment; this can lead to discordant recommendations. In this study we aim to evaluate whether Oncotype DX improves confidence and agreement among oncologists in adjuvant chemotherapy recommendations. We randomly select 30 patients with ER+/HER2− eBC and recurrence score (RS) available from an institutional database. We ask 16 breast oncologists with varying years of clinical practice in Italy and the US to provide recommendation for the addition of chemotherapy to endocrine therapy and their degree of confidence in the recommendation twice; first, based on clinicopathologic features only (pre-RS), and then with RS result (post-RS). Pre-RS, the average rate of chemotherapy recommendation is 50.8% and is higher among junior (62% vs 44%; p < 0.001), but similar by country. Oncologists are uncertain in 39% of cases and recommendations are discordant in 27% of cases (interobserver agreement K 0.47). Post-RS, 30% of physicians change recommendation, uncertainty in recommendation decreases to 5.6%, and discordance decreases to 7% (interobserver agreement K 0.85). Interpretation of clinicopathologic features alone to recommend adjuvant chemotherapy results in 1 out of 4 discordant recommendations and relatively high physician uncertainty. Oncotype DX results decrease discordancy to 1 out of 15, and reduce physician uncertainty. Genomic assay results reduce subjectivity in adjuvant chemotherapy recommendations for ER +/HER2− eBC.

Breast cancer-associated genes 1 and 2 (BRCA1 and BRCA2) are tumor suppressor genes encoding a large protein that is involved in many essential biological processes. BRCA mutated patients show an increased risk to develop several malignancies, including cutaneous malignancies, although inconsistently across multiple studies. We carried out an observational study on the main dermatological and dermoscopic aspects in a population of patients with BRCA 1/2 mutations, to identify the main clinical and dermoscopical features in this class of patients. A total of 52 patients with BRCA mutations were included in the current analysis. Clinical, dermoscopical, and pathological data were obtained during the dermatologic visits. Out of the entire cohort, 67.3% of patients showed brown hairs and 63.5% of patients showed brown eyes, with phototype III as the most frequent phototype (69.2%). A total of 2.017 melanocytic lesions in all patients were analyzed; specifically, 40 patients (76.9%) showed a total number of nevi > 10, while regarding the main observed dermoscopic features, a prevalence of reticular pattern in 63% of cases was observed, followed by a mixed pattern in 19.2% of cases. Regarding the cutaneous examination, eruptive angiomas (eCAs) were the main dermatologic manifestations in 46.2% of patients. Out of 52 patients and during a follow-up of 24 months one patient developed an in situ melanoma. Interestingly, none of the patients with eCAs showed a TN > 10, highlighting an inverse correlation. To date, there is insufficient evidence to warrant increased surveillance in patients with BRCA mutations or with a positive family history for BRCA mutations, in the absence of standard cutaneous risk factors. Further studies with larger samples of patients are needed to better investigate dermatological and dermatoscopic features in BRCA mutation carriers.

Clinicopathological prognostic features have limited value to identify with precision newly diagnosed patients with hormone receptor (HR)-positive, HER2-negative breast cancer (BC), who would benefit from chemotherapy (CT) in addition to adjuvant hormonal therapy (HT). The 21-gene Oncotype DX Breast Recurrence Score ® (RS) assay has been demonstrated to predict CT benefit, hence supporting personalized decisions on adjuvant CT. The multicenter, prospective, observational study PONDx investigated the real-life use of RS ® results in Italy and its impact on treatment decisions. Physicians’ treatment recommendations (HT ± CT) were documented before and after availability of RS results, and changes in recommendations were determined. In the HR+ HER2− early BC population studied ( N = 1738), physicians recommended CT + HT in 49% of patients pre-RS. RS-guided treatment decisions resulted in 36% reduction of CT recommendations. PONDx confirms that RS results provide clinically relevant information for CT recommendation in early-stage BC, resulting in a reduction of more than a third of CT use.

Abstract Background. High-TMB (HTMB) is an emerging promising agnostic biomarker for predicting benefit from immune-checkpoint inhibitors, independently of tumor type. At ASCO 2019, the TAPUR trial reported an interesting 21% ORR in heavily pretreated metastatic BC patients with very HTMB [vHTMB, ≥9 mutations/megabase (Muts/Mb)]. We aimed to define the differential gene expression and methylation landscape between low and high TMB in each BC subtype. Methods. In TCGA, we identified 848 patients with WES data available for TMB estimation. [ER+/HER2- (LumA by PAM50)) n = 364; ER+/HER2- (LumB by PAM50), n = 147; HER2+, n = 158; and TN, n = 179]. High TMB was defined according to two different cut-offs: ≥9 (vHTMB) and≥5 Muts/Mb (HTMB). The second arbitrary cut-off was used to define a larger group allowing to better characterize the different molecular landscapes associated with high and low TMB in each BC subtype. The HTMB group was compared with an equal number of tumors with low TMB. We assessed the differential RNA expression and methylation of single genes and pathways (defined using Gene Ontology - GO). “Common” genes and pathways were defined as recurrently associated with TMB (p<0.05) in all subtypes and with a combined p value ≤0.00001. Results. The overall prevalence of vHTMB (≥9) was 4.5%, with no substantial differences across subtypes (4.4%, LumA; 4.8% LumB; 5.7% HER2+; 3.3% TN). The prevalence of HTMB (≥5) was 13.7%, but it was different across BC subtypes (p=8.0E-07) (8.2%, LumA; 12.9% LumB; 13.3% HER2+; 25.7% TN). We found more “common” genes down-regulated (n=70) than up-regulated (n=3) in HTMB group. Two of these three genes (HSPE1 and FEZF1.AS1) have been associated with poor prognosis in BC. When we considered the “common” pathways, only 3 were up-regulated in HTMB, all implicated in post-transcriptional repression of gene expression (gene silencing by miRNA and mRNA binding involved in post-transcriptional gene silencing). Conversely, 66 were significantly down-regulated (including transcription coregulator and coactivator activity, protein serine/threonine kinase activity and ubiquitin-protein transferase activity and binding). Some genes and pathways were associated with TMB only in a specific BC subtype (p ≤0.00001). For instance, 16 pathways were down-regulated in the HTMB group of TNBC. These inlcuded 12 pathways implicated in immune response. Conversely, in LumB, 11 pathways were up-regulated in HTMB group and implicated in immune response. Intrestingly, these pathways were all significantly down-regulated in the HTMB group of LumA and TN. In HTMB group, we found 7 and 4 “common” genes hypermetylated and hypomethylated, respectively. Four pathways were commonly hypermethylated (chromatin silencing at rDNA, telomere organization and positive regulation of G1/S transition of mitotic cell cycle) and five were hypomethilated (including mitotic sister chromatid segregation). Considering private alterations, in TNBC, 23 of 27 significant pathways were hypermetylated in HTMB group including double-strand break repair via nonhomologous end joining, epigenetic negative regulation of gene expression, and regulation of gene silencing by miRNA. Conclusions. Very-high TMB which is considered potentially druggable (≥9 Muts/Mb) is rare in BC, and equally frequent in all subtypes. Instead, HTMB (≥5 Muts/Mb) is more frequent in TNBC. BCs with HTMB had a different molecular landscape. Overall, several genes are recurrently down-regulated in HTMB group, and this is at least partly due to miRNA regulated post-trascriptional silencing, which might rapresents a new mechanism of immune escape. The positive association between TMB and immune genes in LumB, as well as the negative association in TN and LumA, suggest that immune editing and surveillance might be dependent on the molecular context. Citation Format: Luca Licata, Barbara Galbardi, Balázs Győrffy, Thomas Karn, Lorenzo Sica, Alessia Rognone, Patrizia Zucchinelli, Daniela Aldrighetti, Stefania Zambelli, Luca Gianni, Giampaolo Bianchini. Molecular differences between high and low tumor mutational burden (TMB) across breast cancer (BC) subtypes [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-05-09.

Northern Italy has been one of the European regions reporting the highest number of COVID-19 cases and deaths. The pandemic spread has challenged the National Health System, requiring reallocation of most of the available health care resources to treat COVID-19-positive patients, generating a competition with other health care needs, including cancer. Patients with cancer are at higher risk of developing critical illness after COVID-19 infection. Thus, mitigation strategies should be adopted to reduce the likelihood of infection in all patients with cancer. At the same time, suboptimal care and treatments may result in worse cancer-related outcome. In this article, we attempt to estimate the individual risk-benefit balance to define personalized strategies for optimal breast cancer management, avoiding as much as possible a general untailored approach. We discuss and report the strategies our Breast Unit adopted from the beginning of the COVID-19 outbreak to ensure the continuum of the best possible cancer care for our patients while mitigating the risk of infection, despite limited health care resources. IMPLICATIONS FOR PRACTICE: Managing patients with breast cancer during the COVID-19 outbreak is challenging. The present work highlights the need to estimate the individual patient risk of infection, which depends on both epidemiological considerations and individual clinical characteristics. The management of patients with breast cancer should be adapted and personalized according to the balance between COVID-19-related risk and the expected benefit of treatments. This work also provides useful suggestions on the modality of patient triage, the conduct of clinical trials, the management of an oncologic team, and the approach to patients' and health workers' psychological distress.

In ER+/HER2- early breast cancer (eBC), oncologists frequently disagree on chemotherapy (CT) recommendation due to the subjective interpretation of classical clinicopathological variables, including Ki67. We aimed to evaluate whether and how Oncotype DX adoption improves the agreement and confidence among oncologists of different countries and experience. We randomly selected 30 patients (pts) with pT1c-2 N0, grade 2-3, Ki67>15%, ER+/HER2- eBC and RS available from the database of San Raffaele Hospital. We asked 16 breast oncologists in Italy (IT) and US (seniors [Sr]: 6 IT, 4 US; juniors [Jr, within 2 years from end of residency]: 3 IT, 3 US) to provide recommendation for addition of CT to endocrine therapy with a degree of confidence twice: firstly based on clinicopathological features only (pre-RS), then with also the RS result available (post-RS). Intra- and inter- observer agreement was assessed by Cohen's kappa (K). Patients' characteristics: median age 50.5 years (30-75), 40% premenopausal, 27% G3, 50% pT2, 70% Ki67>25%. In pre-RS, the average rate of CT recommendation was 50.8% (range 27.7%-76.7%) and was higher in Jr (61.7% vs 44.3%; p<0.001), but similar by country. Oncologists were uncertain in 39.0% of cases and provided discordant indications in 26.7% (3.3% - 53.3%, interobserver agreement K 0.47, range -0.14 - 0.93). Comparing pre- and post-RS, the average change of treatment indication was 29.6% (19.6% less CT; 10.0% more CT) (intraobserver agreement K 0.40; range 0.05-0.60), with no differences by group. In post-RS, both confidence and agreement in recommendation increased significantly: confidence increased in 65.2% with only 5.6% of oncologists uncertain. Average interobserver agreement was near perfect (K 0.85, range 0.47 – 1.00), especially in US (K 0.93) and Jr (K 0.93) (p<0.001). This corresponded to only 6.7% (0% - 26.7%) discordancy. Subjective interpretation of clinicopathological features resulted in 1 out of 4 pts receiving discordant indications and higher uncertainty. Oncotype DX decreased the discordancy to only 1 out of 15 pts with lower uncertainty. The increased consensus among oncologists is an underappreciated benefit from using genomic tests in breast cancer.

UNLABELLED:The cancer genetic counseling (CGC) identifies genetic mutations for hereditary neoplastic diseases, but little is known on its psychological effects on subjects.METHODS:The present study involved women who underwent genetic counseling for breast or ovarian cancer: 19 unaffected, 43 current patients, and 28 past patients. The aim of the study was to examine the relation between coping strategies and the quality of life during genetic counseling before testing, considering the effects of psychopathological symptoms and the health status.RESULTS:Results showed that the use of avoidance strategies led to a decrease in quality of life, and that this relationship was entirely mediated by the intensity of psychopathological symptoms, while the health status did not show any effect on it.CONCLUSIONS:The study, which is the first in Italy, suggests the importance of assessing coping strategies in subjects who undergo the CGO to identify individuals who are at risk of decrease of psychological well-being. Indeed, psychological counselling improving coping strategies could preserve the psychological well-being of individuals.

Biliary tract cancer is a rare malignant tumor. Accordingly, to perform prospective and randomized trials is difficult and the knowledge of its natural history and optimal management remains limited. Chemotherapy is commonly used to improve the outcome and to delay tumor progression in advanced disease. Only recently, cisplatin-gemcitabine combination was identified as the new standard first-line therapy. Despite the outcome improvement, disease progression is a constant and approximately half of patients failing upfront treatment maintain a good performance status and are willing to undergo further treatment. No standard salvage chemotherapy regimen has been identified yet. Experiences of salvage therapy in advanced biliary tract cancer are sparse and yielded disappointing results. Well designed multi-institutional randomized trials are warranted to clarify the role and the activity of a second-line therapy.

Second-line chemotherapy in recurrent and/or metastatic head and neck cancer (r/mHNSCC) patients showed dismal results with limited tumor response and reduced life expectancy. Outside of clinical trials, data on efficacy of second line treatment after first line anti-EGFR-AB combination therapy are not available.Data regarding r/mHNSCC consecutive pts treated with cetuximab and platinum from 2009 to 2014 at our center were retrospectively collected. The analyses of response, Progression-Free Survival (PFS) and Overall Survival (OS), each evaluated starting from first and second-line treatment, were performed. Survival curves were estimated with the Kaplan-Meier method and compared using the log-rank test.We identified 117 patients treated with first-line platinum and cetuximab-based therapy. Sixty-four (55%) patients did not receive second-line treatment due to worsening in performance status, 2 were not assessable for response thus 51 patients were included for analysis. Fifty-six percent were smokers/former smokers and 78% were male. Primary tumor sites were oropharynx (39%), oral cavity (31%), larynx/hypopharynx (24%) and others (6%). Regimens used in second-line were mostly monotherapies. Twenty-one % of the patients were treated within a clinical trial.Response rate (PR, CR) was 6% with 45% showing SD as best response. Median PFS was 2.2 months (95%CI:1.5–2.8 months) and OS 6.1 months (95%CI:3.7–7.2 months).Within our single center experience only half of the patients with r/mHNSCC were able to receive second-line treatment. Response rate was unsatisfactory, but median OS seems higher than previously reported in an anti-EGFR-AB naïve population (Leon 2005).

Context Pancreatic adenocarcinoma (PA) is mostly metastatic at time of diagnosis with a poor survival. Objective We decided to explore whether metastatic site correlates with prognosis. Methods Patients with pathologic diagnosis of metastatic PA, treated at our Institution with upfront combination chemotherapy between April 1997 and August 2010 were eligible for this analysis. Baseline tumor assessment consisted of contrast enhanced computed tomography scan of the abdomen and the thorax. Results Two-hundreds and sixty-five patients with metastatic PA, median age 60 years; median PS 90; median CA 19-9 1,048 were eligible; 19 (7.2%) had prior pancreatic surgery. Metastases were located: in a single organ (n=150; 56.6%); liver (n=227; 85.3%); peritoneum (n=32; 12.1%); lung (n=53; 19.9%). Lung was the only metastatic site in 15 cases (5.6%). Median and 1-year overall survival (OS) was 9.0 months and 32.2%. Prior surgery correlated with better OS (11.7 and 51.0% versus 8.9 and 30.8%; P=0.006); liver metastases with worse OS (median and 1-year OS: 8.8 months and 29.7% versus 11.1 and 47.4%; P=0.005); while no difference in OS was observed based on number of metastatic sites (P=0.37); peritoneal (P=0.50) or lung metastases (P=0.10). Patients with lung as isolated metastatic site lived longer (17.3 months and 66.7%) with respect to the whole population (9.0 months and 30.1%; P=0.01) and to patients with lung metastases associated to other metastatic sites (8.8 months and 34.2%; P=0.07). Conclusions Prior surgery and metastatic site correlate with prognosis and should be used as a stratification criterion in prospective trials. Patients with lung as isolated metastatic site has a particularly good prognosis.

Background: Despite great advances in diagnostic and surgical techniques and perioperative treatments have been made, prognosis of gastric cancer is still hardly definable. At the present the concept of gastric carcinogenesis, while confirming the Correa model, draws attention to growth factors (gastrin, Hepatic growth factor, TGFa, VEGF) that seems to be responsible for excessive proliferation of tumor cells. Moreover Cox 2 * PG2 system plays a role in cell proliferation, apoptosis and angiogenesis and this system is believed to operate in gastric mucosa after HP infection.

Background: At the time of upfront treatment failure, over half of the patients with advanced pancreatic cancer are candidates for further treatment. Methods: Patients with metastatic gemcitabine-resistant pancreatic cancer were treated with mitomycin 8 mg/m2 on day 1, ifosfamide 2,500 mg/m2 and mesna 3,000 mg/m2 on days 1–3 every 28 days until progressive disease. A positive responder was defined as a patient who was progression free at 6 months from trial enrolment. According to the Fleming design, a sample size of 34 patients was estimated assuming p0 = 0.05 and p1 = 0.20. Results: Between May 2006 and December 2007, 21 patients (median age 56 years; median Karnofsky performance score 80) were enrolled. One patient died before receiving any treatment. Eighteen patients interrupted chemotherapy due to progressive disease (n = 15), toxicity (n = 2) or refusal (n = 1). Grade >2 toxicity consisted of neutropenia in 80% of patients, thrombocytopenia and fatigue in 20% and anemia in 10%. Only 1 patient was progression free at 6 months (5%). One patient had a partial response (5%) and 2 patients had stable disease (10%). Median survival was 3.7 months. Conclusion: Based on the poor outcome observed and on the high level of grade 3–4 toxicity, the trial was prematurely stopped and the mitomycin and ifosfamide regimen was considered insufficiently active in gemcitabine-pretreated advanced pancreatic cancer.