Antibody-drug conjugates in lung and breast cancer: current evidence and future directions-a position statement from the ETOP IBCSG Partners Foundation.

Following the approval of the first antibody-drug conjugates (ADCs) in the early 2000s, development has increased dramatically, with 14 ADCs now approved and >100 in clinical development. In lung cancer, trastuzumab deruxtecan (T-DXd) is approved in human epidermal growth factor receptor 2 (HER2)-mutated, unresectable or metastatic non-small-cell lung cancer, with ADCs targeting HER3 (patritumab deruxtecan), trophoblast cell-surface antigen 2 [datopotamab deruxtecan and sacituzumab govitecan (SG)] and mesenchymal-epithelial transition factor (telisotuzumab vedotin) in late-stage clinical development. In breast cancer, several agents are already approved and widely used, including trastuzumab emtansine, T-DXd and SG, and multiple late-stage trials are ongoing. Thus, in the coming years, we are likely to see significant changes to treatment algorithms. As the number of available ADCs increases, biomarkers (of response and resistance) to better select patients are urgently needed. Biopsy sample collection at the time of treatment selection and incorporation of translational research into clinical trial designs are therefore critical. Biopsy samples taken peri- and post-ADC treatment combined with functional genomics screens could provide insights into response/resistance mechanisms as well as the impact of ADCs on tumour biology and the tumour microenvironment, which could improve understanding of the mechanisms underlying these complex molecules. Many ADCs are undergoing evaluation as combination therapy, but a high bar should be set to progress clinical evaluation of any ADC-based combination, particularly considering the high cost and potential toxicity implications. Efforts to optimise ADC dosing/duration, sequencing and the potential for ADC rechallenge are also important, especially considering sustainability aspects. The ETOP IBCSG Partners Foundation are driving strong collaborations in this field and promoting the generation/sharing of databases, repositories and registries to enable greater access to data. This will allow the most important research questions to be identified and prioritised, which will ultimately accelerate progress and help to improve patient outcomes.

Adherence to oral anticancer treatments: network and sentiment analysis exploring perceived internal and external determinants in patients with metastatic breast cancer.

PURPOSE: Adherence to oral anticancer treatments (OATs) is a critical issue in metastatic breast cancer (MBC) to enhance survivorship and quality of life. The study is aimed to analyze the main themes and attributes related to OATs in MBC patients. This research is part of a project titled "Enhancing Therapy Adherence Among Metastatic Breast Cancer Patients" designed to produce a predictive model of non-adherence, a decision support system, and guidelines to improve adherence to OATs. METHODS: The study consists of an exploratory observational and qualitative analysis using a focus group method. A semi-structured interview guide was developed to handle relevant OAT themes. Wordcloud plots, network analysis, and sentiment analysis were performed. RESULTS: Nineteen female MBC patients participated in the protocol (age mean 55.95, SD = 6.87). Four main themes emerged: (theme 1) individual clinical pathway; (theme 2) barriers to adherence; (theme 3) resources to adherence; (theme 4) patients' perception of new technologies. The Wordcloud and network analysis highlighted the important role of treatment side effects and the relationship with the clinician in the modulation of adherence behavior. This result is consistent with the sentiment analysis underscoring patients experience fear of issues related to clinical values and ineffective communication and discontinuity of the doctor in charge of the patient care. CONCLUSION: The study highlighted the key role of the individual, relational variables, and side effects as internal and external determinants influencing adherence to MBC. Finally, the opportunity offered by eHealth technology to connect with other patients with similar conditions and share experiences could be a relief for MBC patients.

Evaluation of endocrine therapy and patients preferences in early breast cancer: results of Elena study.

PURPOSE: The development of the adjuvant therapy requires that clinicians and patients should discuss the magnitude of benefit of treatment for individual patient, estimating the pros and cons and the personal preferences. The aim of the present study was to determine the preferences of women treated with adjuvant hormonal therapy (HT) for breast cancer. METHODS: The analyses were conducted into three different groups of early breast cancer patients to evaluate the survival benefit needed to make treatment worthwhile before starting HT (A), after a few months from the beginning (B) and after several years of HT (C). The questionnaires, showing hypothetical scenarios based on potential survival times and rates without HT, were used to determine the lowest gains women judged necessary to make the treatment worthwhile. RESULTS: A total of 452 patients were included in the study: 149 in group A, 150 in group B and 153 in group C. In group C, 65% of patients were receiving HT with aromatase inhibitors (with or without a LHRH analogue). In the groups A, B, C 8%, 20% and 26%, respectively, received adjuvant chemotherapy. Overall, 355 women (79%) had children. The responses were quite similar between the three groups. A median gain of 10 years was judged necessary to make adjuvant HT worthwhile based on the hypothetical scenario of untreated mean survival time of 5 and 15 years. Median gain of 20% more women surviving was judged necessary to make adjuvant HT worthwhile based on an untreated 5-year survival rate expectation of 60%. Cognitive dysfunction was considered the side effect least compatible with the continuation of treatment in all three groups. CONCLUSIONS: This is a large study of patient preferences on HT. Compared with other studies with similar design, the patients included in the present study required larger benefits to make adjuvant therapy worthwhile.

Do all patients with advanced HER2 positive breast cancer need upfront-chemo when receiving trastuzumab? Randomized phase III trial SAKK 22/99.

Background: HER2-targeted therapy plus chemotherapy is standard treatment in advanced HER2+ breast cancer. Trastuzumab alone followed by addition of chemotherapy at disease progression versus upfront combination therapy has not been elucidated. Patients and methods: One-hundred seventy-five patients with measurable/evaluable HER2+ advanced disease without previous HER2-directed therapy were randomized to trastuzumab alone followed, at disease progression, by the combination with chemotherapy (Arm A) or upfront trastuzumab plus chemotherapy (Arm B). Chemotherapy could be stopped after ≥6 cycles in responding patients, trastuzumab was continued until progression. The primary endpoint of this superiority trial was time to progression (TTP) on combined trastuzumab-chemotherapy (Combination-TTP) in both arms. Secondary endpoints included response rate, TTP, overall survival, quality of life and toxicity. Results: Combination-TTP was longer than expected in both arms, 12.2 months in Arm A and 10.3 months in Arm B and not significantly different (hazard ratio [HR] 0.7; 95% CI 0.5-1.1; P =0.1). Overall survival was also not significantly different (HR 0.9; 95% CI 0.6-1.5; P = 0.55). In Arm A, the median TTP before introduction of chemotherapy was 3.7 months (95% CI 2.3-5.4), yet at 2 years 6% of patients were still on trastuzumab alone. Patients without visceral disease had a Combination-TTP of 21.8 months in arm A, compared with 10.1 months in arm B (unplanned analysis HR 2.1, 95% CI 1.1-4.2, P = 0.03). Patients with visceral disease showed no difference. Toxicity was chemotherapy-related. Conclusion: The outcome of patients receiving sequential trastuzumab-chemotherapy or upfront combination was similar. We failed to demonstrate superiority of the sequential approach. These results nevertheless suggest chemotherapy and its toxicity can be deferred, especially in patients with indolent, non-visceral disease. Despite a larger non-inferiority confirmatory study would be needed, these findings represent an additional proof of concept that de-escalation strategies can be discussed in individual patients.

Outcomes of special histotypes of breast cancer after adjuvant endocrine therapy with letrozole or tamoxifen in the monotherapy cohort of the BIG 1-98 trial.

BACKGROUND: We investigated the outcomes of postmenopausal women with hormone receptor-positive, early breast cancer with special histotypes (mucinous, tubular, or cribriform) enrolled in the monotherapy cohort of the BIG 1-98 trial. PATIENTS AND METHODS: The intention-to-treat BIG 1-98 monotherapy cohort (5 years of therapy with tamoxifen or letrozole) included 4922 women, of whom 4091 had central pathology review. Histotype groups were defined as: mucinous (N = 100), tubular/cribriform (N = 83), ductal (N = 3257), and other (N = 651). Of 183 women with either mucinous or tubular/cribriform tumors, 96 were randomly assigned to letrozole and 87 to tamoxifen. Outcomes assessed were disease-free survival (DFS), overall survival (OS), breast cancer-free interval (BCFI), and distant recurrence-free interval (DRFI). Median follow-up in the analytic cohort was 8.1 years. RESULTS: Women with tubular/cribriform breast cancer had the best outcomes for all end points compared with the other three histotypes, and had less breast cancer recurrence (97.5% 5-year BCFI) than those with mucinous (93.5%), ductal (88.9%), or other (89.9%) histotypes. Patients with mucinous or tubular/cribriform carcinoma had better DRFI (5-year rates 97.8% and 98.8%, respectively) than those with ductal (90.9%) or other (92.1%) carcinomas. Within the subgroup of women with special histotypes, we observed a nonsignificant increase in the hazard of breast cancer recurrence with letrozole [hazard (letrozole versus tamoxifen): 3.31, 95% confidence interval 0.94-11.7; P = 0.06]. CONCLUSIONS: Women with mucinous or tubular/cribriform breast cancer have better outcomes than those with other histotypes, although the observation is based on a limited number of events. In postmenopausal women with these histotypes, the magnitude of the letrozole advantage compared with tamoxifen may not be as large in patients with mucinous or tubular/cribriform disease. CLINICALTRIALSGOV: NCT00004205.

Multiplexed high-throughput immune cell imaging in patients with high-risk triple negative early breast cancer: Analysis from the International Breast Cancer Study Group (IBCSG) Trial 22-00.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer (BC) subtype, with dismal prognosis and limited option in advanced settings, yet stromal tumor infiltrating lymphocytes (sTILs) in this subtype has a predictive role. PATIENTS AND METHODS: The International Breast Cancer Study Group (IBCSG) Trial 22-00 is a randomized phase III clinical trial testing the efficacy of low-dose metronomic oral Cyclophosphamide-Methotrexate (CM) maintenance following standard adjuvant chemotherapy treatment for early-stage hormone receptor-negative breast cancer patients. A case-cohort sampling was used. We characterized immune cells infiltrates in patients with TNBC by 6 plex immunofluorescence (IF) staining for CD4, FOXP3, CD3, cytokeratine and CD8 RESULTS: We confirmed that high immune CD3+ T cells as well as stromal and intra-epithelial Tregs (CD4+Foxp3+ T cells) infiltrates were associated with a better Distant Recurrence-Free Interval (DRFI), especially in LN+ patient, regardless of the treatment. More importantly, we showed that the spatial distribution of immune cells at baseline is crucial, as CM maintenance was detrimental for T cells excluded LN+ TNBC patients. CONCLUSIONS: immune spatial classification on immune cells infiltrates seems crucial and could help patients' selection in clinical trial and greatly improve responses to specific therapies.

CMF revisited in the 21st century.

Over the last 35 years, classical CMF (combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil) has been a milestone in the adjuvant treatment of women with breast cancer. However, after an early burst of success lasted just over 10 years, classical CMF has been supplanted by 'third-generation' regimens containing taxanes and anthracyclines. Questions have been raised in the past years concerning the true effectiveness of adjuvant CMF for specific subgroups of patients and particularly, recent retrospective data support the fact that the CMF might have a role in the treatment of patients with triple-negative breast cancer. One possible justification for supporting this role of CMF may be sought in the mechanism of action of drugs used in the regimen, as triple-negative cells may be sensitive to alkylating agents that cause double-strand breaks in DNA. The lesson learned from the CMF could lead us to identify new combinations of drugs that could include the optimal chemotherapy backbone for triple-negative breast cancer such as platinum compounds or alkylating agents or Poly (ADP-ribose) polymerase inhibitors. In conclusion, although we have learned a lot from the use of CMF, many questions are still open and hopefully stimulate our thinking, as clinicians, leading us to find new and more effective ways to treat breast cancer.

Outcome and clinical-biological characteristics of patients with advanced breast cancer undergoing removal of ovarian/pelvic metastases.

BACKGROUND: Patients with metastatic breast cancer to the ovary, without tumor debulking and after systemic therapy, have a 5-year survival rate < 10%. PATIENTS AND METHODS: We analyzed a series of 37 patients, operated in one institution over 10 years, for both the primary tumor (PT) and ovarian/pelvic metastases (OPM). Estrogen receptors (ER), progesterone receptors (PgR), HER-2 and Ki-67 were determined. RESULTS: Patients were predominantly young: 27 (73%) patients were < 50 years. Average ER/PgR expression did not change significantly between PT (mean ER = 66%, PgR = 35%) and OPM (mean ER = 67%, PgR = 28%). Median time to OPM was 42 months (range 0-176); 5-year OS after OPM was 51% (95% confidence interval 32% to 67%). When combining ER and PgR status, patients with ER > 50% on both PT and OPM and with PgR > 50% on PT and/or OPM (good prognosis, 11 patients) had a better outcome versus0 patients with ER and PgR ≤ 50% on both PT and OPM (bad prognosis, eight patients) and also versus the remaining patients (intermediate prognosis, 18 patients), P value = 0.010. CONCLUSION: Patients with OPM from breast cancer show a favorable prognosis after tumor debulking, whether it was radical or not, especially when a high expression of ER and PgR is present in both PT and OPM.

CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer.

Cyclin-dependent kinase 12 (CDK12) overexpression is implicated in breast cancer, but whether it has a primary or only a cooperative tumorigenic role is unclear. Here, we show that transgenic CDK12 overexpression in the mouse mammary gland per se is sufficient to drive the emergence of multiple and multifocal tumors, while, in cooperation with known oncogenes, it promotes earlier tumor onset and metastasis. Integrative transcriptomic, metabolomic and functional data reveal that hyperactivation of the serine-glycine-one-carbon network is a metabolic hallmark inherent to CDK12-induced tumorigenesis. Consistently, in retrospective patient cohort studies and in patient-derived xenografts, CDK12-overexpressing breast tumors show positive response to methotrexate-based chemotherapy targeting CDK12-induced metabolic alterations, while being intrinsically refractory to other types of chemotherapy. In a retrospective analysis of hormone receptor-negative and lymph node-positive breast cancer patients randomized in an adjuvant phase III trial to 1-year low-dose metronomic methotrexate-based chemotherapy or no maintenance chemotherapy, a high CDK12 status predicts a dramatic reduction in distant metastasis rate in the chemotherapy-treated vs. not-treated arm. Thus, by coupling tumor progression with metabolic reprogramming, CDK12 creates an actionable vulnerability for breast cancer therapy and might represent a suitable companion biomarker for targeted antimetabolite therapies in human breast cancers.

Should liver metastases of breast cancer be biopsied to improve treatment choice?

BACKGROUND: Currently, the acquisition of tissue from metastatic deposits is not recommended as a routine practice. Our aim was to evaluate the discordance rate of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) receptor status between primary tumor and liver metastases and its potential impact on treatment choice. PATIENTS AND METHODS: We retrospectively analyzed a database including 1250 ultrasound-guided liver biopsies carried out at the European Institute of Oncology from August 1999 to March 2009. ER, PgR, and HER2 status were determined by immunohistochemistry and/or FISH. Differences between proportions were evaluated using Fisher's exact test. RESULTS: We identified 255 consecutive patients with matched primary and liver tissue samples. Changes in ER status were observed in 37 of 255 patients (14.5%). Changes in PgR status were observed in 124 of 255 patients (48.6%). Changes in HER2 status were observed in 24 of 172 assessable patients (13.9%). We observed a discordance in receptor status (ER, PgR, and HER2) between primary tumor and liver metastases, which led to change in therapy for 31 of 255 of patients (12.1%). CONCLUSIONS: Biopsy of metastases for reassessment of biological features should be considered in all patients, when safe and easy to carry out, since it is likely to impact treatment choice.

Systematic review and meta-analysis of post-progression outcomes in ER+/HER2- metastatic breast cancer after CDK4/6 inhibitors within randomized clinical trials.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and endocrine therapy (ET) deeply transformed the treatment landscape of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer. Randomized clinical trials suggest that second progression-free survival (PFS2) was not compromised and time to subsequent chemotherapy (TTC) may be delayed. We carried out a meta-analysis to assess the benefit on PFS2 and on delaying the TTC. METHODS: We conducted a systematic literature search of randomized clinical trials with CDK4/6 inhibitors and ET reporting PFS2 or TTC of HR+/HER2- pre- or postmenopausal metastatic breast cancer. We also reviewed abstracts and presentations from all major conference proceedings. We calculated the pooled hazard ratios (HR) for PFS2 and TTC using random-effects models with 95% confidence intervals (CI). I2 was used to quantify heterogeneity between results of the studies. RESULTS: Eight studies (MONALEESA-2/3/7, MONARCH-2/3, PALOMA-1/2/3) were included in this analysis (N = 4580 patients). PFS2 benefit was observed in patients who received CDK4/6 inhibitors plus ET (pooled HR = 0.68, 95% CI = 0.62-0.74, I2 = 0%) and also a delay in subsequent TTC (pooled HR = 0.65, 95% CI = 0.60-0.71, I2 = 0%). A benefit in terms of PFS (pooled HR = 0.55, 95% CI = 0.51-0.59, I2 = 0%) and overall survival (pooled HR = 0.76, 95% CI = 0.69-0.84, I2 = 0%) was also observed. CONCLUSIONS: CDK4/6 inhibitors plus ET compared with ET alone improve PFS2 and TTC. The delay of chemotherapy may postpone the start of a more toxic treatment option, delaying related toxicities and potentially maintaining a better quality of life for patients, for a longer time. The benefit in PFS2 may postpone the onset of endocrine resistance and help further validate this treatment approach.

A phase I-II study of the histone deacetylase inhibitor valproic acid plus chemoimmunotherapy in patients with advanced melanoma.

We explored in a phase I/II clinical trial the combination of valproic acid (VPA), a clinically available histone deacetylase inhibitor, with standard chemoimmunotherapy in patients with advanced melanoma, to evaluate its clinical activity, to correlate the clinical response with the biological activity of VPA and to assess toxicity. Patients were treated initially with VPA alone for 6 weeks. The inhibition of the target in non-tumour peripheral blood cells (taken as a potential surrogate marker) was measured periodically, and valproate dosing adjusted with the attempt to reach a measurable inhibition. After the treatment with valproate alone, dacarbazine plus interferon-alpha was started in combination with valproate. Twenty-nine eligible patients started taking valproate and 18 received chemoimmunotherapy and are assessable for response. We observed one complete response, two partial remissions and three disease stabilisations lasting longer than 24 weeks. With the higher valproate dosages needed to reach a measurable inhibition of the target, we observed an increase of side effects in those patients who received chemoimmunotherapy. The combination of VPA and chemoimmunotherapy did not produce results overtly superior to standard therapy in patients with advanced melanoma and toxicity was not negligible, casting some doubts on the clinical use of VPA in this setting (at least in the administration schedule adopted).

Variation of circulating tumor cell levels during treatment of metastatic breast cancer: prognostic and therapeutic implications.

BACKGROUND: This study aimed to evaluate the prognostic significance of circulating tumor cells (CTCs) detection in advanced breast cancer patients. PATIENTS AND METHODS: We tested 80 patients for CTC levels before starting a new treatment and after 4, 8 weeks, at the first clinical evaluation and every 2 months thereafter. CTCs were detected using the CellSearch System. RESULTS: Forty-nine patients had >or=5 CTCs at baseline. At the multivariate analysis, baseline number of CTCs was significantly associated with progression-free survival [hazard ratio (HR) 2.5; 95% confidence interval (CI) 1.2-5.4]. The risk of progression for patients with CTCs >or=5 at last available blood draw was five times the risk of patients with 0-4 CTCs at the same time point (HR 5.3; 95% CI 2.8-10.4). Patients with rising or persistent >or=5 CTCs at last available blood draw showed a statistically significant higher risk of progression with respect to patients with <5 CTCs at both blood draws (HR 6.4; 95% CI 2.8-14.6). CONCLUSION: CTCs basal value is a predictive indicator of prognosis and changes in CTC levels during therapy may indicate a clinical response. Testing CTC levels during targeted treatments might substitute other measurement parameters for response evaluation.

Optimizing clinical care of patients with metastatic breast cancer: a new oral vinorelbine plus trastuzumab combination.

BACKGROUND: Trastuzumab (T) combined with i.v. vinorelbine (i.v.VNR) is an active regimen for patients with advanced breast cancer (ABC). In order to further improve quality of life of patients undergoing treatment for ABC, a new regimen using oral vinorelbine (oVNR) (d1 + d3) plus q3wks T was tested (ToVNR). PATIENTS AND METHODS: Thirty-nine patients with ABC, human epidermal growth factor receptor 2/neu 3+ or FISH positive received 288 treatment cycles with T 6 mg/kg (loading dose, 8 mg/kg) on d1 and oVNR 55 mg/m(2) on d1 + d3, q3wks until disease progression or unacceptable toxicity. RESULTS: Thirty-seven patients and 286 treatment cycles were evaluated (two patients were lost to follow-up). Treatment was very well tolerated. Two patients had complete response (CR), 14 partial response (PR), 17 stable disease (SD) and four disease progression (PD) (overall response rate: 43%). Clinical benefit rate (CR + PR + SD >24 months) was 73%. Median time to progression was 8.9 months (range 2-27) and median duration of response was 10.9 months (range 2-27). CONCLUSIONS: The ToVNR combination is active and very well tolerated. It favorably compares with the combination of T and weekly i.v. administered VNR, allowing a more convenient once every three weeks hospital admission and leaving patients and care providers free from the unpleasant effect of i.v.VNR.

Brain metastases in patients with advanced breast cancer.

BACKGROUND: The incidence of brain metastases (BM) is apparently rising in patients with advanced breast cancer (ABC). We performed a case control study to define current features of breast cancer related to central nervous system (CNS) metastases. PATIENTS AND METHODS: From March 1999 to May 2006, we identified 72 patients with symptomatic BM of breast cancer. A comparison group was randomly selected assigning to each case two patients with primary breast cancer and no BM, matched for year of diagnosis, age and tumour stage (pT status and nodal status). RESULTS: Cases had a significantly higher rate of negative estrogen receptors (ERs) (60% in cases vs. 29% in controls), negative progesterone receptors (PgRs) (79% vs. 43%), HER2/neu over expression (44% vs. 13%) and immunostaining for Ki-67 > or =20% (84% vs. 55%), with p-value <0.001 for all four parameters in univariate analyses. On multivariate analysis, HER2/neu over expression and Ki-67 -20% were independent predictive factors of brain relapse (Odds Ratio (OR) 2.55, 95% confidence intervals (CI) 1.10-5.94 and OR 2.97, 95% CI 1.01-8.73, respectively). Endocrine unresponsive tumours (both ER and PgR <10%) showed an increased risk of relapse with BM of borderline significance (OR 1.91, 95% CI 0.87-4.12). CONCLUSION: Patients with ER and PgR negative tumours either with or without HER-2/neu over expression should be considered at higher risk of BM.

Paclitaxel in metastatic breast cancer: a trial of two doses by a 3-hour infusion in patients with disease recurrence after prior therapy with anthracyclines.

BACKGROUND: To date, anthracyclines are the most active drugs against breast tumors, and the taxane paclitaxel (Taxol) looks very promising. Both classes of drugs are affected by cellular multidrug-resistance mechanisms, and therefore their sequential use raises the possibility of clinical cross-resistance. It is therefore important to assess the activity of paclitaxel in patients with clinical resistance to anthracyclines. PURPOSE: We assessed the safety and efficacy of paclitaxel administered by the logistically convenient 3-hour infusion to breast cancer patients who had disease progression within 12 months since prior therapy with anthracyclines. METHODS: Fifty-one patients with metastatic breast cancer who had all relapsed or whose disease had progressed within 12 months from completion of an anthracycline-containing chemotherapy protocol (six receiving adjuvant therapy, 19 receiving neoadjuvant therapy, and 26 receiving treatment for metastatic disease) were enrolled in this phase II trial from June 1992 to May 1994. After medication to prevent type I acute hypersensitivity reactions, paclitaxel was given intravenously over 3 hours at 175 mg/m2 to the first 15 patients and at 225 mg/m2 to the next 36 patients. The median age was 50 years (range, 31-62 years), and the median Eastern Cooperative Oncology Group performance status was 0 (range, 0-2). RESULTS: Patients received a median of five cycles (range, one to 11 cycles). After initial doses of 175 and 225 mg/m2, paclitaxel could be increased by 25 mg/m2 in 73% and 58% of cycles, respectively. Among 50 assessable patients, seven achieved a complete response and 12 achieved a partial response (response rate, 38% [95% confidence interval = 25%-53%]). The median duration of response was 7 months (range, 4-16 months), and the median time to disease progression for all patients was 5 months. Grade 4 neutropenia occurred in 3% of the cycles and in 12% of the patients and was never associated with fever and infection. Common toxic effects were myalgia and arthralgia (94% of the patients; 4% grade 3), peripheral neuropathy (92% of the patients; 8% grade 3), and alopecia (all patients). Pruritus and neuropathy were significantly more frequent and severe, respectively, with the higher dose (P < .01 by chi 2 test). Frequency and severity of other toxic effects were similar at either starting dose. Ten patients had symptoms of neuro-optic toxicity. Only one patient had a grade 2 hypersensitivity reaction. CONCLUSIONS: Paclitaxel at starting doses of 175 and 225 mg/m2 given as a 3-hour infusion can safely be administered to, and is active in women whose disease has progressed after prior treatment with anthracyclines. There was evidence of increased toxicity at the higher dose but no suggestion of better efficacy. IMPLICATION: Paclitaxel by a 3-hour infusion in combination with doxorubicin should be investigated in patients with metastatic breast cancer. Unless randomized trials demonstrate greater efficacy of the more toxic higher dose, it is suggested that a dose of 175-200 mg/m2 be administered with the 3-hour infusion schedule.

Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study.

PURPOSE: To define the maximum-tolerated dose (MTD) and better tolerated sequence of paclitaxel by 3-hour infusion plus bolus doxorubicin (DOX) and to evaluate antitumor efficacy. PATIENTS AND METHODS: Thirty-five women with metastatic breast cancer (dominant visceral metastases in 56%, and involvement of > or = three sites in 67%) who never received chemotherapy of any type were studied. Paclitaxel every 3 weeks (125 mg/m2 starting dose) was increased by 25-mg/m2 steps in subsequent cohorts of patients. DOX (60 mg/m2 fixed dose) was administered 15 minutes before the start of or after the end of paclitaxel for a maximum of eight cycles. Subsequently, patients in continuous response could receive single-agent paclitaxel (175 to 200 mg/m2 every 3 weeks). The drug sequence was alternated in consecutive patients and in the first two cycles. RESULTS: Severe neutropenia that lasted greater than 7 days (n = 4), febrile neutropenia (n = 7) and grade III oral mucositis (n = 6) defined the MTD of paclitaxel at 200 mg/m2 in 34 assessable patients. Grade II peripheral neuropathy occurred in 33% of patients. Six women (18%) developed clinically reversible congestive heart failure (CHF) after a median of 480 mg/m2 total DOX. Drug sequence had no effect on toxicities. High efficacy on all metastatic sites in 32 assessable patients accounted for a 41% complete response (CR) rate (95% confidence interval [CI], 24% to 59%) and 94% overall-response rate (95% CI, 79% to 99%). After a median follow-up of 12 months (range 3 to 18), the median response duration is 8 months (range, 2+ to 18+) for complete responders and 11 months (range 1+ to 15+) for partial responders. CONCLUSION: The rate of CR and incidence of CHF may be an expression of therapeutic and toxic enhancement due to the schedule used in this trial. Until clarification of this possibility, this promising combination should be used in investigational trials.

Response of bilateral choroidal metastases of breast cancer to therapy with trastuzumab.

Intraocular metastases, especially those of the choroidal plexus, are not common in metastatic breast cancer patients and are typically associated with a poor prognosis and impaired quality of life. A 45-year-old woman with breast cancer overexpressing HER2 and metastasizing to choroidal plexus, lymph nodes and skin received a combination of trastuzumab and paclitaxel as first-line treatment. Subsequently, at progression, trastuzumab was reintroduced together with vinorelbine. Administration of trastuzumab with either paclitaxel or vinorelbine led to a rapid improvement of the ocular symptoms, associated with a rapid objective response of all metastatic lesions and a prompt improvement in the quality of life. Choroidal metastases from breast cancer overexpressing HER2 are responsive to trastuzumab and chemotherapy (paclitaxel or vinorelbine). The susceptibility of ocular metastases to this approach seems different to that of other sanctuary disease sites.

Pharmacokinetics of anticancer agents in patients with impaired liver function.

This report reviews published information on the clinical pharmacokinetics of antitumour agents in patients with liver dysfunction, associated with primary liver disease or liver metastases. Information was available for anthracyclines and their related compounds, antimetabolites, cyclophosphamide, vinca alkaloids, taxanes and epipodophyllotoxins. Changes in the pharmacokinetic profile or metabolism in patients with mild or severe hepatobiliary dysfunction are described and the relationships between serum levels, parameters employed for measuring hepatic function and toxic or therapeutic effects are examined. Current knowledge of the pharmacokinetics of antineoplastic agents in liver disease is far from complete, mostly obtained in small numbers of non-homogeneous patients often presenting only moderate liver dysfunction, and empirical guidelines for dose assessment are still largely applied in clinical practice. Because of the complex pathophysiological mechanisms of liver insufficiency in cancer patients, there is still doubt whether endogenous markers are useful. Although caution in treating cancer patients with liver insufficiency is compulsory, for most compounds there seems no need to recommend dose reductions for moderate impairment. However, for the tubulin acting agents, vincristine, vinblastine and possibly for paclitaxel and docetaxel, there is strong evidence that dose adjustment is mandatory in order to avoid excessive neutropenia and neurotoxicity.