Taxane versus vinorelbine in combination with trastuzumab and pertuzumab for first-line treatment of metastatic HER2-positive breast cancer: a retrospective two-center study.

BACKGROUND: The combination of a taxane with trastuzumab and pertuzumab is standard of care for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The combination of vinorelbine with trastuzumab and pertuzumab showed anti-tumor activity in a phase 2 trial. PATIENTS AND METHODS: The databases of two tertiary medical centers were retrospectively searched for patients with HER2-positive metastatic breast cancer who underwent first-line treatment in 2013-2019 with a taxane or vinorelbine in combination with trastuzumab and pertuzumab. Groups were compared for progression-free survival (PFS), overall survival (OS), and toxicity profile. RESULTS: The study included 87 patients in the taxane group and 65 in the vinorelbine group. Overall median PFS was significantly longer in the taxane group [HR 0.56 (0.36-0.88), P = 0.01], but on multivariate analysis the difference was not statistically significant [HR 0.68 (0.4-1.1, P = 0.11)]. PFS was comparable in both groups of patients with recurrent disease [HR 0.94 (0.5-1.79), P = 0.85]. However, in patients with de novo metastatic disease, the difference in favor of the taxane group was pronounced [HR 0.4 (0.2-0.78), P = 0.007] and maintained significance on multivariate analysis [HR 0.46 (0.2-0.97, P = 0.04)]. There was no statistical significant difference in OS in the whole cohort [HR 0.69 (0.39-1.23)] or the subgroups. CONCLUSIONS: Patients with HER2-positive metastatic breast cancer had similar survival with first-line treatment of taxane or vinorelbine combined with trastuzumab and pertuzumab. When the analysis was adjusted for prognostic factors, there was no PFS benefit for taxanes except in the subgroup with de novo disease.

Prognostic Value of the Detection of Lymphovascular Invasion in Hormone Receptor-Positive Early Breast Cancer in the Era of Molecular Profiling.

BACKGROUND: Lymphovascular invasion (LVI) is considered a negative prognostic factor in early breast cancer, but its role in decision-making regarding adjuvant chemotherapy is unclear in the current era of molecular profiling. This study sought to evaluate the association of LVI status with the recurrence score (RS) on the multigene Oncotype DX (ODX) assay and its impact on outcome. METHODS: Patients with early estrogen receptor-positive breast cancer who underwent ODX analysis in 2005-2012 were retrospectively identified. Clinical data were collected from the medical records. The Cox proportional-hazards ratio was used to determine recurrence rates. The prognostic significance of LVI was evaluated by competing risks analysis. RESULTS: LVI was detected in 38 of 657 patients (6%). LVI was not associated with ODX RS (p = 0.225). However, it was significantly associated with other known prognostic factors and with worse 5-year disease-free survival (HR 2.93; 95% CI 1.02-8.39; p = 0.04). Overall survival (OS) analysis according to the ODX subgroups showed that the presence of LVI was associated with worse 5-year OS (p = 0.04) only in the intermediate-risk group, while LVI had no effect on the low- or high-risk groups. CONCLUSIONS: Although LVI was not significantly associated with a higher ODX RS, it may infer a worse outcome, especially in ODX intermediate-risk patients.

Early Breast Cancer in the Elderly: Characteristics, Therapy, and Long-Term Outcome.

OBJECTIVE: The number of older adults diagnosed with breast cancer is increasing. However, data on breast cancer characteristics, treatment, and survival in elderly women are sparse. METHODS: The database of a tertiary cancer center was searched for all women aged ≥65 years who were diagnosed with early breast cancer in 2004-2007. Patients were divided into 2 age groups: 65-75 years and >75 years. Data on tumor, treatment, and outcome parameters were compared. RESULTS: The cohort included 390 patients. The older group underwent more mastectomies but less axillary surgery or adjuvant systemic therapy. Median overall survival (OS) was 9.5 years in the older group and not reached in the younger group; the 8-year disease-free survival rates were 85 and 88%, respectively (p = 0.27). Both age and tumor subtype had an effect on OS and recurrence rates (p < 0.001 for OS; p = 0.16 for recurrence). The worst outcome was noted in women aged >75 years with triple-negative (TN) disease. CONCLUSION: The treatment approach was different between both age groups, despite similar tumor characteristics. TN subtype presented as the most aggressive disease in both age groups. Physicians should be alert to these findings and select treatment on a case-by-case basis.

The association between smoking and breast cancer characteristics and outcome.

BACKGROUND: Smoking is associated with an increased incidence of hormone receptor positive breast cancer. Data regarding worse breast cancer outcome in smokers are accumulating. Current literature regarding the impact of smoking on breast cancer characteristics is limited. We evaluated the impact of smoking on breast cancer characteristics and outcome. METHODS: This was a retrospective single center study. All women diagnosed from 4/2005 through 3/2012 and treated in our institute for early, estrogen receptor positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer, whose tumors were sent for Oncotype DX analysis were included. Medical records were reviewed for demographics, clinico-pathological parameters, treatment and outcome. Data regarding smoking were retrieved according to patients' history at the first visit in the oncology clinic. Patients were grouped and compared according to smoking history (ever smokers vs. never smokers), smoking status (current vs. former and never smokers) and smoking intensity (pack years ≥30 vs. the rest of the cohort). Outcomes were adjusted in multivariate analyses and included age, menopausal status, ethnicity, tumor size, nodal status and grade. RESULTS: A total of 662 women were included. 28.2% had a history of smoking, 16.6% were current smokers and 11.3% were heavy smokers. Smoking had no impact on tumor size, nodal involvement and Oncotype DX recurrence score. Angiolymphatic and perineural invasion rates were higher in current smokers than in the rest of the cohort (10.4% vs. 5.1%, p = 0.045, 8.3% vs. 3.5%, p = 0.031, respectively). Smoking had no other impact on histological characteristics. Five-year disease free survival and overall survival rates were 95.7% and 98.5%, respectively. Smoking had no impact on outcomes. Adjusted disease free survival and overall survival did not influence the results. CONCLUSIONS: Smoking had no clinically significant influence on tumor characteristics and outcome among women with estrogen receptor positive, HER2 negative, early breast cancer. As the study was limited to a specific subgroup of the breast cancer population in this heterogeneous disease and since smoking is a modifiable risk factor for the disease, further research is required to clarify the possible impact of smoking on breast cancer.

The Association between Angiotensin Receptor Blocker Usage and Breast Cancer Characteristics.

PURPOSE: To evaluate the association between angiotensin receptor blocker (ARB) usage and breast cancer characteristics and outcomes. METHODS: All patients who were treated in our institute for estrogen receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer between April 2005 and March 2012 and whose tumors were sent for Oncotype-DX analysis were included. Medical records were retrospectively reviewed. Data regarding ARB usage were retrieved. Usage of several prespecified medications for hypertension was also evaluated. Each medication group was compared with the rest of the cohort. RESULTS: A total of 671 patients were included. Forty-six (7%) patients were treated with ARB. ARB usage was associated with macroscopic nodal involvement (p < 0.001) and a more advanced stage at diagnosis (p < 0.001). These findings remained significant in the multivariate analysis. Patients treated with ARB also had a higher incidence of invasive lobular carcinoma subtype (p = 0.009), a worse 5-year breast cancer-specific survival (94.7 vs. 98.8%, p = 0.024) and a worse 5-year overall survival (94.6 vs. 98.8%, p = 0.015), but these differences were not demonstrated in the multivariate analysis. CONCLUSIONS: Patients treated with ARB presented with a more advanced breast cancer disease and some distinct histological features. Further research is required to elucidate the effect of ARB treatment on breast cancer.

Colorectal cancer in young patients: is it a distinct clinical entity?

BACKGROUND: The incidence of colorectal cancer in young patients is increasing. It remains unclear if the disease has unique features in this age group. METHODS: This was a single-center, retrospective cohort study which included patients diagnosed with colorectal cancer at age ≤40 years in 1997-2013 matched 1:2 by year of diagnosis with consecutive colorectal cancer patients diagnosed at age >50 years during the same period. Patients aged 41-50 years were not included in the study, to accentuate potential age-related differences. Clinicopathological characteristics, treatment, and outcome were compared between groups. RESULTS: The cohort included 330 patients, followed for a median time of 65.9 months (range 4.7-211). Several significant differences were noted. The younger group had a different ethnic composition. They had higher rates of family history of colorectal cancer (p = 0.003), hereditary colorectal cancer syndromes (p < 0.0001), and inflammatory bowel disease (p = 0.007), and a lower rate of polyps (p < 0.0001). They were more likely to present with stage III or IV disease (p = 0.001), angiolymphatic invasion, signet cell ring adenocarcinoma, and rectal tumors (p = 0.02). Younger patients more frequently received treatment. Young patients had a worse estimated 5-year disease-free survival rate (57.6  vs. 70 %, p = 0.039), but this did not retain significance when analyzed by stage (p = 0.092). Estimated 5-year overall survival rates were 59.1 and 62.1 % in the younger and the control group, respectively (p = 0.565). CONCLUSIONS: Colorectal cancer among young patients may constitute a distinct clinical entity. Further research is needed to validate our findings and define the optimal approach in this population.

Earlier Age of Breast Cancer Onset in Israeli BRCA Carriers-Is it a Real Phenomenon?

Data on genetic anticipation in breast cancer are sparse. We sought to evaluate age at diagnosis of breast cancer in daughters with a BRCA mutation and their mothers. A review of all carriers of the BRCA mutation diagnosed with breast cancer at the Genetics Institute of a tertiary medical center in 2000-2013 yielded 80 women who could be paired with a mother with breast cancer who was either a carrier of the BRCA mutation or an obligate carrier according to pedigree analysis. Age at diagnosis, type of mutation (BRCA1, BRCA2), year of birth, and ethnicity were recorded. Paired t-test was used to analyze differences in age at cancer diagnosis between groups and subgroups. Mean age at diagnosis of breast cancer was 50.74 years (range 22-88) in the mothers and 43.85 years (range 24-75) in the daughters. The difference was statistically significant (p < 0.001). These findings were consistent regardless of type of BRCA mutation, ethnicity, or mother's year of birth. However, on separate analysis of pairs in which the mother was diagnosed before the age of 50 years, there was no significant difference in mean age at diagnosis between mothers and daughters (~42 years for both). Daughters who carry a BRCA mutation are diagnosed with breast cancer at an earlier age than their carrier mothers, with the exception of pairs in which the mother was diagnosed before the age of 50 years. Future breast-screening guidelines may need to target specific subpopulations of BRCA mutation carriers.

A Dedicated Follow-Up Clinic for BRCA Mutation Carriers.

BACKGROUND: Women who carry the BRCA gene mutation have an up to 80% chance of developing cancer, primarily of breast and ovarian origin. Confirmation of carrier status is described by many women as an overwhelming, life-changing event. Healthy individuals harboring a BRCA mutation constitute a high risk population with unique needs, often overlooked by health authorities. As such, we felt the need to create a specialized service dedicated specifically to this high risk population. The clinic staff comprises an experienced multidisciplinary team of health professionals who can support the medical and emotional needs of this population. Since its inception in 2001 the clinic has served 318 women. The mean age of patients is 46 years. With a median follow-up of 46 months, 21 women have developed malignancies, including 17 breast cancers, 1 ovarian cancer and 3 additional cancers. All but one of the patients above the age of 40 underwent bilateral salpingo-oophorectomy (BSO). The median and mean ages at BSO were 46.5 and 48 years, respectively (range 33-68). However, only 28.3% underwent bilateral preventive mastectomy. A multidisciplinary clinic for BRCA mutation carriers provides a "home" for this unique population with unmet needs. The high rate of BSO in women before natural menopause indicates that both the medical community and this population are aware of international guidelines supporting this procedure. We believe that a dedicated clinic, with a multidisciplinary team, is likely to contribute to the health, quality of life and survival of BRCA carriers.

Low molecular weight heparin (LMWH) for primary thrombo-prophylaxis in patients with solid malignancies - systematic review and meta-analysis.

BACKGROUND: Patients receiving chemotherapy for cancer are at increased risk for venous thromboembolism (VTE). We performed a meta-analysis of all randomized controlled trials (RCTs) which evaluated low molecular weight heparin (LMWH) as primary prophylaxis in ambulatory patients with solid malignancies. METHODS: A comprehensive search was conducted until October 2013. Primary outcome was symptomatic VTE. Secondary outcomes were pulmonary embolism (PE), any VTE, deep vein thrombosis (DVT), mortality and adverse events. RESULTS: Eleven trials met the inclusion criteria, and evaluated a total of 6942 patients. Primary prophylaxis with LMWH reduced symptomatic VTE (RR 0.46, 95% CI 0.32-0.67) and the rate of PE (RR 0.49, 95% CI 0.29-0.84). In the subgroup analysis of VTE in patients with lung and pancreatic cancers LMWH further reduced VTE [RR 0.42 (95% CI 0.25-0.71); RR 0.31 (95% CI 0.18-0.55), respectively]. Meta-analysis of six trials which reported survival outcomes revealed no statistically significant benefit for LMWH in one-year mortality rates (RR 0.93, 95% CI 0.83-1.04). There was no significant increase in major bleeding events (RR 1.28, 95% CI 0.84-1.95). CONCLUSIONS: LMWH reduces the incidence of symptomatic VTE and PE in patients receiving chemotherapy for cancer, with no apparent increase in major bleeding. The benefit is most apparent in pancreatic cancer and also lung cancer. VTE prophylaxis should be considered for these specific populations.

[What is the "seed of evil" mediating the pathway for the formation of metastases?].

The metastatic process remains one of the most enigmatic aspects of cancer pathogenesis. The concept of "cancer stem cells" (CSC) has evolved over the past decade, elucidating the presence of a distinct population of cells which is defined by their high tumorigenic capacity and long-term self-renewal ability. In this editorial, we discuss the association between cancer stem cells and circulating tumor cells (CTC) (see article by Grinshpun et al. in this issue) and the role of CSC in mediating the formation of cancer metastases. Intensive research is ongoing on the clinical significance of CTC in a wide variety of malignancies; CTC are a heterogeneous population of cells which include CSC as well, a major player in the formation of metastases. A better understanding of the unique properties of CSC and their interaction with the microenvironment will enable the development of ways to detect and target this cell population.

Mitomycin C and capecitabine: An additional option as an advanced line therapy in patients with metastatic colorectal cancer.

BACKGROUND: In recent years survival of patients with metastatic colorectal cancer (mCRC), though still limited, has improved significantly; clearly, when the disease becomes refractory to standard regimens, additional treatment options are needed. Studies have shown that mitomycin C (MMC), an antitumor antibiotic, and capecitabine, a precursor of 5-fluorouracil, may act synergistically in combination. The efficacy of MMC/capecitabine has been demonstrated in the first-line setting, but only a few small studies have tested it in the advanced-line setting, with contradictory results. AIM: To summarize our experience using MMC/capecitabine as an advanced line treatment for mCRC. METHODS: A retrospective study was conducted at a tertiary medical center including all patients with histologically proven mCRC who were treated with MMC/capecitabine after at least two previous lines of standard chemotherapy in 2006-2020. Data on patient demographics and past medical history, laboratory, pathological, and radiological factors, and treatment and survival were collected from the files. Survival analyses were performed using the Kaplan-Meier method. The association of patient and tumor characteristics with treatment effectiveness and toxicity was evaluated with univariate and multivariate proportional hazard Cox regression analyses. P ≤ 0.05 was considered statistically significant. RESULTS: The cohort consisted of 119 patients of median age 64 years (range 37-85). Patients received a median of 2 MMC/capecitabine cycles (range 0.5-9.0). Thirty-four patients (28.6%) experienced grade ≥ 3 toxicity, including 2 (1.7%) with grade 4; there was no drug-related mortality. The objective response rate was 0.8%, and the disease control rate, 24.4%. Median progression-free survival (PFS) was 2.1 mo (range 0.2-20.3), and median overall survival, 4.8 mo (range 0.2-27.5). The 6-month overall survival rate was 44%; 8.7% of patients remained progression-free. Factors associated with longer PFS were lower gamma-glutamyl transferase level (P = 0.030) and primary tumor location in the left colon (P = 0.017). Factors associated with longer overall survival were lower gamma-glutamyl transferase level (P = 0.022), left-colon tumor location (P = 0.044), low-to-moderate histological grade (P = 0.012), Eastern Cooperative Oncology Group performance status 0-1 (P = 0.036), and normal bilirubin level (P = 0.047). CONCLUSION: MMC/capecitabine is an active, available, and relatively safe regimen for use beyond standard lines of therapy in mCRC. Several clinical and laboratory parameters can identify patients more likely to benefit.

Differences in Toxicity Between Ashkenazi and Sephardic Jews With Colon Cancer Treated With Adjuvant Chemotherapy: A Prospective Study.

BACKGROUND/AIM: Ethnicity of cancer patients is increasingly being recognized as an important factor that may influence intergroup variation in toxicity and efficacy of chemotherapy. Data from our institution suggested that differences in chemotherapy-associated toxicity are not limited to distanced ethnic subgroups, such as Caucasians, Afro-Americans, or Asians, but may exist even between two closely related Caucasian ethnic subgroups, such as Ashkenazi and Sephardic Jews. This study aimed to explore differences in severity and frequency of various side effects, including neurotoxicity between patients from the two Jewish subgroups receiving oxaliplatin-containing adjuvant chemotherapy for colon cancer (CC). PATIENTS AND METHODS: We recruited 75 patients, with performance status 0-1 and no background of neuropathy between 2012 and 2016. All patients completed a neurotoxicity questionnaire (NQ) and a QoL questionnaire (QoLQ) at baseline and the NQ also at each treatment cycle; during follow up, patients filled out the NQ and the QoLQ every four months for a total of one year. RESULTS: Of the 75 participants, 66 were evaluable for the study including 34 (52%) Sephardic and 32 (48%) Ashkenazi Jews. Grade ≥2 vomiting and diarrhea occurred more often in Sephardic than in Ashkenazi patients (p=0.008 and 0.012, respectively). Of the 66 evaluable patients, 11 (17%) developed grade 3 neurotoxicity; of these, 9 were Sephardic and 2 were Ashkenazi (p=0.028). There were no significant differences in the dynamics of QoL between both subgroups. CONCLUSION: Sephardic patients receiving oxaliplatin-containing regimens are at an increased risk for neurotoxicity and other side effects as compared to their Ashkenazi counterparts.

Chemotherapy-induced ovarian failure as a prototype for acute vascular toxicity.

BACKGROUND: Chemotherapy-related amenorrhea is a frequent side effect observed in young breast cancer patients. Studies in mice revealed that chemotherapy-induced gonadal toxicity may result from vascular damage. We prospectively evaluated ovarian blood flow and function in young breast cancer patients following chemotherapy. METHODS: Young female patients with localized breast cancer undergoing adjuvant or neoadjuvant anthracycline- or taxane-based chemotherapy were evaluated using transvaginal ultrasound prior to initiation of and immediately after cessation of chemotherapy. Doppler-flow velocity indices of the ovarian vasculature-resistance index (RI), pulsatility index (PI)-and size measurements were visualized. Hormonal profiles, anti-Müllerian hormone (AMH) levels, and menopausal symptoms were assessed at the same time points. RESULTS: Twenty breast cancer patients were enrolled in the study. The median age was 34 ± 5.24 years. Ovarian blood flow was significantly reduced shortly following chemotherapy: RI decreased by 52.5% and PI decreased by 24.2%. The mean ovarian size declined by 19.08%. Patients who were treated with sequential chemotherapy experienced further reductions in ovarian blood flow and ovarian size after the second sequence. AMH levels dropped dramatically in all patients following treatment. Hormonal profiles after treatment depicted a postmenopausal profile for most patients, accompanied by related symptoms. CONCLUSIONS: Our results may imply a mechanism of chemotherapy-induced ovarian toxicity manifested by decreased ovarian blood flow accompanied by a reduction in ovarian size and diminished post-treatment AMH levels. Based upon our former preclinical studies, we assume that this may derive from an acute insult to the ovarian vasculature and may represent an initial event triggering a generalized phenomenon of end-organ toxicity.

The combination of docetaxel, cisplatin, and 5-fluorouracil in advanced gastric cancer: a single-institution experience.

The addition of docetaxel to cisplatin and 5-fluorouracil was shown to confer a survival benefit in patients with advanced gastric cancer (one; AGC), although with increased toxicity. We hereby report our experience with the use of docetaxel, cisplatin, and 5-fluorouracil (DCF). Data on all consecutive patients who received first-line treatment with DCF at our institute were analyzed retrospectively. Twenty-three patients were included. The median age was 63 years. Patients received an average of 10 cycles (range, 1-24). All experienced grade ≥3 toxicity, requiring hospitalization in 35%. There was one toxic death. The median progression-free and overall survival rates were 10.0 and 12.8 months, respectively; the 2-year and 3-year survival rates were 22 and 17%, respectively. The DCF regimen is indeed associated with substantial toxicity, although manageable. Nevertheless, the observed benefit was remarkable compared with any previous report on chemotherapy in AGC, and should therefore represent a valid treatment option in AGC and a platform for future combinations.

Gastric cancer: biology and clinical manifestations in Israel.

BACKGROUND: Gastric cancer (GC) in Israel remains incompletely characterized. The aim of this study was to define the clinical and pathological characteristics of GC in Israel and to compare them to the general Western population. PATIENTS AND METHODS: This is a retrospective analysis of 461 consecutive GC patients treated at a single institution between 1995 and 2007. Epidemiological and clinical-pathological data were retrieved from the patients' medical files and the institutional electronic database and analyzed using standard statistical methods. RESULTS: Epidemiology, clinical manifestations, histopathological findings, clinical course, and prognostic factors for disease outcome were all similar to those reported in the Western literature. Findings unique to the Israeli population included: (1) rarity of GC-associated risk factors; (2) increased GC incidence in Ashkenazi Jews; (3) high incidence of second primary malignancy and family history of cancer; and (4) no dominancy of proximal GCs. CONCLUSION: There do not appear to be any major differences in the biology or clinical manifestations of GC in Israel. Western recommendations for diagnosis and treatment of GC may therefore be applied to the Israeli patient population.

Tailoring neoadjuvant chemotherapy for locally advanced breast cancer: a historical prospective study.

BACKGROUND: Despite the growing number of clinical trials assessing preoperative systemic chemotherapy (PST) for locally advanced breast cancer, the optimal regimen has still to be defined. PURPOSE: This was to evaluate the toxicity, operability rate, pathological response rate and disease-free and overall survival associated with a PST regimen consisting of the sequential administration of single agents according to the individual tumor response. METHODS: Medical files were reviewed of 102 consecutive patients with breast cancer treated in 2000-2007 with a neoadjuvant sequential regimen of doxorubicin followed by taxane. The number of cycles and the addition of taxane were based on tumor response. RESULTS: Seventy percent of the patients had inoperable disease at diagnosis and 29% were given preoperative therapy for breast conservation. All patients underwent surgery, 65% achieved breast conservation. An overall pathological complete response (breast and nodes) was achieved in 14% of the patients, and a complete nodal pathologic response in 34%. At a median follow-up of 54 months, the overall survival rate was 82% and the disease-free survival rate was 70%. There was no treatment-related mortality. Febrile neutropenia occurred in 19% of the patients. CONCLUSIONS: A neoadjuvant regimen of doxorubicin with or without a sequential taxane, in which the number of cycles and the sequential administration of taxane are determined according to clinical response, appears to be safe and effective for patients with locally advanced breast cancer and yields a high rate of breast conservation. Tailored PST can spare patients receiving unnecessary chemotherapy.

[Adjuvant treatment with trastuzumab in early breast cancer].

The introduction of new biological agents into the clinic has had a major impact on breast cancer care. Of all well-studied biological agents, Trastuzumab is the only one that has become part of the standard therapy for advanced as well as for early breast cancer. Dr. Tahover and her colleagues' review in this issue of "Harefuah" presents the pivotal trials that have brought a change of practice in the adjuvant treatment of patients with breast cancer and HER2 positive tumors. More than 10,000 patients with tumors that were defined as human epidermal growth factor receptor 2, ErbB-2 positive have been recruited into these trials. Trastuzumab was given concomitantly with or sequentially after chemotherapy. The review teaches us that despite this large cohort, several crucial issues need further clarification: Exactly who are the candidates for this specific treatment? What is the preferred protocol for the combination of Trastuzumab and chemotherapy? What is the optimal duration of treatment with Trastuzumab in the adjuvant setting? In this editorial we discuss these topics based on published data from prospective and retrospective studies.