Very high quantitative tumor HER2 content and outcome in early breast cancer.

BACKGROUND: It is unknown how a very high tumor total HER2 (human epidermal growth factor receptor-2) content (H2T) influences outcome in early breast cancer treated with adjuvant trastuzumab plus chemotherapy. PATIENTS AND METHODS: H2T was measured using a novel quantitative assay (HERmark(®)) from formalin-fixed tumor tissue of 899 women who participated in the FinHer trial (ISRCTN76560285). In a chromogenic in situ hybridization (CISH) test, 197 (21.9%) patients had HER2-positive cancer and were randomly assigned to receive trastuzumab or control. RESULTS: Cancer H2T levels varied 1808-fold. High H2T levels were correlated with a positive HER2 status by CISH (P < 0.0001). A nonlinear association was present between H2T and the hazard of distant recurrence in a subpopulation treatment effect pattern plot analysis in CISH-positive disease. Patients with very high H2T (defined by ≥22-fold the median of HER2-negative cancers; 13% of CISH-positive cancers) did not benefit from adjuvant trastuzumab [hazard ratio (HR) 1.23; 95% confidence interval (CI) 0.33-4.62; P = 0.75], whereas the rest of the patients with HER2-positive disease by CISH (87%) did benefit (HR 0.52; 95% CI 0.28-1.00; P = 0.050). CONCLUSION: Patients with HER2-positive breast cancer with very high tumor HER2 content may benefit less from adjuvant trastuzumab compared with those whose cancer has more moderate HER2 content.

Docetaxel versus docetaxel alternating with gemcitabine as treatments of advanced breast cancer: final analysis of a randomised trial.

BACKGROUND: Alternating administration of docetaxel and gemcitabine might result in improved time-to-treatment failure (TTF) and fewer adverse events compared with single-agent docetaxel as treatment of advanced breast cancer. PATIENTS AND METHODS: Women diagnosed with advanced breast cancer were randomly allocated to receive 3-weekly docetaxel (group D) or 3-weekly docetaxel alternating with 3-weekly gemcitabine (group D/G) until treatment failure as first-line chemotherapy. The primary end point was TTF. RESULTS: Two hundred and thirty-seven subjects were assigned to treatment (group D, 115; group D/G, 122). The median TTF was 5.6 and 6.2 months in groups D and D/G, respectively (hazard ratio 0.85, 95% confidence interval 0.63-1.16; P = 0.31). There was no significant difference in time-to-disease progression, survival, and response rate between the groups. When adverse events were evaluated for the worst toxicity encountered during treatment, there was little difference between the groups, but when they were assessed per cycle, alternating treatment was associated with fewer severe (grade 3 or 4) adverse effects (P = 0.013), and the difference was highly significant for cycles when gemcitabine was administered in group D/G (P < 0.001). CONCLUSION: The alternating regimen was associated with a similar TTF as single-agent docetaxel but with fewer adverse effects during gemcitabine cycles.

Follow-up cost of breast cancer patients with localized disease after primary treatment: a randomized trial.

We studied the cost of follow-up of 472 breast cancer patients without distant metastasis after primary treatment in four different schedules in a randomized trial. The mean follow-up was 4.2 years. The four schedules differed in frequency of follow-up visits (every third or sixth month) and in intensity of diagnostic examinations (routine or on clinical grounds). Neither the frequency of visits nor the intensity of diagnostic examinations had any effect on disease-free or overall survival of patients. The total costs of follow-up, however, were different in the four follow-up schedules and varied between arms per patient from 1050 to 2269 euros and per detected recurrence from 4166 to 9149 euros. Outpatient visits every third month compared to every sixth month and routine examinations in the follow-up of asymptomatic primary breast cancer patients do not improve patient disease-free or overall survival, but increase the costs of follow-up 2.2 times.

Role of chest X-ray in diagnosis of the first breast cancer relapse: a randomized trial.

Between May 1991 and December 1995, follow-up after primary therapy for 472 consecutive patients with localized breast cancer was randomly assigned to assess the efficacy of routine chest X-ray in detecting intrathoracic relapse as the first metastatic event. One group had regular chest X-rays while the other group had chest radiographs only when clinically needed (spontaneous). Patients were followed up until December 1999 or death. In the routine group, 243 patients had 1429 chest X-rays (mean 5.9 chest X-rays per patient). In the spontaneous group, 229 patients had 411 chest X-rays (mean 1.8 chest X-rays per patient). Both sensitivity and specificity were somewhat higher in the spontaneous arm compared to the routine arm. Patient sensitivity was 30% in the regular arm and 36% in the spontaneous arm. Film sensitivity was 11% in the regular arm and 20% in the spontaneous arm. Patient specificity was 85% in the regular arm and 86% in the spontaneous arm. The predictive values were practically the same in both arms. Patient positive predictive values were 22% in both arms and film positive predictive values were 21% in the regular and 22% in the spontaneous arm. Patient negative predictive values were 90% in the regular and 92% in the spontaneous arm. Film negative predictive values were 93% in the regular and 89% in the spontaneous arm. The differences in accuracy were not statistically significant between the arms. There were no significant differences in disease free survival or overall survival. The 5-year disease free survival was 86% in the regular and 89% in the spontaneous arm and the overall survival was 88 and 85% in the regular versus spontaneous arm, respectively. Routine chest X-ray in the follow-up of breast cancer patient is evidently of little use and is not likely to be of benefit to the patient in terms of disease free survival or overall survival as compared to the spontaneous schedule.

Paclitaxel-ifosfamide for anthracycline-resistant advanced breast cancer.

Thirty-one patients with advanced breast cancer either resistant to anthracycline-based regimens or relapsing after anthracycline-based adjuvant chemotherapy received a combination of a 3-h infusion of paclitaxel 135 mg/m2 on day 1 and a 4-h infusion of ifosfamide 1.7 g/m2 on days 2 to 4 of a 22-day cycle. For inclusion in the study, patients had to have measurable or evaluable progressive metastasis or local disease, and to have received only one prior regimen for metastatic disease; 31 patients with a median age of 49 years (range: 30-69) entered the study. Nine patients (29%) had lung metastasis, while 17 (55%) had liver metastasis, and 19 (61%) had bone metastasis. Only seven patients (23%) had lymph node metastasis and four (13%) had skin metastasis. A median of seven cycles of treatment was delivered. Responses were evaluated according to World Health Organization (WHO) guidelines and side effects according to National Cancer Institute (NCI) criteria. A panel of oncologists and one radiologist reviewed all responses. At baseline, only three patients (10%) were free from the adverse effects of the prior therapy; severe nonhematological toxicity occurred in less than 8% of patients. However neutropenia grade 3-4 occurred in 88%, while only 3% had severe infections. Severe thrombocytopenia and anemia were rare (4% and 8%, respectively). The overall response rate was 42% (13% complete response). Median survival and progression-free survival rates after initiation of treatment were 19.3 months and 6.1 months, respectively. With an objective response rate of 42% and median survival of 19 months, the combination of paclitaxel and ifosfamide seems to offer a promising regimen with acceptable side effects in advanced breast cancer patients relapsing after anthracycline-based adjuvant treatment or resistant to anthracycline treatment.

Ca 15-3 in the follow-up of localised breast cancer: a prospective study.

Altogether, 243 female breast cancer patients with localised disease diagnosed between 1991 and 1995 in the Tampere University Hospital area were followed prospectively after primary treatment until the first relapse. In the follow-up period, the serum tumour marker Ca 15-3 was analysed every 6 months to ascertain the validity of this marker in detecting the first relapse. The sensitivity and specificity of the test were analysed in different metastatic situations. During the 5 years of follow-up, 59 (24%) relapses were discovered. Ca 15-3 was elevated in 21/59 (36%) of the relapsed cases at least once. The 59 patients were subjected to 199 tests, of which 25 (13%) were positive. Among the 184 patients without recurrence, there were 6 (3%) with a positive Ca 15-3 level. The test failed to detect locoregional relapse or contralateral breast cancer. It was elevated in approximately half of bone-only metastases and in all of the liver-only metastases. In the pulmonary-only recurrences, the marker value was not elevated. We conclude that the Ca 15-3 tumour marker test is specific, but not sensitive enough to indicate the first relapse earlier than other methods. The positive predictive value especially remained poor in patients with a relatively good prognosis. Our results confirm that the test is not suitable alone for breast cancer follow-up.

The effect of age and density of the breast on the sensitivity of breast cancer diagnostic by mammography and ultasonography.

PURPOSE: We studied which, age of the patient or density of the breast accounts for the sensitivity of mammography and ultrasonography (US). Furthermore we studied whether the overall impression on the density of the breast or the density in tumour area accounts for the sensitivity of mammography and ultrasonography. MATERIALS AND METHODS: The material consisted of 572 consecutive histologically and 5 cytologically verified breast cancer cases. Mammography and US examinations were performed immediately before breast cancer operations and information on the findings were received from the original patient files and classified as malignant or benign. The density of breast parenchyma to fatty, mixed or dense in total breast and separately in tumour area was defined by a radiologist group from the original mammograms by comparing to model mammograms. The sensitivity (Se) of mammography and US was compared in 3 age groups (26-49, 50-59 and 60-92) and in the different density classes. RESULTS: Sensitivity of mammography increased by age (density-adjusted OR = 0.2, 95%, CI 0.1-0.5) in age group 26-49 compared to age group 60-92) and with fattiness of the breast (age-adjusted OR= 0.4, 95%, CI 0.1-1.0 for dense breast parenchyma in tumour area compared to fatty breast). Sensitivity of US was inversely related to age (density-adjusted OR = 2.3, 95%, CI 1.0-5.2 in age group 26-49 compared to age group 60-92) and directly related with fattiness of breast (age-adjusted OR = 0.5, 95%, CI 0.2-0.9 by dense breast parenchyma in tumour area compared to fatty breast). Density in the tumour area compared to total breast density was related only mariginally better sensitivity both of mammography (0.4 vs. 0.6) and of US (0.5 vs. 0.6). CONCLUSION: Sensitivity of both mammography and sensitivity of US are independently related both to the age of the patient and to the density of the breast. The effect of age is inverse and that of density parallel between mammography and US on sensitivity. The effect of overall breast density was close to the effect of density at the site of the tumour on the sensitivity of both mammography and US.

The visibility of cancer on previous mammograms in retrospective review.

AIM: To study how many tumours were visible in restrospect on mammograms originally reported as normal or benign in patients coming to surgery with proven breast cancer. The effect of making the pre--operative mammogram available was also assessed. MATERIALS AND METHODS: Three hundred and twenty initial mammograms of consecutive new breast cancer cases were analysed by a group of radiologists in the knowledge that all patients were later diagnosed with breast cancer. The films were read twice, first without and then with the later (pre-operative) mammograms available. The parenchymal density in the location of the tumour was classified as fatty, mixed or dense, and the tumours were classified as visible or not visible. The reasons for the invisibility of the tumour in the earlier examination were analysed. RESULTS: Fourteen per cent (45) of cancers were retrospectively visible in earlier mammograms without the pre-operative mammograms having been shown, and 29% (95) when pre-operative mammograms were shown. Breast parenchymal density decreased with age and the visibility of tumours increased with age. When considered simultaneously, the effect of age (over 55 vs under 55) was greater (OR = 2.9) than the effect of density (fatty vs others) (OR = 1.5). The most common reasons for non-detection were that the lesion was overlooked (55%), diagnosed as benign (33%) or was visible only in one projection (26%). Growing density was the most common (37%) feature of those lesions originally overlooked or regarded as benign. CONCLUSIONS: Tumours are commonly visible in retrospect, but few of them exhibit specific signs of cancer, and are recognized only if they grow or otherwise change. It is not possible to differentiate most of them from normal parenchymal densities. Saarenmaa, I. (2001). Clinical Radiology56, 40-43.

Validity of radiological examinations of patients with breast cancer in different age groups in a population based study.

By studying which radiological examinations had been performed before breast cancer operations the aim was to assess, how much benefit ultrasonography (US) and fine or core needle biopsy (FNAB, CNB) gave in addition to mammography, and whether the sensitivity of these examinations varied with the age of the patient. There were 659 consecutive histologically and six cytologically verified breast cancer cases included in the study. Information on mammography, US and FNAB findings were retrieved from the original patient files and classified as malignant or benign. The sensitivity (Se) of these was compared in three age groups (26-49, 50-59 and 60-92). Seventeen (3%) tumours had operations without any radiological examination and 73 (11%) without cytological or histological verification. The sensitivity of mammography (Se=0.92) was statistically significantly higher than the sensitivity of FNAB (Se=0.85, P=0.002) or US (Se=0.86, P=0.003). The sensitivity of mammography increased with age; US sensitivity was slightly higher amongst younger than older patients; the sensitivity of FNAB did not depend on the age of the patient. The sensitivity using a cutoff level of class 5 for mammography was higher (50% typical malignant findings) than for US (45%) or FNAB (30%). Among cases with benign mammographic finding (classes 1-2), the US finding was malignant (classes 3-5) in 4% and FNAB was malignant in 7%. Mammography is a reliable method of breast examination especially for women over 50 years of age. Ultrasonography is beneficial, particularly in younger women, but it is mainly performed as a complementary examination to a mammography and therefore could not be evaluated as an independent examination. FNAB and CNB results were not related to the age of the patient.