Background
Trastuzumab emtansine (T-DM1) is approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC), and has high efficacy. ...However, some patients exhibit primary resistance to T-DM1, and thus methods that can predict resistance in clinical practice are needed. Genomic analysis of circulating tumor DNA (ctDNA) in plasma is a non-invasive and reproducible method. This study aimed to predict primary resistance to T-DM1 by combining genomic analysis of ctDNA and other clinicopathological features of patients with HER2-positive ABC.
Methods
The study population comprised 34 patients with HER2-positive ABC who had been treated with T-DM1. Correlations between clinicopathological characteristics of patients and primary resistance to T-DM1 were examined, and
HER2
gene copy number and
PIK3CA
gene mutations were analyzed using plasma ctDNA samples obtained from 16 patients before T-DM1 administration.
Results
Among the 34 patients, nine (26.5%) had progressive disease at the first efficacy analysis; these patients were considered to have primary resistance to T-DM1. No significant difference was found in the rate of primary resistance to T-DM1 between groups. Among 16 patients whose ctDNA was analyzed, four showed primary resistance to T-DM1. These four patients showed negative HER2 gene amplification in ctDNA and were ER-positive and/or PR-positive by immunohistochemistry.
Conclusions
HER2 gene amplification in ctDNA and ER and PR status may predict primary resistance to T-DM1. A liquid biopsy before the initiation of T-DM1 treatment could be a non-invasive way to predict whether a patient would exhibit primary resistance to T-DM1.
The initial therapeutic strategy for hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer is based on the first metastatic site; however, little evidence is available regarding the ...influence of metastatic distribution patterns of first metastatic sites on prognosis. In this study, we aimed to identify the metastatic distribution patterns of first metastatic sites that significantly correlate with survival after recurrence.
We performed a retrospective review of records from 271 patients with recurrent metastatic HR+/HER2- breast cancer diagnosed between January 2000 and December 2015. We assessed survival after recurrence according to the metastatic distribution patterns of the first metastatic sites and identified significant prognostic factors among patients with single and multiple metastases.
Prognosis was significantly better in patients with a single metastasis than in those with multiple metastases (median overall survival after recurrence: 5.86 years vs. 2.50 years, respectively, p < 0.001). No metastatic organ site with single metastasis was significantly associated with prognostic outcome, although single metastasis with diffuse lesions was an independent risk factor for worse prognosis (HR: 3.641; 95% CI: 1.856-7.141) and more easily progressing to multiple metastases (p = 0.002). Multiple metastases, including liver metastasis (HR: 3.145; 95% CI: 1.802-5.495) or brain metastasis (HR: 3.289; 95% CI: 1.355-7.937), were regarded as significant independent poor prognostic factors; however, multiple metastases not involving liver or brain metastasis were not significantly related to prognosis after recurrence.
Single metastases with diffuse lesions could more easily disseminate systemically and progress to multiple metastases, leading to a poor prognosis similar to multiple metastases. Our findings indicate that the reconsideration of the determinant factors of therapeutic strategies for first recurrence in HR+/HER2- breast cancer may be needed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose: Detection of sentinel lymph node (SLN) metastasis in breast cancer patients has conventionally been determined by intraoperative
histopathologic examination of frozen sections followed by ...definitive postoperative examination of permanent sections. The
purpose of this study is to develop a more efficient method for intraoperative detection of lymph node metastasis.
Experimental Design: Cutoff values to distinguish macrometastasis, micrometastasis, and nonmetastasis were determined by measuring cytokeratin
19 (CK19) mRNA in histopathologically positive and negative lymph nodes using one-step nucleic acid amplification (OSNA).
In an intraoperative clinical study involving six facilities, 325 lymph nodes (101 patients), including 81 SLNs, were divided
into four blocks. Alternate blocks were used for the OSNA assay with CK19 mRNA, and the remaining blocks were used for H&E
and CK19 immunohistochemistry–based three-level histopathologic examination. The results from the two methods were then compared.
Results: We established CK19 mRNA cutoff values of 2.5 × 10 2 and 5 × 10 3 copies/μL. In the clinical study, an overall concordance rate between the OSNA assay and the three-level histopathology was
98.2%. Similar results were obtained with 81 SLNs. The OSNA assay discriminated macrometastasis from micrometastasis. No false
positive was observed in the OSNA assay of 144 histopathologically negative lymph nodes from pN0 patients, indicating an extremely
low false positive for the OSNA assay.
Conclusion: The OSNA assay of half of a lymph node provided results similar to those of three-level histopathology. Clinical results
indicate that the OSNA assay provides a useful intraoperative detection method of lymph node metastasis in breast cancer patients.
Purpose: Accurate assessment of metastasis in sentinel lymph nodes (SLN) of breast cancer is important but involves a heavy workload
for the pathologist. We conducted a multicenter clinical trial in ...Japan to evaluate a new automated assay system for cytokeratin
19 mRNA, the one-step nucleic acid amplification (OSNA) assay (Sysmex), to detect lymph node metastasis of breast cancer.
Experimental Design: Surgically obtained axillary lymph nodes were sectioned into four pieces, two of which were examined with the OSNA assay.
The other two adjacent pieces were examined with H&E and immunohistochemical staining for cytokeratin 19. Serial sections
at 0.2-mm intervals were used in trial 1 to determine the specificity of the OSNA assay, and three pairs of sections cut from
the sliced surfaces of the pieces were used in trial 2 to compare the accuracy of the OSNA assay with that of a routine pathologic
examination for SLNs in Japan.
Results: In trial 1, the sensitivity and specificity were 95.0% 95% confidence interval (95% CI), 75.1-99.9% and 97.1% (95% CI,
91.8-99.4%), respectively, for 124 axillary lymph nodes obtained from 34 patients. In trial 2, the agreement between findings
of the assay and of the pathologic examination was 92.9% (95% CI, 90.1-95.1%) for 450 axillary lymph nodes obtained from 164
patients.
Conclusion: The OSNA assay can detect lymph node metastasis as accurately as can conventional pathology and thus can be an effective
addition to or alternative for rapid intraoperative examination of SLNs.
Purpose
In the CLEOPATRA study of patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer, the Japanese patient subgroup did not demonstrate the ...improved progression-free survival (PFS) of pertuzumab plus trastuzumab and docetaxel vs. placebo that was seen in the overall population. Therefore, COMACHI was conducted to confirm the efficacy and safety of this treatment regimen in this patient subgroup.
Methods
This was a phase IV study of pertuzumab plus trastuzumab and docetaxel in Japanese patients with histologically/cytologically confirmed inoperable or recurrent HER2-positive breast cancer. All patients received pertuzumab, trastuzumab, and docetaxel intravenously every 3 weeks until disease progression/unacceptable toxicity. The primary endpoint was investigator-assessed PFS. Secondary endpoints were overall survival (OS), investigator-assessed objective response rate, and duration of response (DoR). Safety was also assessed.
Results
At final analysis, median investigator-assessed PFS was 22.8 months (95% CI 16.9–37.5). From first dose, OS rate at 1 year was 97.7%; and at 2 and 3 years were 88.5% and 79.1%, respectively. Of the 118 patients with measurable disease at baseline, response rate was 83.9% (95% CI 77.3–90.5) and median investigator-assessed DoR was 26.3 months (95% CI 17.1–not evaluable). Treatment was well tolerated, with no new safety signals detected.
Conclusions
Our results suggest similar efficacy and safety for pertuzumab plus trastuzumab and docetaxel in Japanese patients compared with the overall population of CLEOPATRA, providing further support for this combination therapy as standard of care for Japanese patients with inoperable or recurrent HER2-positive breast cancer.
We previously reported the synergistic effect of S-1 and eribulin in preclinical models. In addition, our phase I study revealed the recommended dose for the phase II study of the combination therapy ...in advanced breast cancer (ABC) patients pre-treated with anthracycline and taxane. Our current study reports on the efficacy and safety of the combined use of eribulin and S-1 in patients with ABC and poor prognosis.
Patients with breast cancer who received prior anthracycline- and/or taxane-based therapy were assigned to receive a combination therapy of eribulin (1.4 mg/m
on days 1 and 8, every 21 days) and S-1 (65 mg/m
, on days 1 to 14, every 21 days) for advanced/metastatic disease. All patients had at least one clinicopathological factor such as being oestrogen receptor negative, Human Epidermal Growth Factor Receptor 2 (HER2) receptor negative, presence of visceral involvement, presence of three or more metastatic sites, or having a disease-free interval shorter than 2 years. The primary endpoint was the independent-reviewer assessed objective response rate (ORR). Secondary endpoints were clinical benefit rate, disease control rate, progression-free survival (PFS), and overall survival (OS).
This study enrolled 33 patients. Confirmed ORR was 33.3% (95% CI: 17.3 to 52.8). Median PFS was 7.5 months (95% CI: 4.0 to 14.3). Median OS time was not reached during the current experimental periods. The most common grade 3/4 adverse event was neutropenia (68.8%).
The combination of eribulin and S-1 is safe and effective for treatment in patients with ABC and poor prognosis.
Current Controlled Trials UMIN000015049 , date of registration: September 5th 2014.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lifestyle factors, including food and nutrition, physical activity, body composition and reproductive factors, and single nucleotide polymorphisms (SNPs) are associated with breast cancer risk, but ...few studies of these factors have been performed in the Japanese population. Thus, the goals of this study were to validate the association between reported SNPs and breast cancer risk in the Japanese population and to evaluate the effects of SNP genotypes and lifestyle factors on breast cancer risk.
A case-control study in 472 patients and 464 controls was conducted from December 2010 to November 2011. Lifestyle was examined using a self-administered questionnaire. We analyzed 16 breast cancer-associated SNPs based on previous GWAS or candidate-gene association studies. Age or multivariate-adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were estimated from logistic regression analyses.
High BMI and current or former smoking were significantly associated with an increased breast cancer risk, while intake of meat, mushrooms, yellow and green vegetables, coffee, and green tea, current leisure-time exercise, and education were significantly associated with a decreased risk. Three SNPs were significantly associated with a breast cancer risk in multivariate analysis: rs2046210 (per allele OR=1.37 95% CI: 1.11-1.70), rs3757318 (OR=1.331.05-1.69), and rs3803662 (OR=1.28 1.07-1.55). In 2046210 risk allele carriers, leisure-time exercise was associated with a significantly decreased risk for breast cancer, whereas current smoking and high BMI were associated with a significantly decreased risk in non-risk allele carriers.
In Japanese women, rs2046210 and 3757318 located near the ESR1 gene are associated with a risk of breast cancer, as in other Asian women. However, our findings suggest that exercise can decrease this risk in allele carriers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Even though most local recurrences after autologous breast reconstruction occur in superficial tissue, they also occur in deep tissue in the reconstructed breast. A 49-year-old woman presented with a ...bloody discharge from the right nipple. Ultrasonography revealed a hypoechoic area in her right breast, which was diagnosed as ductal carcinoma in situ on histopathology. We performed nipple-sparing mastectomy and immediate reconstruction of the breast with a latissimus dorsi myocutaneous flap. At 6 years postoperatively, the patient presented with a palpable mass. Ultrasonography revealed a solid mass lesion subcutaneously in the right breast. Computed tomography revealed multiple enhanced solid mass lesions in the subcutaneous and deep tissues of the reconstructed breast. The mass in the deep tissue of the reconstructed breast was diagnosed as an invasive micropapillary carcinoma by biopsy. For local recurrence, we performed wide excision of the reconstructed breast. The masses in the subcutaneous and deep tissues of the reconstructed breast were diagnosed as invasive micropapillary carcinoma. Superficial recurrence was first detected by physical examination, and deep recurrence was later detected with further imaging. We present a case of local recurrences that occurred in the deep tissue, in addition to superficial tissue of the reconstructed breast.
Little evidence is currently available on significant determinants of post-recurrence survival for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer. The objective of ...this study was to evaluate factors influencing post-recurrence survival in HR+/HER2-breast cancer.
A cohort of 236 patients with recurrent HR+/HER2- breast cancer was retrospectively analyzed to identify significant factors correlating with prognosis after recurrence.
Multivariate analysis revealed independent prognostic factors of poor survival as follows: short intervals between recurrence and the end of adjuvant endocrine therapy (ET; p=0.046); short disease-free intervals (p=0.019); liver metastasis (p=0.007) or multiple metastases (p<0.001) at recurrence; and a poor response to first-line treatment (p<0.001). A poor first-line treatment response was significantly associated with a shorter response to a subsequent treatment line (p=0.007). Logistic regression analysis indicated that liver metastasis significantly increased the risk of a poor first-line-ET response (p=0.009).
The first-line treatment response was the key to post-recurrence survival in patients with HR+/HER2- breast cancer. Particularly poor responses led to subsequent unfavorable prognostic outcomes.
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