Adjuvant therapies for special types of breast cancer

Summary Recent developments in the adjuvant treatment of breast cancer include an increasing attention to systemic therapies prescribed in homogeneous groups of patients according to the higher chance of benefit. A clear consequence of the current adjuvant treatment strategy is the importance of accurate and reliable histopathological assessment. A proper pathological evaluation may effectively support the definition of prognosis and treatment choice in niches of patients diagnosed with special types of breast cancer. Through the identification of special types of breast cancer, that account for up to 25% of all invasive breast carcinomas, it is possible to select patients with a very good prognosis often close to that of the general population (e.g. tubular and pure cribriform carcinoma). Other features, such as those related with invasive classical lobular carcinoma, might have important correlates of responsiveness to therapy other than indicators of outcome. It was in fact demonstrated that the response to primary chemotherapy is significantly lower in invasive lobular carcinoma, if compared with the ductal histotype. However, the use of available information on special types of breast cancer has been limited in tailoring adjuvant therapy, owing to the absence of standardized criteria and partial reproducibility for diagnosis. Moreover, due to the relative rarity of the disease a large number of features that identify for special types of breast carcinomas have today no particular correlation with the prognosis, and limited data are available on the biology of a large number of breast cancer subtypes. The development of more effective therapies for patients with special types of breast cancer requires tailored treatment investigations through international cooperation and should not rely on information predominantly contributed from small retrospective analyses. Examination of patterns of relapse and treatment response within subpopulations in multiple randomized trials is also mandatory to make progress and reach consensus on how to treat individual patients with special types of breast cancer

New criteria for selecting elderly patients for breast cancer adjuvant treatment studies.

Learning Objectives After completing this course, the reader will be able to: List the factors that should be considered when choosing the appropriate adjuvant treatment for an elderly women with operable breast cancer.Discuss the possible explanations that account for the underrepresentation of elderly patients in breast cancer clinical trials.Describe the clinical trials that are being specifically conducted in elderly patients with early breast cancer to evaluate different forms of adjuvant treatments. CME Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.co

Assessment of telomere length during post-natal period in offspring produced by a bull and its fibroblast derived clone

Objective: To investigate the telomere length in bovine offspring produced by a cloned and control bull, and the telomerase activity in embryos produced with the same technology. Methods: Five daughters of a control and five daughters of a bull cloned using a fibroblast of the control were produced by IVF using sperm of the two bulls. Blood samples of the offspring were collected at 2, 6, and 12 months of age and the relative telomere length (RTL) was assessed by flow cytometry. At same time the body growth, hematological profile, and clinical biochemistry of the same progeny was extensively surveyed, and results have been reported in a previous work. Thereafter, the telomerase activity was assessed using a real time PCR quantitative assay in groups of embryos produced with the same technology. Results: The offspring of the clone exhibited a modest, but significant (P<0.05), shortening of the telomeres (21.36%, 20.56% and 20.56%) compared to that of the control (23.78%, 23.53% and 22.43%) as mean values determined at 2, 6 and 12 months, respectively. Shortening of telomeres in respect to the age was not significant. No statistical difference was reported between telomerase activity assessed in 144 cloned (3.4−03 ± 2.4−03 amoles/μL) and 80 control (2.1−03 ± 1.8−03 amoles/μL) embryos. Conclusions: The results have revealed a moderate shortening of telomeres in the offspring of the clone with respect to control. However, this study did not evidence differences in the two progenies that suggest welfare problems during the first year of life

Induced pluripotent stem cells and cerebral organoids from the critically endangered Sumatran rhinoceros

Less than 80 Sumatran rhinos (SR, Dicerorhinus sumatrensis) are left on earth. Habitat loss and limited breeding possibilities are the greatest threats to the species and lead to a continuous population decline. To stop the erosion of genetic diversity, reintroduction of genetic material is indispensable. However, as the propagation rate of captive breeding is far too low, innovative technologies have to be developed. Induced pluripotent stem cells (iPSCs) are a powerful tool to fight extinction. They give rise to each cell within the body including gametes and provide a unique modality to preserve genetic material across time. Additionally, they enable studying species-specific developmental processes. Here, we generate iPSCs from the last male Malaysian SR Kertam, who died in 2019, and characterize them comprehensively. Differentiation in cells of the three germ layers and cerebral organoids demonstrate their high quality and great potential for supporting the rescue of this critically endangered species

Selection of reference genes for quantitative real-time PCR in equine in vivo and fresh and frozen-thawed in vitro blastocysts

<p>Abstract</p> <p>Background</p> <p>Application of reverse transcription quantitative real-time polymerase chain reaction is very well suited to reveal differences in gene expression between <it>in vivo </it>and <it>in vitro </it>produced embryos. Ultimately, this may lead to optimized equine assisted reproductive techniques. However, for a correct interpretation of the real-time PCR results, all data must be normalized, which is most reliably achieved by calculating the geometric mean of the most stable reference genes. In this study a set of reliable reference genes was identified for equine <it>in vivo </it>and fresh and frozen-thawed <it>in vitro </it>embryos.</p> <p>Findings</p> <p>The expression stability of 8 candidate reference genes (<it>ACTB</it>, <it>GAPDH</it>, <it>H2A/I</it>, <it>HPRT1</it>, <it>RPL32</it>, <it>SDHA</it>, <it>TUBA4A</it>, <it>UBC</it>) was determined in 3 populations of equine blastocysts (fresh <it>in vivo</it>, fresh and frozen-thawed <it>in vitro </it>embryos). Application of geNorm indicated <it>UBC</it>, <it>GAPDH</it>, <it>ACTB </it>and <it>HPRT1 </it>as the most stable genes in the <it>in vivo </it>embryos and <it>UBC</it>, <it>RPL32</it>, <it>GAPDH </it>and <it>ACTB </it>in both <it>in vitro </it>populations. When <it>in vivo </it>and <it>in vitro </it>embryos were combined, <it>UBC</it>, <it>ACTB</it>, <it>RPL32 </it>and <it>GAPDH </it>were found to be the most stable. <it>SDHA </it>and <it>H2A/I </it>appeared to be highly regulated.</p> <p>Conclusions</p> <p>Based on these results, the geometric mean of <it>UBC</it>, <it>ACTB</it>, <it>RPL32 </it>and <it>GAPDH </it>is to be recommended for accurate normalization of quantitative real-time PCR data in equine <it>in vivo </it>and <it>in vitro </it>produced blastocysts.</p

neoadjuvant pegylated liposomal doxorubicin in combination with cisplatin and infusional fluoruracil ccf with and without endocrine therapy in locally advanced primary or recurrent breast cancer

Abstract Purpose To explore the activity of pegylated liposomal doxorubicin (PLD) as neoadjuvant therapy of breast cancer. Methods The combination of PLD with cisplatin and infusional fluorouracil (CCF) for 8 courses was investigated in patients with primary or recurrent T2-T4a-d N0-3 M0 breast cancer. Patients with ER and/or PgR ≥10% tumors also received letrozole (±triptorelin). Results Forty patients entered the study. Four patients had recurrent tumors and 13 had cT4d tumors. Overall, clinical response rate was 77.5% whereas a pathological complete response (pCR) was obtained in 3 patients (7.7%), 4 when considering bilateral tumors. Noticeably 3 pCR were observed among the 10 patients with T4d ER positive tumors (33%). Eleven patients discontinued treatment before completion of the 8 planned courses. Conclusions Our results indicated that CCF yielded an appreciable rate of clinical responses in a series of very locally advanced tumors and an unusually high rate of pCR in T4d ER positive tumors, suggesting an enhanced cutaneous activity of PLD

preoperative therapy with trastuzumab and oral vinorelbine endocrine therapy in patients with her2 positive breast cancer

Abstract Background Combined trastuzumab and intravenous vinorelbine yielded high clinical activity as preoperative treatment in patients (pts) with HER 2/ neu positive breast cancer. Patients and methods We tested a preoperative combination of trastuzumab with oral vinorelbine (oV) in pts with locally advanced (T2-T4 N0-3 M0) HER2-positive breast cancer. Trastuzumab was administered i.v q 3 wks and oV was administered at the dose of 55 mg/sqm on days 1 and 3 q 3 wks, for 8 courses. Pts with ER ≥ 10% tumors received endocrine therapy with letrozole 2.5 mg/day, plus monthly triptorelin if premenopausal. Results Forty-five pts entered the study. The overall response rate (CR + PR) was 76% (95% CI: 60%–87%). pCR was observed in 4 pts (10%). Among ER-positive tumors 21/25 pts obtained a clinical response (84%) and two pts obtained a pCR (8%). Conclusions The combination of trastuzumab and oral vinorelbine demonstrated encouraging activity in patients with HER 2 positive ER-positive tumors. Alternative strategies should be investigated in patients with endocrine non responsive disease

increased mean corpuscular volume of red blood cells predicts response to metronomic capecitabine and cyclophosphamide in combination with bevacizumab

Abstract Background There is an urgent need for the identification of commonly assessable predictive factors in the treatment of patients with metastatic breast cancer. Methods During the course of a treatment including low dose metronomic oral cyclophosphamide and capecitabine plus i.v. bevacizumab (plus erlotinib in one third of the patients) for metastatic breast cancer, we observed that a relevant number of patients developed repeatedly elevated levels of mean corpuscular volume (MCV) of red blood cells without a significant fall in hemoglobin levels. We conducted a retrospective analysis on these 69 patients to evaluate if the increase in MCV could be associated to tumor response. Results During the course of treatment 42 out of 69 patients (61%) developed macrocytosis. Using Cox proportional hazards modeling that incorporated macrocytosis (MCV≥100 fl) as a time-dependent covariate, macrocytosis resulted in a halved risk of disease progression (HR 0.45; 95% CI, 0.22–0.92, p-value 0.028). In a landmark analysis limited to patients with no sign of progression after 24 weeks of treatment, median time to progression was 72 weeks (48 weeks after landmark) in patients who had developed macrocytosis, and 43 weeks (19 weeks after landmark) in patients who had not (p = 0.023). Conclusion Macrocytosis inversely related to risk of disease progression in patients treated with metronomic capecitabine plus cyclophosphamide and bevacizumab for metastatic breast cancer. This finding may be explained through thymidylate synthase inhibition by capecitabine. Whether bevacizumab has a role in determining macrocytosis, similarly to what happens with sunitinib, has to be further investigated. If other studies will confirm our findings, macrocytosis might be used as an early marker of response during metronomic treatment with capecitabine and cyclophosphamide with or without bevacizumab

topoisomerase iiα gene status and prediction of pathological complete remission after anthracycline based neoadjuvant chemotherapy in endocrine non responsive her2 neu positive breast cancer

Abstract Purpose Topoisomerase IIα (Topo II) is a potential marker of responsiveness to anthracycline-based therapy. We analyzed the role of Topo II gene status in the prediction of pathological complete remission (pCR) after primary anthracycline-based chemotherapy in non- endocrine responsive breast cancers overexpressing Her2/neu. Methods Twenty-three patients, with T2–T4, ER and PgR absent, overexpressing Her2/neu breast cancers treated with anthracycline-based chemotherapy were evaluated. Topo II gene status was assessed by FISH in pre-treatment tumor specimens and the results were correlated to pathological and clinical responses. Results Overall, six patients had a pCR (26%). Topo II was amplified in 5 (22%) of the tumors. In all patients with Topo II amplification, Her2/neu gene amplification was also detected. Among patients without amplification, one had polysomia of chromosome (Cr) 17 and four patients had deletion of the Topo II gene. A higher probability of pCR was observed when Topo II amplification and Cr 17 polysomy were present: pCR was reported in 3 of 5 amplified tumors (60%), in the polysomic tumor (amplified plus polysomic 67%) and in only 2 out of 13 tumors without alteration of Topo II status (15%). If we compare the frequency of pCR in tumors with amplification or polysomy versus the frequency of tumors with not amplification (deletion or no modification), a significant difference was detected ( p =0.02). One progressive disease (PD) was reported in one tumor with Topo II deletion (1/4, 25%) and one in tumor without any modification of Topo II gene status (1/13, 8%). Conclusions In patients with endocrine unresponsive and Her2 overexpressing tumors, Topo II amplification or the presence of chromosome 17 polysomy correlate with a significantly high probability of achieving pCR after neoadjuvant, anthracycline-based chemotherapy. Further prospective studies in order to more clearly define the predictive role of Topo II status in this subgroup of patients are warranted

Pegylated liposomal doxorubicin in combination with low-dose metronomic cyclophosphamide as preoperative treatment for patients with locally advanced breast cancer.

Abstract Aim To evaluate the role of pegylated liposomal doxorubicin with low-dose metronomic cyclophosphamide as primary systemic treatment in locally advanced breast cancer. Patients and Methods The activity and safety of intravenous pegylated liposomal doxorubicin 20 mg sqm−1 biweekly for eight courses in combination with metronomic cyclophosphamide 50 mg day−1 orally were evaluated in 29 patients with locally advanced breast cancer who were not suitable to receive a standard chemotherapy due to age or co-morbidities or who asked for a regimen with low incidence of toxic effects irrespective of age. Results The rate of breast-conserving surgery was 44.8%. Eighteen patients (62.1%) achieved a partial response (including one pathological complete response), 10 (34.5%) a stable disease and one patient experienced a progressive disease. Treatment was well tolerated, with no grade 4 toxicities, and with grade 3 skin toxicity in three patients and hand–foot syndrome in four patients. Conclusion The regimen was well tolerated but with limited activity in the preoperative setting. Other options (e.g., endocrine therapy in estrogen receptor -positive disease) should be considered in locally advanced breast cancer patients who are not suitable to receive a standard chemotherapy