Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in the world [1]. It is more... more Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in the world [1]. It is more common in developed countries, with an estimated 70,800 new cases in the United States (US) in 2014. Accounting for 4.3% of all cancers in the US, NHL ranks as the seventh most common cancer among males and the sixth most common cancer among females. NHL consists of more than 40 major subtypes with distinct genetic, morphologic, and clinical features. The incidence of NHL subtypes also varies by age, sex, ethnicity, and geographic region [2, 3]. Hodgkin lymphoma (HL) affects approximately 9050 new patients in the US each year [4], representing approximately 11.2% of all lymphomas. The disease has a bimodal distribution with an increased incidence in young adults as well as in patients 55 years and older [5].
PurposeThe aim of this study was to assess the frequency of second primary non-breast cancer afte... more PurposeThe aim of this study was to assess the frequency of second primary non-breast cancer after breast cancer diagnosis and treatment, and its correlation with clinicopathological features.MethodsData from 21,527 patients with primary breast cancer were collected retrospectively in a single cancer centre; 4.1% of the women developed a second non-breast cancer. The most frequently observed second primary tumor affected the digestive tract (27.8%). The frequency of observed cancers was similar to that expected in the general population, excepting for an excess of melanoma [SIR 1.98 (1.52–2.53)], uterine cancers [SIR 1.44 (1.17–1.74)], ovarian cancers [SIR 1.67 (1.31–2.10)], thyroid tumors [SIR 1.54 (1.23–1.92)], and leukemia [SIR 1.57 (1.11–2.16)].ResultsClinicopathological breast cancer stratification showed a general increased risk of developing a second cancer in older patients, excluding ovarian cancer. An increased risk of developing ovarian cancer after breast cancer diagnosis was observed, in particular, in triple-negative [HR 3.47 (1.91–6.29)], G3 tumors [HR 2.54 (1.10–5.83)] and in positive breast cancer family history [HR 2.19 (1.22–3.94)]. Breast cancer survivors in hormonal therapy treatment are at higher risk for developing a second thyroid cancer [HR 4.00 (1.46–10.9)]. Conversely, adjuvant chemotherapy offered a protective effect on thyroid cancer risk development [HR 0.46 (0.28–0.76)].ConclusionsOlder age represents the major risk of developing a second primary non-breast cancer, excluding ovarian cancer. Clinical surveillance is required to prevent ovarian and thyroid cancers, respectively, in patients with positive family history, triple negative, G3 breast cancer and during hormonal therapy treatment in postmenopausal status.
Recent studies have reported germline mutations in cases of lobular breast cancer (LBC) not assoc... more Recent studies have reported germline mutations in cases of lobular breast cancer (LBC) not associated with the classical hereditary diffuse gastric cancer syndrome. A multidisciplinary workgroup discussed genetic susceptibility, pathophysiology and clinical management of hereditary LBC (HLBC). The team has established the clinical criteria for screening and results' interpretation, and created consensus guidelines regarding genetic counselling, breast surveillance and imaging techniques, clinicopathological findings, psychological and decisional support, as well as prophylactic surgery and plastic reconstruction. Based on a review of current evidence for the identification of HLBC cases/families, genetic testing is recommended in patients fulfilling the following criteria: (A) bilateral LBC with or without family history of LBC, with age at onset <50 years, and (B) unilateral LBC with family history of LBC, with age at onset <45 years. In asymptomatic mutant carriers, bre...
ABSTRACT Introduction: Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblast... more ABSTRACT Introduction: Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). Ribociclib is an orally bioavailable, highly selective small molecule inhibitor of CDK4/6 that induces G1 arrest at sub-micromolar concentrations in a variety of pRb-positive cancer cells in vitro. Ribociclib is a new standard of care for metastatic HR+/HER2 negative metastatic breast cancer. Area covered: In this article, we review the preclinical and clinical development of ribociclib as well as discussing the role for novel applications of these agents outside the arena of HR-positive, HER2-negative advanced breast cancer. Expert opinion: Results of pivotal phase II and III trials investigating ribociclib in patients with advanced-stage (HR)-positive breast cancer have demonstrated a substantial improvement in progression-free survival, with a safe toxicity profile. Mechanisms of acquired resistance to CDK4/6 inhibitors are beginning to emerge and might enable rational post-CDK4/6 inhibitor therapeutic strategies to be identified. Extending the use of CDK4/6 inhibitors beyond ER-positive breast cancer is challenging, and will likely require biomarkers that are predictive of a response. The use of combination therapies to optimize CDK4/6 targeting is under development.
Challenges in breast cancer treatment Neoadjuvant treatment (NAT) is a consolidated approach for ... more Challenges in breast cancer treatment Neoadjuvant treatment (NAT) is a consolidated approach for the care of locally advanced breast cancer (BC). The main objective of NAT is to obtain a tumor downstaging [1] with a cytoreductive surgery that may comprise the sentinel lymph node biopsy [2,3]. Preoperative therapy is suitable for a conservative surgery in several patients. Moreover, it consents prognostic indication that could help in the choice of treatments to obtain the maximum level of tumor response. Complete tumor response is defined as pathological complete remission (pCR) [4]. To date, pCR is obtained in about 20% of treated patients; neoadjuvant chemotherapy regimen could comprise taxane, anthracycline and anti-HER2 inhibitors for HER2-positive cases [5]. Patients with triplenegative and HER2-positive disease represent the best choice to obtain a high pCR and a better prognosis [6]. A count part of patients with locally advanced BC are classified as ‘nonresponder’, often they present a tumor progression during NAT. It remains difficult to decide for these patients; whenever surgery is still possible, this approach is preferred; otherwise a second line of c hemotherapy is considered. It is urgent to define the best choice, before to candidate patients for NAT, to improve the pCR in neoadjuvant setting. Modern strategies are to consider molecular biomarkers that predict NAT response, to avoid u nnecessary therapies. PIK3CA oncogenic mutations PI3K activation is critical for cell survival, proliferation, differentiation and migration. PI3Ks belong to the lipid kinases family that have been involved in signal transduction through the tyrosine kinases, frequently overexpressed in human cancers. PI3K activation through PI3K catalytic alpha (PIK3CA) subunit mutations is found frequently in colorectal cancers [7] and represents an example of a disturbed KRAS signaling pathway. PIK3CA oncogenic mutations were described to characterize both sporadic and hereditary colorectal cancers with microsatellite instability (MSI) pattern. In the sporadic setting, PIK3CA mutations were described to occur in about 16% of the cases, whereas they occur preferentially associated with the presence of KRAS or BRAF oncogenic mutations in about 6% of cases [8]. PIK3CA gene mutations were also described to occur in about 15% of hereditary MSI colorectal carcinomas [9]. PIK3CA mutations were found also in about 15% of the MSI gastric carcinoma. It has been described that PIK3CA somatic mutations occur in targeted codons, socalled hotspots (codons 542, 545 and 1047). PIK3CA alterations could affect the helical domain (codon 515, 542 and 545) and the kinase domain (codon 1047) [10]. PIK3CA mutations have been identified less frequent in some cases such as head (<10%), melanoma, prostate, pancreas and lung c ancer [11]. PIK3CA oncogenic mutations in neoadjuvant treatments for breast cancer
Hereditary breast and ovarian cancer is an inherited syndrome associated with BRCA1/2 germline de... more Hereditary breast and ovarian cancer is an inherited syndrome associated with BRCA1/2 germline defects. The identified mutations are classified as missense, large deletion, insertion, nonsense and splice-site variants with a deleterious impact on BRCA1/2 function. Part of these forms the well-documented truncating mutations, and missense variants represent a clinical dilemma as the pathogenic role is yet to be clearly shown. In this systematic review, we collected these missense variations with a documented deleterious function. We focused on English language articles from MEDLINE. This study included all BRCA1/2 germline missense mutations identified in breast and ovarian cancer patients. The method of this study followed the &amp;amp;#39;PRISMA statement for reporting systematic reviews and meta-analyses&amp;amp;#39;. A total of 61 BRCA1/2 germline and pathogenic missense mutations were identified: 70.5% affected BRCA1 and 29.5% BRCA2, respectively. In BRCA1, the majority of mutations were located in the BRCA C-terminus (48.8%), leading to a disruption of function. Conversely, no specific associations were verified between mutations and the BRCA2 gene. The European population was the most affected by BRCA1 and the Asian population by BRCA2 mutant patterns. The identification of novel BRCA1/2 missense mutations requires specific genetic tests to assess pathogenicity. With this systematic review, we are, to the best of our knowledge, the first to collect the overall amount of data on these pathogenic mutants with the aim of improving the management of carriers and their kindred.
Breast cancer is the commonest malignancy in women worldwide. The reduced aggressiveness of breas... more Breast cancer is the commonest malignancy in women worldwide. The reduced aggressiveness of breast cancer surgery has made it possible treat patients in the day surgery setting. The European Institute of Oncology, Milan, opened its new Day Center in May 2010. From May 2010 to December 2014, 17,087 patients with breast conditions were treated by the Institute&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Division of Senology, 4132 (24.2%) of these in the day surgery setting, including malignant and benign conditions; 204 (4.9%) were not discharged on the day of surgery, being converted to inpatients; five (0.1%) patients returned to hospital for persistent hematoma. Our experience of performing breast cancer surgery in the day surgery setting is in line that of the literature. It is safe, but requires a well-organized unit and multidisciplinary medical team to function smoothly, with much attention paid to patient comfort and education, so as to ensure maximum patient acceptance and satisfaction.
Hereditary diffuse gastric cancer is an autosomal dominant inherited disease associated of CDH1 g... more Hereditary diffuse gastric cancer is an autosomal dominant inherited disease associated of CDH1 germline mutations (that encodes for the E-cadherin protein), and lobular breast cancer is the second most frequent type of neoplasia. Recently, novel E-cadherin constitutional alterations have been identified in pedigree clustering only for lobular breast carcinoma without evidence of diffuse gastric tumors and in absence of BRCA1/2 mutations. This first evidence opens novel questions about the inherited correlation between diffuse gastric and lobular breast cancers. In this brief review we revise the literature data about the CDH1 mutation frequency affecting exclusively lobular breast cancer, providing clinical recommendation for asymptomatic mutation carriers.
Dose-dense chemotherapy with anthracyclines and taxanes has improved either disease free survival... more Dose-dense chemotherapy with anthracyclines and taxanes has improved either disease free survival or overall survival in high risk patients with early breast cancer. The activity and safety of a dose-dense schedule (q14 days) of adriamycin 60 mg/sqm and cyclophosphamide 600 mg/sqm (AC) x 4 cycles followed by docetaxel 75 mg/sqm for 4 cycles with hematopoietic support in patients with stage IIIB breast cancer was explored. Patients with ER > or =10% tumors received concomitant endocrine therapy with 3-month triptorelin and letrozole. Fifteen patients with histologically proven cT4b (three patients) and cT4d (twelve patients) M0 breast cancer were enrolled. Median age was 48 years (range 25-66). Eight clinical responses including one pathological complete remission (pCR), three stable disease (including minor responses) and four progression of disease, one during AC and three during taxotere, were observed. Four patients had grade 3-4 non hematological toxicities and all except one...
Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in the world [1]. It is more... more Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in the world [1]. It is more common in developed countries, with an estimated 70,800 new cases in the United States (US) in 2014. Accounting for 4.3% of all cancers in the US, NHL ranks as the seventh most common cancer among males and the sixth most common cancer among females. NHL consists of more than 40 major subtypes with distinct genetic, morphologic, and clinical features. The incidence of NHL subtypes also varies by age, sex, ethnicity, and geographic region [2, 3]. Hodgkin lymphoma (HL) affects approximately 9050 new patients in the US each year [4], representing approximately 11.2% of all lymphomas. The disease has a bimodal distribution with an increased incidence in young adults as well as in patients 55 years and older [5].
PurposeThe aim of this study was to assess the frequency of second primary non-breast cancer afte... more PurposeThe aim of this study was to assess the frequency of second primary non-breast cancer after breast cancer diagnosis and treatment, and its correlation with clinicopathological features.MethodsData from 21,527 patients with primary breast cancer were collected retrospectively in a single cancer centre; 4.1% of the women developed a second non-breast cancer. The most frequently observed second primary tumor affected the digestive tract (27.8%). The frequency of observed cancers was similar to that expected in the general population, excepting for an excess of melanoma [SIR 1.98 (1.52–2.53)], uterine cancers [SIR 1.44 (1.17–1.74)], ovarian cancers [SIR 1.67 (1.31–2.10)], thyroid tumors [SIR 1.54 (1.23–1.92)], and leukemia [SIR 1.57 (1.11–2.16)].ResultsClinicopathological breast cancer stratification showed a general increased risk of developing a second cancer in older patients, excluding ovarian cancer. An increased risk of developing ovarian cancer after breast cancer diagnosis was observed, in particular, in triple-negative [HR 3.47 (1.91–6.29)], G3 tumors [HR 2.54 (1.10–5.83)] and in positive breast cancer family history [HR 2.19 (1.22–3.94)]. Breast cancer survivors in hormonal therapy treatment are at higher risk for developing a second thyroid cancer [HR 4.00 (1.46–10.9)]. Conversely, adjuvant chemotherapy offered a protective effect on thyroid cancer risk development [HR 0.46 (0.28–0.76)].ConclusionsOlder age represents the major risk of developing a second primary non-breast cancer, excluding ovarian cancer. Clinical surveillance is required to prevent ovarian and thyroid cancers, respectively, in patients with positive family history, triple negative, G3 breast cancer and during hormonal therapy treatment in postmenopausal status.
Recent studies have reported germline mutations in cases of lobular breast cancer (LBC) not assoc... more Recent studies have reported germline mutations in cases of lobular breast cancer (LBC) not associated with the classical hereditary diffuse gastric cancer syndrome. A multidisciplinary workgroup discussed genetic susceptibility, pathophysiology and clinical management of hereditary LBC (HLBC). The team has established the clinical criteria for screening and results' interpretation, and created consensus guidelines regarding genetic counselling, breast surveillance and imaging techniques, clinicopathological findings, psychological and decisional support, as well as prophylactic surgery and plastic reconstruction. Based on a review of current evidence for the identification of HLBC cases/families, genetic testing is recommended in patients fulfilling the following criteria: (A) bilateral LBC with or without family history of LBC, with age at onset <50 years, and (B) unilateral LBC with family history of LBC, with age at onset <45 years. In asymptomatic mutant carriers, bre...
ABSTRACT Introduction: Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblast... more ABSTRACT Introduction: Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). Ribociclib is an orally bioavailable, highly selective small molecule inhibitor of CDK4/6 that induces G1 arrest at sub-micromolar concentrations in a variety of pRb-positive cancer cells in vitro. Ribociclib is a new standard of care for metastatic HR+/HER2 negative metastatic breast cancer. Area covered: In this article, we review the preclinical and clinical development of ribociclib as well as discussing the role for novel applications of these agents outside the arena of HR-positive, HER2-negative advanced breast cancer. Expert opinion: Results of pivotal phase II and III trials investigating ribociclib in patients with advanced-stage (HR)-positive breast cancer have demonstrated a substantial improvement in progression-free survival, with a safe toxicity profile. Mechanisms of acquired resistance to CDK4/6 inhibitors are beginning to emerge and might enable rational post-CDK4/6 inhibitor therapeutic strategies to be identified. Extending the use of CDK4/6 inhibitors beyond ER-positive breast cancer is challenging, and will likely require biomarkers that are predictive of a response. The use of combination therapies to optimize CDK4/6 targeting is under development.
Challenges in breast cancer treatment Neoadjuvant treatment (NAT) is a consolidated approach for ... more Challenges in breast cancer treatment Neoadjuvant treatment (NAT) is a consolidated approach for the care of locally advanced breast cancer (BC). The main objective of NAT is to obtain a tumor downstaging [1] with a cytoreductive surgery that may comprise the sentinel lymph node biopsy [2,3]. Preoperative therapy is suitable for a conservative surgery in several patients. Moreover, it consents prognostic indication that could help in the choice of treatments to obtain the maximum level of tumor response. Complete tumor response is defined as pathological complete remission (pCR) [4]. To date, pCR is obtained in about 20% of treated patients; neoadjuvant chemotherapy regimen could comprise taxane, anthracycline and anti-HER2 inhibitors for HER2-positive cases [5]. Patients with triplenegative and HER2-positive disease represent the best choice to obtain a high pCR and a better prognosis [6]. A count part of patients with locally advanced BC are classified as ‘nonresponder’, often they present a tumor progression during NAT. It remains difficult to decide for these patients; whenever surgery is still possible, this approach is preferred; otherwise a second line of c hemotherapy is considered. It is urgent to define the best choice, before to candidate patients for NAT, to improve the pCR in neoadjuvant setting. Modern strategies are to consider molecular biomarkers that predict NAT response, to avoid u nnecessary therapies. PIK3CA oncogenic mutations PI3K activation is critical for cell survival, proliferation, differentiation and migration. PI3Ks belong to the lipid kinases family that have been involved in signal transduction through the tyrosine kinases, frequently overexpressed in human cancers. PI3K activation through PI3K catalytic alpha (PIK3CA) subunit mutations is found frequently in colorectal cancers [7] and represents an example of a disturbed KRAS signaling pathway. PIK3CA oncogenic mutations were described to characterize both sporadic and hereditary colorectal cancers with microsatellite instability (MSI) pattern. In the sporadic setting, PIK3CA mutations were described to occur in about 16% of the cases, whereas they occur preferentially associated with the presence of KRAS or BRAF oncogenic mutations in about 6% of cases [8]. PIK3CA gene mutations were also described to occur in about 15% of hereditary MSI colorectal carcinomas [9]. PIK3CA mutations were found also in about 15% of the MSI gastric carcinoma. It has been described that PIK3CA somatic mutations occur in targeted codons, socalled hotspots (codons 542, 545 and 1047). PIK3CA alterations could affect the helical domain (codon 515, 542 and 545) and the kinase domain (codon 1047) [10]. PIK3CA mutations have been identified less frequent in some cases such as head (<10%), melanoma, prostate, pancreas and lung c ancer [11]. PIK3CA oncogenic mutations in neoadjuvant treatments for breast cancer
Hereditary breast and ovarian cancer is an inherited syndrome associated with BRCA1/2 germline de... more Hereditary breast and ovarian cancer is an inherited syndrome associated with BRCA1/2 germline defects. The identified mutations are classified as missense, large deletion, insertion, nonsense and splice-site variants with a deleterious impact on BRCA1/2 function. Part of these forms the well-documented truncating mutations, and missense variants represent a clinical dilemma as the pathogenic role is yet to be clearly shown. In this systematic review, we collected these missense variations with a documented deleterious function. We focused on English language articles from MEDLINE. This study included all BRCA1/2 germline missense mutations identified in breast and ovarian cancer patients. The method of this study followed the &amp;amp;#39;PRISMA statement for reporting systematic reviews and meta-analyses&amp;amp;#39;. A total of 61 BRCA1/2 germline and pathogenic missense mutations were identified: 70.5% affected BRCA1 and 29.5% BRCA2, respectively. In BRCA1, the majority of mutations were located in the BRCA C-terminus (48.8%), leading to a disruption of function. Conversely, no specific associations were verified between mutations and the BRCA2 gene. The European population was the most affected by BRCA1 and the Asian population by BRCA2 mutant patterns. The identification of novel BRCA1/2 missense mutations requires specific genetic tests to assess pathogenicity. With this systematic review, we are, to the best of our knowledge, the first to collect the overall amount of data on these pathogenic mutants with the aim of improving the management of carriers and their kindred.
Breast cancer is the commonest malignancy in women worldwide. The reduced aggressiveness of breas... more Breast cancer is the commonest malignancy in women worldwide. The reduced aggressiveness of breast cancer surgery has made it possible treat patients in the day surgery setting. The European Institute of Oncology, Milan, opened its new Day Center in May 2010. From May 2010 to December 2014, 17,087 patients with breast conditions were treated by the Institute&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Division of Senology, 4132 (24.2%) of these in the day surgery setting, including malignant and benign conditions; 204 (4.9%) were not discharged on the day of surgery, being converted to inpatients; five (0.1%) patients returned to hospital for persistent hematoma. Our experience of performing breast cancer surgery in the day surgery setting is in line that of the literature. It is safe, but requires a well-organized unit and multidisciplinary medical team to function smoothly, with much attention paid to patient comfort and education, so as to ensure maximum patient acceptance and satisfaction.
Hereditary diffuse gastric cancer is an autosomal dominant inherited disease associated of CDH1 g... more Hereditary diffuse gastric cancer is an autosomal dominant inherited disease associated of CDH1 germline mutations (that encodes for the E-cadherin protein), and lobular breast cancer is the second most frequent type of neoplasia. Recently, novel E-cadherin constitutional alterations have been identified in pedigree clustering only for lobular breast carcinoma without evidence of diffuse gastric tumors and in absence of BRCA1/2 mutations. This first evidence opens novel questions about the inherited correlation between diffuse gastric and lobular breast cancers. In this brief review we revise the literature data about the CDH1 mutation frequency affecting exclusively lobular breast cancer, providing clinical recommendation for asymptomatic mutation carriers.
Dose-dense chemotherapy with anthracyclines and taxanes has improved either disease free survival... more Dose-dense chemotherapy with anthracyclines and taxanes has improved either disease free survival or overall survival in high risk patients with early breast cancer. The activity and safety of a dose-dense schedule (q14 days) of adriamycin 60 mg/sqm and cyclophosphamide 600 mg/sqm (AC) x 4 cycles followed by docetaxel 75 mg/sqm for 4 cycles with hematopoietic support in patients with stage IIIB breast cancer was explored. Patients with ER > or =10% tumors received concomitant endocrine therapy with 3-month triptorelin and letrozole. Fifteen patients with histologically proven cT4b (three patients) and cT4d (twelve patients) M0 breast cancer were enrolled. Median age was 48 years (range 25-66). Eight clinical responses including one pathological complete remission (pCR), three stable disease (including minor responses) and four progression of disease, one during AC and three during taxotere, were observed. Four patients had grade 3-4 non hematological toxicities and all except one...
Uploads
Papers by Mattia Intra