Breast Cancer in Women: An OverviewYoung
Breast cancerIt is now established knowledge that women with breastcancer are treated with combinations of surgery,chemotherapy and radiotherapy. Continued research effortsare making treatments more personalized with the hope tominimize side effects and to improve overall survival rates.Despite recent progress on cancer therapy, current evi-dence-based medicine shows that progress against breastcancer over the past decade is slow. This is translated intofew months of survival prolongation in the metastatic field.This is not surprising if we consider important limitationsof currently available targeted therapies. The reasons forhigh intrinsic and acquired resistance rates to availabletargeted drugs include their temporary antitumor activityand the lack of consideration of interpatient and intratumorheterogeneity. The understanding of this extremely com-plex heterogeneity is crucial in the ‘war’ against breasttumorigenesis and metastasis .It has to be highlighted that important progress has beenmade for HER2-positive breast cancer, which accounts for20% of all breast cancer patients. The identification of theHER2 pathway and its dysfunction when theHER2gene isamplified has led to the development of the famous anti-HER2 monoclonal antibody (mAb), trastuzumab . PhaseIII randomized controlled trials reported that trastuzumab inaddition to chemotherapy in HER2-positive breast cancersignificantly improves overall survival in metastatic andadjuvant settings. For these reasons, trastuzumab has beenthe standard first line of treatment for these patients
Breast cancerIt is now established knowledge that women with breastcancer are treated with combinations of surgery,chemotherapy and radiotherapy. Continued research effortsare making treatments more personalized with the hope tominimize side effects and to improve overall survival rates.Despite recent progress on cancer therapy, current evi-dence-based medicine shows that progress against breastcancer over the past decade is slow. This is translated intofew months of survival prolongation in the metastatic field.This is not surprising if we consider important limitationsof currently available targeted therapies. The reasons forhigh intrinsic and acquired resistance rates to availabletargeted drugs include their temporary antitumor activityand the lack of consideration of interpatient and intratumorheterogeneity. The understanding of this extremely com-plex heterogeneity is crucial in the ‘war’ against breasttumorigenesis and metastasis .It has to be highlighted that important progress has beenmade for HER2-positive breast cancer, which accounts for20% of all breast cancer patients. The identification of theHER2 pathway and its dysfunction when theHER2gene isamplified has led to the development of the famous anti-HER2 monoclonal antibody (mAb), trastuzumab . PhaseIII randomized controlled trials reported that trastuzumab inaddition to chemotherapy in HER2-positive breast cancersignificantly improves overall survival in metastatic andadjuvant settings. For these reasons, trastuzumab has beenthe standard first line of treatment for these patients
Breast cancer biology in young womenGeneral consideration
It has to be highlighted that in USA each year, approximately10,000 women aged\40 years are diagnosed with invasivebreast cancer, accounting for 4–5% of all women diagnosedwith breast cancer. In the West, it is reported that\4% ofwomen diagnosed with breast cancer are aged\35 years. Asfor the East, the Asian breast cancer Society reports that 13%of women diagnosed with breast cancer are aged\40 years,while 5% are aged\35 years. This dramatic increase ofbreast cancer cases in young women is very importantbecause the behavior of these tumors is in the majority ofcases more aggressive in comparison with older women.This leads unfortunately to a disproportionate number of lostlives because of cancer each year .Notably, the usual presentation of advanced stages atdiagnosis, more aggressive pathological characteristics, agreater rate of triple-negative and HER2-overexpressingtumors, and higher rates of recurrence at any clinical stagein comparison with older women represent the main causesof the ‘aggressive’ nature of breast cancer in young women. To date, it is supported that the increased risk of loco-regional recurrence in young women with breast cancer,methods for fertility preservation in these women, psy-chological interventions and potential, challenges andperspectives associated with longer survival rates remainhighly uncertain, unexplored and controversial [17].Recent evidence suggests that young age at diagnosis ofbreast cancer represent an independent prognostic factor ofsurvival . Several large-scale studies report that youngage at diagnosis is highly associated with huge risk ofrecurrence and death [19,20]. In addition, endocrinereceptors, HER2 and proliferation markers, appear to bedifferent in young women. Recent studies support thatmore aggressive and invasive subtypes of breast cancer aremore frequent in young women . Moreover, theresearchers believe that hormonal therapy efficacy is sig-nificantly lower in young women . Tamoxifen role andits relationship with endometrium cancer in young womenare also controversial. More frequently in young womenoccur type I endometrial cancers.
Breast cancer heterogeneity, mutational backgroundand current evidence
Recent studies have made an important effort to assess themutational landscape of breast cancer using powerful next-generation sequencing (NGS) analyses . Point muta-tions have been observed in TP53 and PIK3CA genes,accounting for*25% of cases. However, there is a lack ofevidence regarding the landscape of somatic mutations inyoung women .It has to be highlighted that Stephens per-formed a powerful whole-genome sequencing (WGS)analyses of 100 breast tumors. No association between totalnumber of somatic base substitution and age at diagnosis inboth ER-positive and ER-negative tumors was observed.Recently, the pattern of somatic mutations was evaluated in167 young breast cancer women, of whom 54 were diag-nosed during pregnancy. An amount of 84 mutations in 19genes were assessed, including 29 different mutations ofPIK3CA and 7 and 6 mutations for ERBB2 and TP53,respectively . The researchers report that no differenceswere observed between the pregnant and non-pregnantgroups of women. Only 5% of patients had a TP53 muta-tion, although it should be noted that only 12% of knownP53 mutations were explored in this study. No ERBB2mutations were observed in this study. Regarding germlinemutations, BRCA1/2 mutations were the most common,accounting for up to 40% of familial breast cancer .The largest analysis on this issue enrolled 3.340 womenwith ageB50 years at diagnosis time. The most importantfinding was that 7% of breast cancer women had a BRCA1mutation. BRCA1 carriers were significantly younger(mean age 41.9 versus 44.1,P\0.001) and had more ER-negative (84.1 versus 38.1%,P\0.001) and HER2- neg-ative (93 versus 79%,P\0.001) tumors . It has to beemphasized that CHEK21100delC represents anothermutation that occurs more frequently in younger patients.Notably, recent evidence assessing 25.600 women reportedthat*2% were CHEK2*1100delC heterozygous .These patients were younger, and most of them were at apremenopausal status and have ER-positive disease
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