open access - Revie: Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers - Journal of Internal Medicine (references to Lynch Syndrome/Familial Melanoma)

Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers - Journal of Internal Medicine

pdf file

Genetic variants associated with breast cancer risk for BRCA1 mutations carriers

Genetic variants associated with breast cancer risk for BRCA2 mutations carriers

Patterns of association and tumour characteristics

Genetic modifiers of ovarian cancer risk

Environmental, hormonal and reproductive modifiers of risk

Common alleles and cancer risks for mutation carriers

Future challenges     "Over the past 5 years, there has been substantial progress in our understanding of genetic factors that modify breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. This was made possible to a great extent because of the availability of large numbers of mutation carriers from the CIMBA consortium and GWAS data. However, the five loci described in this review that are associated with breast cancer risk for BRCA1 mutation carriers are estimated to explain only approximately 3% of the genetic variability in breast cancer risk for BRCA1 mutation carriers. Similarly, the 11 SNPs associated with breast cancer risk for BRCA2 mutation carriers are estimated to account for approximately 6% of the genetic variability in breast cancer risk for BRCA2 mutation carriers. Therefore, the majority of the genetic variability in breast cancer risk for mutation carriers still remains unexplained. Several more breast and ovarian cancer susceptibility alleles have been identified through GWAS in the general population, but have not yet been investigated in mutation carriers [61, 63, 72, 75]. Given the observed association patterns in mutation carriers with previously identified loci, it is expected that at least a subset of these will also be associated with breast or ovarian cancer risk for mutation carriers. Additional genetic modifiers of risk may also be identified through not only the ongoing GWAS in BRCA1 and BRCA2 mutation carriers but also other GWAS from the general population or by GWAS focusing on specific cancer subtypes such as oestrogen-receptor-negative or triple-negative breast cancers, or serous ovarian cancer. However, it is likely that several of the alleles identified through population-based GWAS may be associated with modest relative risks in the range of 1.05–1.10. Despite sample sizes of approximately 15 000 BRCA1 and 10 000 BRCA2 mutation carriers, CIMBA would still be underpowered to detect modifying polymorphisms conferring such modest relative risks. Given the rarity of BRCA1 and BRCA2 mutations, increasing sample sizes is currently only possible through increased collaboration between studies and through continued recruitment of mutation carriers........

Conclusions

As more cost-effective mutation screening techniques become available, the number of identified BRCA1 and BRCA2 mutation carriers in the population is likely to increase. Therefore, it will be important that all mutation carriers are provided with accurate information on their risk of developing breast and ovarian cancer, so that informed decisions on clinical management are made. Our understanding of factors influencing cancer risk variability in mutation carriers has increased over the last few years and is likely to improve further in the near future. Therefore, we are getting closer to the goal of being able to provide more individualized clinical management. Understanding how cancer risks are modified in BRCA1 and BRCA2 mutation carriers will also provide further insights for studying the biological mechanisms of cancer development in mutation carriers. These may lead to the development of novel therapies and more accurate prediction of breast and ovarian cancer progression in mutation carriers.

Studying genetic modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has provided useful insights in study design, analytical methodology and applications, which could be used for studying modifiers of disease in carriers of other high-risk mutations such as the mismatch repair genes MSH2, MLH1, MSH6, PMS2 in colorectal cancer (Lynch Syndrome) and CDKN2A in melanoma but also other noncancer-related diseases.

 

 

 

 

 

 

open access: Breast manifestations of systemic diseases

Metastases from other solid organ primaries
"Breast cancer is the most common type of primary malignancy
in women, but metastatic spread to the breast from other solid
organs, although rare, has been reported 51–53 and may be the
first sign of malignancy.54..."
                           
                    ~~~~~~~~~~~~~~~~~~~

Abstract: Although much emphasis has been placed on the primary presentations of breast cancer, little focus has been placed on how systemic illnesses may affect the breast. In this article, we discuss systemic illnesses that can manifest in the breast. We summarize the clinical features, imaging, histopathology, and treatment recommendations for endocrine, vascular, systemic inflammatory, infectious, and hematologic diseases, as well as for the extramammary malignancies that can present in the breast. Despite the rarity of these manifestations of systemic disease, knowledge of these conditions is critical to the appropriate evaluation and treatment of patients presenting with breast symptoms.


References as noted above (Metastases from other solid organ primaries):

51. Akcay MN. Metastatic disease in the breast. Breast. 2002;11(6):
526–528.

52. Lee SK, Kim WW, Kim SH, et al. Characteristics of metastasis in thebreast from extramammary malignancies. J Surg Oncol. 2010;101(2):137–140.

Blogger's Note:  - excerpt from reference #52  above:


"The breast is an uncommon site for metastasis from
extramammary tumors with incidence of 0.4 - 1.3%.1,2 In
about 25–40% of cases, metastasis to the breast is the
initial manifestation of the disease.2 The common
sources of primary tumors are haematological
malignancies, malignant melanoma, lung tumors, renal
cell carcinoma, ovarian tumors, thyroid carcinomas and
small bowel carcinoid.4,6  Other tumors metastasized to
breast are prostate, stomach, malignant mesothelioma
and rhabdomyosarcoma.9"

53. Young JL Jr, Ward KC, Wingo PA, Howe HL. The incidence of
malignant non-carcinomas of the female breast. Cancer Causes Control.
2004;15(3):313–319.

54. Hamby LS, McGrath PC, Cibull ML, Schwartz RW. Gastric carcinoma
metastatic to the breast. J Surg Oncol. 1991;48(2):117–121.

JMIR-Results of an Online Community (FORCE) Needs Assessment for Psychoeducational Interventions Among Partners of Hereditary Breast Cancer Previvors and Survivors (specifically breast cancer)

Clinical Characteristics

"Clinical characteristics assessed included whether respondents’ partners had a diagnosis of breast cancer, had been tested for a BRCA1/2 genetic mutation, and had surgery to remove her breasts (ie, prophylactic mastectomy) or ovaries (ie, prophylactic oophorectomy), or for breast reconstruction. Based on these items, 3 variables were created to indicate whether each respondent’s partner had (1) a diagnosis of breast cancer, (2) received BRCA1/2 genetic testing, and (3) undergone any of the 3 surgery types we inquired about."

Researchers find discordance between standard human epidermal growth factor receptor 2 (HER2) testing and HER2 status reported on Oncotype DX

"“Our study on HER2 discordance highlights the fact that one test cannot provide all the answers [regarding optimal treatment for women with breast cancer]. The oncology community needs to continue using the validated HER2 assays in clinical treatment decisions and reexamine their overreliance on the Oncotype DX test,” Dr. Bhargava says.

Dr. Hayes agrees, noting that the Oncotype DX HER2 assay was not developed, validated, or approved as a predictive test to determine which patients should receive anti-HER2 therapies."

Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations

"....The present study strengthens the known links between BRCA2 and pancreatic and prostate cancer, but throws further doubt onto any association with BRCA1.

New associations with upper gastro-intestinal malignancy need to be treated with caution and confirmed by large prospective studies"

open access: Jan 2012 - Assessing the malignant potential of ovarian inclusion cysts in postmenopausal women within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a prospective cohort study

Objective  To evaluate the malignant potential of ultrasound-detected ovarian inclusion cysts in the development of ovarian cancer (OC) in postmenopausal women.

Design  Prospective cohort study.

Setting  UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

Population  Postmenopausal women.

Conclusions  Postmenopausal women with ultrasound-detected inclusion cysts do not seem to be at increased risk of ovarian or breast/endometrial (hormone-dependent) cancers.

see also 

Table 1.   Details of ovarian cancers detected in the cohort of women with inclusion cysts in year 1 

Table 2.   Details of ovarian cancers detected in the cohort of women with normal scans in year 1 

Table 3.   Relative risks of developing gynaecological cancers in women with inclusion cysts

abstract: Outcomes for Patients who Develop Both Breast and Colorectal Cancer

BACKGROUND: Patients diagnosed with both breast and colorectal cancer are not uncommon and will likely be seen more often as the population ages and treatment modalities improve. Survival outcomes for such patients have not been previously reported.  

METHODS: The 1988-2007 Surveillance, Epidemiology, and End Results data were used to identify women diagnosed with both breast and colorectal cancer. Disease-specific survival rates were compared.  

RESULTS: We identified 4,835 women who were diagnosed with both breast and colorectal cancer. Of these, 2,844 (58.8%) were diagnosed with breast cancer first and 1,807 (37.4%) were diagnosed with colorectal cancer first; 184 (3.8%) had synchronous cancers. At 5 years following the second cancer diagnosis, 163 (3.4%) died of breast cancer and 477 (9.9%) died of colorectal cancer (P < 0.05). Comparing primary site groups between years 1 and 5 after the second cancer diagnosis showed that the relative risk of death from breast cancer declined by 46%, though it did not reach statistical significance (P = 0.24), while it significantly increased by 46% for colorectal cancer death (P = 0.0004). These findings persisted regardless of patient age, stage at diagnosis, or breast tumor histology.  

CONCLUSION: For women diagnosed with both breast and colorectal cancer, the cumulative risk of death at 5 years following the second cancer diagnosis is 3 times more likely to be due to colorectal cancer than to breast cancer. Colorectal cancer specific mortality increases with time, while breast cancer specific mortality decreases with time. Consideration should be given to these findings when discussing prognosis and making treatment decisions.

Genetic variants associated with breast-cancer risk : The Lancet Oncology (Steven A Narod)

Note: register (free) to view

Lynch Syndrome Hereditary Cancers Public Awareness Day | Fight Colorectal Cancer

Increased Risk of Cancer

If a parent carries a Lynch mutation there is a 50-50 chance that their child will inherit Lynch syndrome with

• 60 to 80 percent increased lifetime risk of colorectal cancer.
• 40 to 70 percent increased risk of endometrial cancer (cancer of the uterus lining).
• 13 percent increased risk for stomach cancer
• 12 percent increased risk of ovarian cancer.
• smaller, but significant risk of small intestine, urinary tract, heptobiliary (liver, gall bladder and bile ducts), skin, and brain cancers.
• Some families may also have increased risk for breast cancer.

Note: 
Lynch Syndrome is also noted for multiple primary cancers (different cancers in one person)

abstract - BRCA1 mutations and colorectal cancer in Poland

"This study suggests that BRCA1 mutations may be associated with early-onset of colorectal cancer."

FDA review indicates possible association between breast implants and a rare cancer anaplastic large cell lymphoma (ALCL) - lymphoma

Lancet (abstract) Retraction: validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy: a substudy of the EORTC 10994/BIG 00-01 clinical trial

Note: full details available to subscribers ($$$)

 Comment

Retraction—validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy: a substudy of the EORTC 10994/BIG 00-01 clinical trial

(Avastin)Bevacizumab in Breast Cancer: Genentech Submits Response to FDA

full free access: Absence of microsatellite instability in mucinous carcinomas of the breast (Lynch Syndrome)

Note: some key excerpt; see also Supplemental Tables 1-4

"Microsatellite instability (MSI) is a form of genetic instability that results from defects in DNA mismatch repair. MSI is reported to be rare in unselected breast cancers, however it is a common feature in subsets of colorectal, ovarian and endometrial cancers. In these anatomical sites, MSI-high carcinomas often display a mucinous histology. The aim of this study was to determine whether mucinous carcinomas of the breast would more frequently display MSI-high than invasive ductal carcinomas of no special type (IDC-NSTs). The expression of four MSI markers (i.e. MSH2, MSH6, MLH1 and PMS2) was immunohistochemically assessed in 35 mucinous breast carcinomas and 35 histological grade- and oestrogen receptor (ER) status-matched IDC-NSTs, and in a series of 245 invasive breast cancers...........
........
Subsets of colorectal [24], gastric [31], pancreatic [31], ovarian [32] and endometrial tumours [22,31,33], and particularly those occurring in the hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome [31], are characterised by microsatellite instability. Interestingly, however, MSI-H appears to be vanishingly rare in breast cancer [21,34]. Likewise, breast cancers displaying an MSI-L status are remarkably rare, whereas in tumours from other anatomical sites, such as colorectal, endometrial or ovarian cancers [27], this phenomenon is not as uncommon. Of note, in some anatomical sites (e.g. colorectal and ovarian), tumours displaying microsatellite instability often display a mucinous histology [32,35,36]. However, the prevalence of MSI in mucinous carcinomas of the breast has not yet been systematically addressed........
...........All 35 pure mucinous carcinomas of the breast analysed were positive for MLH1 and MSH6 as determined by IHC, and 33 out of 35 (94.2%) and 32 out of 34 cases (94.1%) showed expression of MSH2 and PMS2, respectively (Table 2 and Figure 1)............cont'd

full free access The Lancet: Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial : The Lancet Oncology

National Guideline Clearinghouse | New This Week focus on breast cancer (New Zealand)

New Zealand Guidelines Group

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General principles of care. In: Management of early breast cancer.

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Staging. In: Management of early breast cancer.

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Surgery for early invasive breast cancer. In: Management of early breast cancer.

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Radiotherapy. In: Management of early breast cancer.

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Systemic therapy: chemotherapy regimens. In: Management of early breast cancer.

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Systemic therapy: endocrine therapies. In: Management of early breast cancer.

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Ductal carcinoma in situ. In: Management of early breast cancer.

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Follow-up. In: Management of early breast cancer.

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Special issues. In: Management of early breast cancer.

Susan G. Komen Foundation Elbows Out Charities Over Use Of The Word 'Cure'

recruiting: Clinical Outcomes in Hereditary Cancer - Full Text View - ClinicalTrials.gov BRCA/pancreatic/breast

Purpose

Compare the clinical characteristics and post-surgical outcomes (overall survival)of pancreatic cancer patients of Ashkenazi descent with or without germline founder mutations in BRCA1 or BRCA2 .

Compare the clinical characteristics and outcomes (time to progression) of breast cancer patients of Ashkenazi descent with or without germline founder mutations in BRCA1 or BRCA2 receiving paclitaxel chemotherapy for metastatic disease.

abstract: Does Neoadjuvant (Avastin) Bevacizumab Increase Surgical Complications in Breast Surgery?

Conclusions Cisplatin/bevacizumab and cisplatin alone neoadjuvant therapy resulted in a significant number of postoperative complications. Specifically, use of expanders/implants may be problematic for patients treated with bev. However, this was a single-arm trial; randomized controlled studies will be needed to determine the optimal use of bevacizumab in the timing of breast cancer surgery.

EvidenceUpdates- A randomized controlled trial of home-based exercise for cancer-related fatigue in women during and after chemotherapy with or without radiation therapy

CONCLUSIONS: Our home-based exercise intervention had no effect on fatigue or related symptoms associated with cancer treatment. The optimal timing of exercise remains to be determined.
IMPLICATIONS FOR PRACTICE: Clinicians need to be aware that some physical activity is better than none, and there is no harm in exercise as tolerated during cancer treatment. Further analysis is needed to examine the adherence to exercise. More frequent assessments of fatigue, sleep disturbance, depression, and pain may capture the effect of exercise.

Comments from Clinical Raters
Oncology - Gynecology

Impact will be muted, as this is a negative trial: exercise is not harmful but doesn't seem to improve any of the outcomes measured, including fatigue.