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Lee21 View Drop Down
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Jan 19 2012 at 5:05pm

Nutrition, supplements and physical activity

Body weight and breast cancer survival

http://www.ncbi.nlm.nih.gov/pubmed/22187127

stay tuned for this study:

http://www.ncbi.nlm.nih.gov/pubmed/21710192

 

Diet and breast cancer

http://www.ncbi.nlm.nih.gov/pubmed?term=fiber%20kampman%20belle

http://www.ncbi.nlm.nih.gov/pubmed?term=thomson%20thompson%20pierce

Open access

http://www.ncbi.nlm.nih.gov/pubmed/19114692

 

Lignans and breast cancer:

http://www.ncbi.nlm.nih.gov/pubmed/17374837

http://www.ncbi.nlm.nih.gov/pubmed/22113872

 

Soy

http://www.ncbi.nlm.nih.gov/pubmed/19221874

open access

http://www.ncbi.nlm.nih.gov/pubmed/20980638

 

Green Tea

http://www.ncbi.nlm.nih.gov/pubmed?term=yuan%20butler%20tea

 

Vitamin D

Open access:

http://www.ncbi.nlm.nih.gov/pubmed/20164683

http://www.ncbi.nlm.nih.gov/pubmed/22234628

 

 

Multivitamins and other dietary supplements

http://www.ncbi.nlm.nih.gov/pubmed/21559824

http://www.ncbi.nlm.nih.gov/pubmed/21953120

 

Physical activity

http://www.ncbi.nlm.nih.gov/pubmed/21935600

http://www.ncbi.nlm.nih.gov/pubmed/21464032

http://health.gov/PAGUIDELINES/guidelines/appendix1.aspx

http://www.medpagetoday.com/HematologyOncology/OtherCancers/30980

 

Websites

Harvard School of Public Health Nutrition site:

http://www.hsph.harvard.edu/nutritionsource/index.html

 

There is another site “The Cancer Project” that has downloadable pdfs on nutrition and cancer.  I am not including the link (just google it) because the organization recommends a strictly vegan diet and has been accused (surprise!) by the meat and dairy industries as a front for animal rights advocacy.  The organization is headed by physicians and the nutrition information is written by a physician and nutritionist.  Since my diagnosis I have changed my diet 180 degrees, using some of the recipes from this site.


2-23-12 entry
Curcumin
http://lpi.oregonstate.edu/infocenter/phytochemicals/curcumin/

3-26-12 entry
http://www.mskcc.org/cancer-care/integrative-medicine/about-herbs-botanicals-other-products
A really good website (MSKCC) to get information on supplements and alternative medicine


Edited by Lee21 - Mar 26 2012 at 8:18pm
12/9/11 @59,IDC,grade3, TNBC,3cm(MRI),SLNB0,stage IIA, BRCA1 variant
1/30/12 DD AC-T, 6/7/12 Lumpectomy, ypT1b(0.8 cm), 7/9/12 Rads x 30
11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Jan 19 2012 at 5:16pm
Addendum:
1) The full article on the role of starch in breast cancer recurrence (the abstract was presented in SABCS) is still not in press.
2) Soy, a good protein source, is still controversial especially for ER+ cancers. Eating soy as whole soy found in soybeans used to make tofu, soy milk, soy yogurt is considered much better than taking soy supplements. Talk to your doctor and nutritionist first though.
12/9/11 @59,IDC,grade3, TNBC,3cm(MRI),SLNB0,stage IIA, BRCA1 variant
1/30/12 DD AC-T, 6/7/12 Lumpectomy, ypT1b(0.8 cm), 7/9/12 Rads x 30
11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Jan 19 2012 at 5:26pm
Addendum 2
forgot to say that "The Oncologist" article on Vit D is open access if you register at the site (no cost involved).  Good summary and the most recent review on a somewhat confusing area.

Folks (gals and guys)  please feel free to add links here to website and articles you think will be of general interest.  I know that is a lot of good information embedded in this forum.  Just hard to find them sometimes... especially for a newbie.
12/9/11 @59,IDC,grade3, TNBC,3cm(MRI),SLNB0,stage IIA, BRCA1 variant
1/30/12 DD AC-T, 6/7/12 Lumpectomy, ypT1b(0.8 cm), 7/9/12 Rads x 30
11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Jan 20 2012 at 1:37pm

More articles on the role of radiation therapy in TNBC:

 

http://www.ncbi.nlm.nih.gov/pubmed/21475999

(this paper looked only at patients with mastectomy who had undergone post mastectomy RT.  Even in this group, TNBC patients had the highest loco-regional recurrence rate of 11.8% and suggested that TNBC patients may be radio-resistant).

Also posted under RT post.



Edited by Lee21 - Feb 17 2012 at 10:34am
12/9/11 @59,IDC,grade3, TNBC,3cm(MRI),SLNB0,stage IIA, BRCA1 variant
1/30/12 DD AC-T, 6/7/12 Lumpectomy, ypT1b(0.8 cm), 7/9/12 Rads x 30
11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote SagePatientAdvocates Quote  Post ReplyReply Direct Link To This Post Posted: Jan 20 2012 at 2:00pm
Dear Lee,

Thank you for posting this study.

I do not know if this study is en-pointe for our community..

The standard of care for TNBC at the moment is often lumpectomy not mastectomy except with BRCA+ women.

This study only looked at mastectomies if I read it correctly..

The only thing, for sure, in my opinion in all of this, is that treatment of TNBC can be very complex with uncertain results. At least that is my unprofessional take on things.

warmly,

Steve

Breast Cancer Res Treat. 2011 Aug;128(3):899-906. Epub 2011 Apr 8.

Risk of locoregional recurrence by receptor status in breast cancer patients receiving modern systemic therapy and post-mastectomy radiation.

Source

Department of Radiation Oncology, University of Miami School of Medicine, Miami, FL 33136, USA.

Abstract

We assessed differences in locoregional outcome based on receptor status combinations in a cohort of stage II-III breast cancer patients treated with modern trimodality therapy. Medical records of 582 consecutively treated patients receiving post-mastectomy radiation (PMRT) between 1/1999 and 12/2009 were reviewed. Rate of local regional recurrence (LRR) was estimated by the method of cumulative incidence allowing for competing risks. The effect of prognostic factors was examined by Gray's test and by Fine and Gray's modeling approach. Median follow-up was 44.7 months. Five-year progression-free survival (PFS) was 73.9% and overall survival (OS) was 84%. The cumulative 5-year incidence of LRR as first site of failure was 6.2% (95% CI 4.2-8.7). Five-year cumulative incidence of LRR was 8.6 versus 4.4% for estrogen receptor (ER) negative versus ER positive (P = 0.017), 8.5 versus 3.4% for progesterone receptor (PR) negative versus PR positive (P = 0.011), and 1.7 versus 7.5% for HER2 positive (86% received trastuzamab) versus HER2 negative (P = 0.032). Five-year cumulative incidence of LRR was 11.8% for the triple negative subtype and 3.9% for other receptor combinations (P < 0.001). Among patients whose disease is ER positive, 5-year LRR rate was 7.8 versus 3.4% for PR negative versus PR positive (P = 0.130). The prognostic value of the triple negative and HER2 negative subtypes was maintained on multivariate analysis. In the era of HER-2 targeted therapy, tumors that are HER-2 over expressing and are treated with trastuzumab have a very low rate of LRR. ER negative, PR negative, and triple negative status are associated with increased risk of LRR.

I am a BRCA1+ grandson, son and father of women affected by breast/oc-my daughter inherited mutation from me, and at 36, was dx 2004 TNBC I am a volunteer patient advocate with SAGE Patient Advocates
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Jan 20 2012 at 2:39pm
Steve,
Thanks for bringing it up.  As you well know, there are many problems with studies on TNBC (1) very few prospective studies; (2) most retrospective with incomplete information on receptor status; (3) limited stratification in multivariate analysis. 

The quoted study is not an exception and does not specifically look at TNBC; it is not a prospective study comparing lumpectormy+RT vs mastectomy vs mastectomy+RT, which is the study we want. The closest we have to that is the Canadian study cited earlier (but still retrospective).  Panoff looks at all comers who had mastectomy with RT. The presenting stage has the following distribution: IIA (7.2%), IIB (23.1%), IIIA (39.1%), IIIB (21%), IIIC(9.4%).  I cannot find data on the % of patients with node positive disease but expect all III to have positive nodes. In this study, the TNBCs had the highest loco-regional recurrence rate. In multivariate analysis (n=580), TNBC vs all others for LRR, the HR (hazard ratio) is 3.58.

Consistent with the difference in clinical opinions offered by our care providers, the medical literature is variable as well and presently (as far as I can tell) there is no consensus.  I think there are women electing to have mastectomy not entirely based on staging recommendations.

With no validated targeted therapy available for TNBCs, we need to consider very carefully the available treatment options including RT.
12/9/11 @59,IDC,grade3, TNBC,3cm(MRI),SLNB0,stage IIA, BRCA1 variant
1/30/12 DD AC-T, 6/7/12 Lumpectomy, ypT1b(0.8 cm), 7/9/12 Rads x 30
11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Jan 20 2012 at 3:07pm
One difference to point out between the Canadian study (Abdulkarim et al.) and Panoff's study is the stage of the patients included in the analysis.  The Canadian study looked at patients with T1-2N0 disease compared to the more advanced group in the Panoff study.

A critique of the Canadian study has been posted :
http://jco.ascopubs.org/content/29/35/4722.long

12/9/11 @59,IDC,grade3, TNBC,3cm(MRI),SLNB0,stage IIA, BRCA1 variant
1/30/12 DD AC-T, 6/7/12 Lumpectomy, ypT1b(0.8 cm), 7/9/12 Rads x 30
11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Jan 21 2012 at 10:25am
Reputable sites to get information for breast cancer:

http://www.cancer.gov/cancertopics/types/breast

(NCI)

 

http://www.cancer.org/Cancer/BreastCancer/index?ssSourceSiteId=null

(American Cancer Society)

 

http://www.cancer.net/patient/Cancer+Types

(American Society of Clinical Oncology)

 

http://ww5.komen.org/IWasDiagnosed/IveBeenDiagnosedwithBreastCancer.html?itc=emoentpnt:5

(Susan G Komen for the cure)




Edited by Lee21 - Feb 17 2012 at 10:35am
12/9/11 @59,IDC,grade3, TNBC,3cm(MRI),SLNB0,stage IIA, BRCA1 variant
1/30/12 DD AC-T, 6/7/12 Lumpectomy, ypT1b(0.8 cm), 7/9/12 Rads x 30
11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Jan 21 2012 at 12:08pm
12/9/11 @59,IDC,grade3, TNBC,3cm(MRI),SLNB0,stage IIA, BRCA1 variant
1/30/12 DD AC-T, 6/7/12 Lumpectomy, ypT1b(0.8 cm), 7/9/12 Rads x 30
11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote SagePatientAdvocates Quote  Post ReplyReply Direct Link To This Post Posted: Jan 21 2012 at 12:15pm
Dear Lee,

thanks for all the links!!!! we all really appreciate your efforts.

I just emailed you the following study which is also not en-pointe because it is not specific to TNBC but it seems to argue for radiation therapy in the patients studied..

warmly,

Steve

Int J Radiat Oncol Biol Phys. 2011 Nov 1;81(3):782-7. Epub 2011 Aug 30.

Local-regional recurrence with and without radiation therapy after neoadjuvant chemotherapy and mastectomy for clinically staged T3N0 breast cancer.

Source

Department of Radiation Oncology, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

Abstract

PURPOSE:

The purpose of this study was to determine local-regional recurrence (LRR) risk according to whether postmastectomy radiation therapy (PMRT) was used to treat breast cancer patients with clinical T3N0 disease who received neoadjuvant chemotherapy (NAC) and mastectomy.

METHODS AND MATERIALS:

Clinicopathology data from 162 patients with clinical T3N0 breast cancer who received NAC and underwent mastectomy were retrospectively reviewed. A total of 119 patients received PMRT, and 43 patients did not. The median number of axillary lymph nodes (LNs) dissected was 15. Actuarial rates were calculated using the Kaplan-Meier method and compared using the log-rank test.

RESULTS:

At a median follow-up of 75 months, 15 of 162 patients developed LRR. For all patients, the 5-year LRR rate was 9% (95% confidence interval [CI], 4%-14%). The 5-year LRR rate for those who received PMRT was 4% (95% CI, 1%-9%) vs. 24% (95% CI, 10%-39%) for those who did not receive PMRT (p <0.001). A significantly higher proportion of irradiated patients had pathology involved LNs and were ≤40 years old. Among patients who had pathology involved LNs, the LRR rate was lower in those who received PMRT (p <0.001). A similar trend was observed for those who did not have pathology involved LN disease. Among nonirradiated patients, the appearance of pathologic LN disease after NAC was the only clinicopathologic factor examined that significantly correlated with the risk of LRR.

CONCLUSIONS:

Breast cancer patients with clinical T3N0 disease treated with NAC and mastectomy but without PMRT had a significant risk of LRR, even when there was no pathologic evidence of LN involvement present after NAC. PMRT was effective in reducing the LRR rate. We suggest PMRT should be considered for patients with clinical T3N0 disease.

Copyright © 2011. Published by Elsevier Inc.

I am a BRCA1+ grandson, son and father of women affected by breast/oc-my daughter inherited mutation from me, and at 36, was dx 2004 TNBC I am a volunteer patient advocate with SAGE Patient Advocates
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Jan 22 2012 at 3:31pm

Tumor size by radiographic measurements:

http://www.ncbi.nlm.nih.gov/pubmed/19886147

correlation with surgical specimen (gold standard)

mammography          r=0.26

ultrasound                 r=0.57

MRI                             r=0.8

(r, correlation coefficient: r=0, no correlation, r=1, 100% concordance)

http://www.ncbi.nlm.nih.gov/pubmed/19800455

MRI correlates with surgical specimen within 0.5 cm (overestimation in 33% and underestimation in 15%).  In cases where there was an overestimate, 65% of these cases had additional pathological findings in the surrounding tissue.

http://www.ncbi.nlm.nih.gov/pubmed/15325659

an earlier study (2004)

mammography          r=0.66

ultrasound                 r=0.48

core biopsy                r=0.28

Note:  MRI is 3D, while US and Mammography are essentially 2D.  Mammography is also a problem with high breast tissue density.

Trying to determine growth of tumor using different radiographic means is probably not reliable.  For example, my tumor was 1.7cm by US on 12/8/11 and 3cm by MRI on 12/30/11. The difference is unlikely to be due to accelerated tumor growth, and more likely due to the US operator skill level (in getting the plane of the longest diameter of the tumor). 

In this paper:

http://www.ncbi.nlm.nih.gov/pubmed/20105090

US   r=0.85

mammography r=0.71

The numbers are better but if you get the paper and look at the figures, there is  significant underestimation by US AND mammography for tumors that are greater than 2 cm.  Just so happens the patients included in this study have smaller tumors <2 cm. Mammography appears to overestimate smaller (<1 cm) tumors also.

New entry 2-4-12

http://www.ncbi.nlm.nih.gov/pubmed/21947592

1. Ann Surg Oncol. 2011 Oct;18(11):3149-54. Epub 2011 Sep 27.

MRI staging after neoadjuvant chemotherapy for breast cancer: does tumor biology
affect accuracy?

McGuire KP, Toro-Burguete J, Dang H, Young J, Soran A, Zuley M, Bhargava R,
Bonaventura M, Johnson R, Ahrendt G.

Department of Surgery, Magee-Womens Hospital, University of Pittsburgh, 300
Halket St., Pittsburgh, PA, USA. mcguirek2@mail.magee.edu

BACKGROUND: A discrepancy often exists between the post-neoadjuvant chemotherapy
(NAC) breast tumor size on magnetic resonance imaging (MRI) and pathologic tumor
size. We seek to quantify this MRI/pathology discrepancy and determine if the
accuracy of MRI post NAC varies with tumor subtype.
METHODS: The University of Pittsburgh Medical Center (UPMC) Cancer Registry and
radiology database were searched for patients with breast cancer who underwent
NAC and MRI staging between 2004 and 2009. We compared radiologic to pathologic
staging and stratified differences based on tumor biology using univariate,
multivariate, and receiver operating characteristic (ROC) analysis.
RESULTS: Two hundred three of 592 patients undergoing surgery after NAC for
breast cancer had MRI staging pre and post chemotherapy. All patients had intact
tumors prior to the initiation of chemotherapy. Average tumor size by MRI was 4.0
cm pre chemotherapy and 1.2 cm post chemotherapy. The average pathologic tumor
size was 1.7 cm (range 0-13 cm). The difference between MRI and pathologic tumor
size was greatest in luminal (1.1 cm) and least in triple-negative (TN) and human
epidermal growth factor receptor 2 (HER2)-positive tumors (<0.1 cm) (p = 0.015)
.
MRI was a good discriminator for pathologic complete response (pCR) [area under
the curve (AUC) 0.777]. Its predictive value for pCR was much greater in TN and
estrogen receptor(ER)-/HER2+ than in luminal tumors (73.6 vs. 27.3%).

CONCLUSIONS: MRI is an effective tool for predicting response to NAC. The
accuracy of MRI in estimating postchemotherapy tumor size varies with tumor
subtype. It is highest in ER-/HER2+ and TN and lowest in luminal tumors.
Knowledge of how tumor subtype affects MRI accuracy can guide recommendations for
surgery following NAC.





Edited by Lee21 - Mar 30 2012 at 12:35pm
12/9/11 @59,IDC,grade3, TNBC,3cm(MRI),SLNB0,stage IIA, BRCA1 variant
1/30/12 DD AC-T, 6/7/12 Lumpectomy, ypT1b(0.8 cm), 7/9/12 Rads x 30
11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Jan 23 2012 at 2:59pm
Staging and prognosis in TNBC:

Nodal status and clinical outcomes in a large cohort of patients with triple-negative breast cancer.

http://www.ncbi.nlm.nih.gov/pubmed/21606433

Clinical relevance of TNM staging system according to breast cancer subtypes

http://www.ncbi.nlm.nih.gov/pubmed/21242587

Triple-negative breast cancers: unique clinical presentations and outcomes

http://www.ncbi.nlm.nih.gov/pubmed/20853062

Tumor size and survival in breast cancer--a reappraisal

http://www.ncbi.nlm.nih.gov/pubmed?term=foulkes%20narod%20reappraisal

Time to disease recurrence in basal-type breast cancers: effects of tumor size and lymph node status

http://www.ncbi.nlm.nih.gov/pubmed/19691094

Tumor size is an unreliable predictor of prognosis in basal-like breast cancers and does not correlate closely with lymph node status

http://www.ncbi.nlm.nih.gov/pubmed?term=foulkes%20ellis%20unreliable

Basal breast cancer molecular subtype predicts for lower incidence of axillary lymph node metastases in primary breast cancer

http://www.ncbi.nlm.nih.gov/pubmed?term=crabb%20chia%20basal

Seems to me that the literature is still confusing with respect to the importance of tumor size and lymph node involvement.  Again all studies are retrospective in nature with minimal multivariate analysis.  Given that TNBC is a heterogeneous disease, it is a possibility that the distribution of TNBC patients varies between the different studies. 

All the more reason that TNBC tumors should be further distinguished based on molecular signatures.  Unless you are in a clinical trial, chances are not much is being done to understand your tumor on a molecular basis. 

If you are cured, great, but we don't know why.  If you have a recurrence, too bad, but we don't know why either.  We just don't have 10-20 years to wait around until definitive results are obtained from Phase III trials stratified according to molecular subtypes. 

2-11-12 entry

Nottingham Prognostic Index in triple-negative breast cancer: a reliable prognostic tool?

http://www.biomedcentral.com/1471-2407/11/299

In contrast to other studies, this paper says TNBC disseminate to the axillary lymph nodes as frequently as other subtypes.

3-5-12 entry

Favorable Prognosis in Patients With T1a/T1bN0 Triple-Negative Breast Cancers Treated With Multimodality Therapy

http://onlinelibrary.wiley.com/doi/10.1002/cncr.27480/abstract

194 patients in retrospective study.  If you are in the lucky minority of having tumors <=1 cm, node negative, and no lymphovascular invasion this study says you'll do great.



Edited by Lee21 - Mar 30 2012 at 12:36pm
12/9/11 @59,IDC,grade3, TNBC,3cm(MRI),SLNB0,stage IIA, BRCA1 variant
1/30/12 DD AC-T, 6/7/12 Lumpectomy, ypT1b(0.8 cm), 7/9/12 Rads x 30
11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote SagePatientAdvocates Quote  Post ReplyReply Direct Link To This Post Posted: Jan 23 2012 at 3:11pm
Dear Lee,

again, thank you for all the links..

The first paper you mentioned above came to the conclusion that breast MRIs are more accurate in finding cancer masses than mammography or ultrasounds. 

So in this age of deteriorating health care how do many women get a Breast MR when many insurance companies give the patients a hard time getting the exam covered?

I agree with the conclusion at the bottom of your post and wondered, in the present economic environment, whether you had any suggestions to accelerate the research efforts we, as a community, so desperately need?

warmly with my thanks, again,

Steve
I am a BRCA1+ grandson, son and father of women affected by breast/oc-my daughter inherited mutation from me, and at 36, was dx 2004 TNBC I am a volunteer patient advocate with SAGE Patient Advocates
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Jan 23 2012 at 3:50pm
Very good points Steve.  I am very frustrated with what's happening in the medical field: on the one hand we have made enormous progress in understanding tumor biology at the molecular level; on the other hand, that progress has not crossed over to the clinical arena, and certainly not over to the standard of care.  The problems are fundamental as you have pointed out: escalating medical costs to the paitent that are not entirely covered by health insurance, even for the best of insurance plans (as I am finding out).  The stressed out economy doesn't help -- at all levels, including funding for basic and translational research.  The only thing I think we as citizens, cancer survivors and cancer co-survivors can do is to keep constant pressure on our representatives in state and congress (write to them and talk to your doctors -- give them an earful).  I can tell you that there is a strong sentiment that the money that has been invested in basic sciences has not paid off and that the money has been and will continue to be diverted into fields such as electronic medical records, where the goal is, as always, to find cost containment measures, not necessarily to the benefit of the patient, but might help to contain medical costs.  I personally think this is incredibly short sighted as many of the blockbuster targeted drugs have come from an understanding of the basic biology of tumor cells : Herceptin, Imatinib, Parp inhibitors .....

The ISPY-2 trial has a different design than the usual Phase1-2-3 design and may eventually be the model to test future drugs.  It is analogous to the BATTLE trial for lung cancer at MDA
http://pharmastrategyblog.com/2011/04/update-on-the-battle-trial-in-lung-cancer.html/
except that in that trial, treatment is modulated depending on outcome whereas the ISPY2 is not, for what reason I do not know.



Edited by Lee21 - Jan 23 2012 at 3:54pm
12/9/11 @59,IDC,grade3, TNBC,3cm(MRI),SLNB0,stage IIA, BRCA1 variant
1/30/12 DD AC-T, 6/7/12 Lumpectomy, ypT1b(0.8 cm), 7/9/12 Rads x 30
11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Jan 23 2012 at 11:36pm
Order of chemo:

http://www.ncbi.nlm.nih.gov/pubmed?term=antolin%20garcia-mata

Not the study referenced elsewhere.  This is a small study from Spain evaluating DD T followed by DD AC for locally advanced BC in the neoadjuvant setting.  Not TNBC and not comparing it to any other regimen.  Endpoint was toxicity.


Weekly taxol:
See the Hudis paper from the Oncologist that I posted already.
On page 5 is a graph comparing AC->T and AT-> weekly T showing a significant improvement with the latter. This is in the adjuvant setting.


Edited by Lee21 - Feb 06 2012 at 12:21pm
12/9/11 @59,IDC,grade3, TNBC,3cm(MRI),SLNB0,stage IIA, BRCA1 variant
1/30/12 DD AC-T, 6/7/12 Lumpectomy, ypT1b(0.8 cm), 7/9/12 Rads x 30
11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Jan 24 2012 at 9:42pm
Another review (pretty comprehensive as of 2010) on treatment options in TNBC:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2882502/?tool=pubmed

This is open access.


Edited by Lee21 - Feb 06 2012 at 12:21pm
12/9/11 @59,IDC,grade3, TNBC,3cm(MRI),SLNB0,stage IIA, BRCA1 variant
1/30/12 DD AC-T, 6/7/12 Lumpectomy, ypT1b(0.8 cm), 7/9/12 Rads x 30
11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Jan 25 2012 at 11:09am
Androgen receptors in TNBC:

1) Hudis review posted already has some discussion about AR

2) http://www.ncbi.nlm.nih.gov/pubmed/20164692

Triple-negative breast cancer: role of the androgen receptor by Gucalp and Traina

3-30-12 entry

Some Triple-Negative Breast Cancers Express Androgen Receptor

By: NEIL OSTERWEIL,  Oncology Report Digital Network

03/29/12 

ORLANDO  – Triple-negative breast tumors are notorious for their ability to evade hormonal agents and targeted therapies. But a subset of these intractable tumors expresses androgen receptors, and may be vulnerable to antiandrogen drugs, investigators suggested at the symposium of the Society of Surgical Oncology.

An evaluation of cancerous and normal breast tissues from 94 patients with triple-negative breast tumors (lacking estrogen-, progesterone-, and HER2-receptor expression), showed that the androgen receptor (AR) was expressed in 23% of tumors, reported Dr. Barbara Pockaj of the Mayo Clinic in Scottsdale, Ariz., and colleagues.

AR–positive cancers occurred more frequently in older patients and were significantly associated with lymph node metastases, compared with AR-negative, triple-negative breast cancers in this small study, she said.

There was a trend toward higher tumor stage at diagnosis among patients with AR-positive tumors, but AR-positive and AR-negative patients did not differ significantly in overall or recurrence-free survival, said Dr. Pockaj.

Previous studies have suggested that 10%-43% of triple-negative breast cancers bear the androgen receptor, but the antibodies and methods used for characterizing the presence of the receptor varied significantly, making it difficult to nail down actual numbers, Dr. Pockaj said.

The investigators examined 177 tissue biopsy cores from 94 patients with triple-negative breast cancer to see whether AR-receptor expression correlated with patient and tumor factors and survival, and where expression of the receptors in different tissues from the same patients correlated with tumor progression.

The receptor was expressed in 88% of normal breast tissues in the samples, a proportion identical to that of the estrogen receptor in normal tissues from the same patients.

AR expression was detected in all 6 of 6 adjacent DCIS (ductal carcinoma in situ) samples from AR-positive patients, and in 9 of 15 DCIS samples from patients with AR-negative cancer.

All lymph node metastases from AR-positive patients were also positive, whereas no lymph node metastases from AR-negative patients were found to express the androgen receptor.

There were no significant differences between AR-positive and -negative patients in tumor grade, angiolymphatic invasion, TNM (tumor, node, metastasis) stage, or tumor size. In contrast, 16 of the 72 (22%) of the AR-negative patients had lymph node metastases, compared with 10 of 22 (46%) AR-positive patients (P = .033).

There were no significant differences in locoregional recurrences, overall survival, or disease-specific survival between positive and negative patients.

Among all 94 patients, however, the presence of lymph node metastases was associated with a significantly worse recurrence-free survival (hazard ratio, 5.502; P = .017). Chemotherapy significantly reduced that risk (HR, 0.099; P = .0004).

In multivariate analysis, the investigators found that AR expression was associated with older age (63 years vs. 57 years; P = .051) and with the presence of lymph nodes metastases (P = .033).

Although larger studies are needed, the data suggest that AR-positive, triple-negative breast cancer "has unique clinical behavior and may need different treatment," Dr. Pockaj said.

A phase II, open-label trial of the antiandrogen bicalutamide (Casodex) in patients with AR-positive, estrogen- and progesterone-receptor–negative, metastatic breast cancer is currently underway in eight U.S. cancer centers.

The current study was supported by the Translational Genomics Research Institute, Phoenix, and the Mayo Clinic, Scottsdale, Ariz. Dr. Pockaj is an employee of the Mayo Clinic.


Copyright © 2012 International Medical News Group, LLC. All rights reserved.
This page was printed from www.imngoncology.com . For reprint inquires, call 877-652-5295, ext. 102.


Edited by Lee21 - Mar 30 2012 at 12:39pm
12/9/11 @59,IDC,grade3, TNBC,3cm(MRI),SLNB0,stage IIA, BRCA1 variant
1/30/12 DD AC-T, 6/7/12 Lumpectomy, ypT1b(0.8 cm), 7/9/12 Rads x 30
11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Jan 25 2012 at 5:54pm
Molecular subtypes of triple negative BC:

Molecular stratification of triple-negative breast cancers (open access)
http://theoncologist.alphamedpress.org/content/16/suppl_1/61.long

and associated podcast
http://theoncologistcommunity.com/breastcancer_podcasts/player.php?assets=perou/application/assets/

Gene expression profiling in breast cancer: classification, prognostication, and prediction (not open access)
http://www.ncbi.nlm.nih.gov/pubmed/22098854





Edited by Lee21 - Feb 06 2012 at 12:21pm
12/9/11 @59,IDC,grade3, TNBC,3cm(MRI),SLNB0,stage IIA, BRCA1 variant
1/30/12 DD AC-T, 6/7/12 Lumpectomy, ypT1b(0.8 cm), 7/9/12 Rads x 30
11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Jan 25 2012 at 7:57pm

Definition of luminal B:

http://www.ncbi.nlm.nih.gov/pubmed/21865043

luminal B: ER+ and/or PR+, HER2-, Ki67 >=14% or ER+ and/or PR+, HER2+

http://www.ncbi.nlm.nih.gov/pubmed/22098854

luminal B: ER+ 90-100%, PR+ 41-53%, HER2+, 15-24%, Ki67 high, basal markers -

basal like: ER+, 0-19%, PR+, 6-13%, HER2+, 9-13%, Ki67 high, basal markers+

This paper argues for different treatment strategies in the adjuvant setting for different subtypes:

http://www.ncbi.nlm.nih.gov/pubmed/22015282

There is a difference in local recurrence between luminal type B vs TNBC

http://www.ncbi.nlm.nih.gov/pubmed/21900114




Edited by Lee21 - Feb 06 2012 at 12:22pm
12/9/11 @59,IDC,grade3, TNBC,3cm(MRI),SLNB0,stage IIA, BRCA1 variant
1/30/12 DD AC-T, 6/7/12 Lumpectomy, ypT1b(0.8 cm), 7/9/12 Rads x 30
11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Jan 26 2012 at 7:16pm

Timeline for Subtyping in TNBC:

Many of the cited articles are open access so you can download from the link.

Highlights

·         6 intrinsic subtypes of BC:

o   luminal A, luminal B, Her2-enriched, basal-like, normal-like, claudin-low

·       TNBC defined by IHC: the absence/low expression of ER, PR, HER2

·       Basal-like defined by gene microarray profiling (Perou, 2000, Sorliet 2001)

·       “core basal phenotype” use of IHC markers suggested:

o   http://www.ncbi.nlm.nih.gov/pubmed/15328174

o   http://www.ncbi.nlm.nih.gov/pubmed/17650314

o   http://www.ncbi.nlm.nih.gov/pubmed/18316557

o   ER-, HER2-, CK5/6+ and/or EGFR+

·       70-80% of TNBCs are also basal-like and the majority of basal (but not all) are also TNBCs.

·       >75% patients with BRCA1 mutations have TNBC subtype

·       From Foulkes New Engl J Med 2010, volume 363, pg 1938:

o   TNBC, often EGFR+, often cytokeratin 5 or 17+, often cyclin E+, TP53 mutation sometimes present, often truncating

o   Basal-like, usually EGFR+, almost always CK5/17+, usually cyclin E+, TP53 mutation usually present, often truncating

o   BRCA1-related, usually EGFR+, usually CK5/17+, usually cyclin E+, TP53 mutation, nearly always present, nearly always truncating

 

Timeline of molecular subtyping :

 

Perou’s original 2000 paper (predates TNBC entity)

http://www.nature.com/nature/journal/v406/n6797/full/406747a0.html

·            Microarray study based on 42 patients of which 36 had IDC

·     I     Identified groups ER+/luminal-like, basal-like, ErbB2 (Her2)+, normal breast

        Basal group also further characterized by IHC: cytokeratins 5/6 or 17 or both

 

Expansion of original 4 subsets to 6 (luminal A, B, C, Basal, Her2-enriched, normal), 2001

http://www.ncbi.nlm.nih.gov/pubmed/11553815

It also should be noted that the ER+ protein category cases based on ligand binding were highly heterogeneous with respect to their gene expression profiles (18/19 were in luminal A, 5/5 in luminal B, 9/10 in luminal C, 2/7 in basal-like, 4/5 in ERBB2+, and 3/5 in normal breast-like tumors). The luminal subtype B + C tumors might represent a clinically distinct group with a different and worse disease course, in particular with respect to relapse (Fig. 3 A and B). Luminal subtype C was associated with the worst outcome of the three presumed subtypes when a six-subtype classification formed the basis for the survival analysis (Fig. 3C). The potential clinical significance of this molecular subtype is highlighted by the similarities in expression of some of the genes that are characteristic of the ER-negative tumors in the basal-like and ERBB2+ subtypes (Fig. 1D), which suggests that the high level of expression of this set of genes is associated with poor disease outcomes.”

 

Comparison includes BRCA1 mutation carriers, 2003

http://www.ncbi.nlm.nih.gov/pubmed/12829800

Concludes that BRCA1 mutations are strongly associated with a basal tumor phenotype

 

Perou (2004) found that a panel of 4 antibodies to ER, HER1 (EGFR), HER2 and CK5/6 can accurately identify basal like tumors

http://www.ncbi.nlm.nih.gov/pubmed/15328174

 

First use of Her2-enriched instead of Her2+ in gene expression subtypes

http://clincancerres.aacrjournals.org/content/14/24/8010.short

Not much discussion here about Her2-enriched – I think to include tumors that behave like Her2+ tumors that might not overexpress Her2 but may overexpress Her2 regulated genes. A small % of the TNBCs belong to the Her2-enriched subtype without overexpression of Her2.

 

Description of the claudin-low subtype, 2009

http://www.ncbi.nlm.nih.gov/pubmed/19435916

http://www.ncbi.nlm.nih.gov/pubmed/20813035

 

The metaplastic tumors gene signature most closely resembles the claudin-low tumors. Metaplastic BCs are aggressive and chemo-resistant.  More stem-cell like defined by CD44+/CD24-, enriched in genes involved in epithelial-to-mesenchymal transformation (breast cells are epithelial normally and they are transformed to a more motile, more metastatic form).

 

These tumors express low levels of hormone receptors and Her2, express some basal epithelial markers but microarray analysis shows them to be distinct from the basal like tumors.

 

Other issues of interest

 

Distinguishing between luminal A and B based on Ki67, 2009

http://jnci.oxfordjournals.org/content/101/10/736.long

The distinction between A and B has a false positive and false negative rate of 25%

 

A recent assessment of agreement in molecular subtyping between different studies:

http://www.ncbi.nlm.nih.gov/pubmed/21421860

“None of the classification systems tested produced almost perfect agreement (Kappa ≥ 0.81) among observers. However, substantial interobserver agreement (70.8% to 76.1% of the samples and free-marginal Kappa scores from 0.635 to 0.701) was consistently observed in all datasets for four molecular subtypes (luminal, basal-like, HER2, and normal breast-like). When luminal cancers were subdivided (luminal A, B, and C), none of the classification systems produced substantial agreement (Kappa ≥ 0.61) in all the datasets analyzed. Analysis of each subtype separately revealed that only two (basal-like and HER2) could be reproducibly identified by independent observers (Kappa ≥ 0.81).”

 

Supervised risk predictor of breast cancer based on intrinsic subtypes, 2009

http://www.ncbi.nlm.nih.gov/pubmed/19204204

 

Practical implications of gene-expression-based assays for breast oncologists

http://www.ncbi.nlm.nih.gov/pubmed/22143140

2-14-12 entry

Transcriptomic landscape of breast cancers through mRNA sequencing

http://www.nature.com/srep/2012/120214/srep00264/full/srep00264.html

Breast cancer is a heterogeneous disease with a poorly defined genetic landscape, which poses a major challenge in diagnosis and treatment. By massively parallel mRNA sequencing, we obtained 1.2 billion reads from 17 individual human tissues belonging to TNBC, Non-TNBC, and HER2-positive breast cancers and defined their comprehensive digital transcriptome for the first time. Surprisingly, we identified a high number of novel and unannotated transcripts, revealing the global breast cancer transcriptomic adaptations. Comparative transcriptomic analyses elucidated differentially expressed transcripts between the three breast cancer groups, identifying several new modulators of breast cancer. Our study also identified common transcriptional regulatory elements, such as highly abundant primary transcripts, including osteonectin, RACK1, calnexin, calreticulin, FTL, and B2M, and “genomic hotspots” enriched in primary transcripts between the three groups. Thus, our study opens previously unexplored niches that could enable a better understanding of the disease and the development of potential intervention strategies.

OPEN ACCESS

2-15-12 entry

Stratifying triple-negative breast cancer: which definition(s) to use?

Adamo and Anders

http://breast-cancer-research.com/content/13/2/105

2-16-12 entry

Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies (OPEN ACCESS)

http://www.jci.org/articles/view/45014

Used gene expression microarray data to classify TNBC into 6 subtypes, which only overlap to a limited extent with the intrinsic subtypes identified by Perou. The 6 subtypes identified in this study are:

Basal (BL1, BL2), immunomodulatory (IM) (which could correspond to the medullary type), mesenchymal (M), mesenchymal stem-like (MSL)(most likely the metaplastic, claudin-low), luminal androgen receptor (LAR).

Only 49% of the TNBC belong to the intrinsic basal subtype whereas 88% of the TNBC have the core basal phenotype (EGFR, cytokeratin 5/6).

Found that the LAR subtype had decreased relapse free survival compared to the other subtypes whereas the M subtype had a higher risk for distant mets.



Edited by Lee21 - Feb 16 2012 at 8:21pm
12/9/11 @59,IDC,grade3, TNBC,3cm(MRI),SLNB0,stage IIA, BRCA1 variant
1/30/12 DD AC-T, 6/7/12 Lumpectomy, ypT1b(0.8 cm), 7/9/12 Rads x 30
11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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