updated entry in chemo in TNBC http://forum.tnbcfoundation.org/topic9440_post97306.html#97306 Identified a gene whose expression status is correlated with whether you get a pCR following neoadjuvant therapy with P-FEC in ER- patients; correlation with molecular subtypes. Need more identification of genes like this to make personalized medicine more of a reality.
Bringing
it up because I remembered someone on the forum mentioned that she was off
chemo yet developed symptoms of pulmonary embolism.Think everyone here should be aware of the
potential risks, while on chemo and the fact that we have cancer.
Several forum questions concerned Taxanes.I did a literature search focusing on what the recommendations are for type of taxane and dosing schedule.
My conclusions so far for high risk BC:
Weekly paclitaxel is superior
(disease free survival) to q3 weekly paclitaxel x4 in the context of AC q3
weeks x 4 but with higher toxicity (peripheral neuropathy)
Weekly paclitaxel and
docetaxel q3 weeks represent reasonable choices; docetaxel q3 weeks has higher
toxicity (myelosuppression, febrile neutropenia, infection)
Docetaxel is too toxic in the
dd setting
SWOG 0221 trial results
pending comparing (1) DD ACx6 -> DD Taxol x6 (2) A (day1), oral C (days1-7)
repeats q7 days x 15 course -> DD Taxol x 6 (3) DD ACx6 -> weekly Taxol
x12
B-38 trial trial
results pending, for node+ disease, compares ACT (every 3 weeks)
x 6 to DD AC -> T to DD AC -> T+gemcitabine
Abraxane
(nab-paclitaxel) is Cremophor-free, nanoparticle albumin bound paclitaxel.Does NOT require steroid
premed. Despite lower toxicity, better delivery, it is significantly more
expensive.
Comparing weekly vs
q3 weekly docetaxel in metastatic BC, at least 2 studies conclude that q3
weekly is better tolerated. In the neoadjuvant setting, one small study says weekly docetaxel is better tolerated than q3 weekly docetaxel but no differences in clinical response, pCR or overall survival (71.5 mo followup)
One study from Greece concluded paclitaxel did not have added benefit in TNBC (a different regimen than the typical ones used in the USA).
I haven't looked for long term taxane maintenace.
European studies have their own unique regimen and not entirely comparable to other trials.
I haven't come across the study that examined efficacy of dd paclitaxel vs standard vs weekly regimens, except for results pending from the SWOG trial.
Reviews
Docetaxel
and Paclitaxel in the Treatment of Breast Cancer: A Review of Clinical Experience
(2004 review)
Conclusion: At the current time, the
pharmacokinetic profile, consistent positive clinical results, and convenience
of an intermittent, short-infusion schedule have made docetaxel the preferred
taxane for many clinicians treating patients with breast cancer.
Choosing
a taxane for adjuvant treatment of breast cancer: more than a flip of the coin?
(2008)
No difference between docetaxel or
paclitaxel but weekly is superior to q3 weeks.
Taxane
vs. taxane: is the duel at an end? A commentary on a phase-III trial of
doxorubicin and docetaxel versus doxorubicin and paclitaxel in metastatic
breast cancer: results of the ERASME 3 study (2008)
Conclusions: ABI-007 (Abraxane)
demonstrated greater efficacy and a favorable safety profile compared with
standard paclitaxel in this patient population.
The improved therapeutic index and elimination of corticosteroid premedication
required for solvent-based taxanes make the novel albumin-bound paclitaxel ABI-007 an important advance in the treatment
of MBC
A phase
II feasibility trial of dose-dense docetaxel followed by doxorubicin/cyclophosphamide
as adjuvant or neoadjuvant treatment for women with node-positive or high-risk
node-negative breast cancer (2008)
Conclusion: Full-dose docetaxel is difficult to administer as part of this
dose-dense treatment regimen. Docetaxel 75 mg/m2 can be administered with improved
subsequent delivery of 4 courses of dose-dense AC. Until comparative clinical studies are available, docetaxel
should not be substituted for paclitaxel in
dose-dense adjuvant chemotherapy for patients with high-risk breast cancer.
Weekly
paclitaxel in the adjuvant treatment of breast cancer (2008)
Conclusions: Weekly paclitaxel (compared to q3 weeks) after standard
adjuvant chemotherapy with doxorubicin and cyclophosphamide improves
disease-free and overall survival in women with breast
cancer. (ClinicalTrials.gov number, NCT00004125 [ClinicalTrials.gov].
Intensive
dose-dense compared with conventionally scheduled preoperative chemotherapy for
high-risk primary breast cancer (2009)
Comparing (1) E q2 weeks x 3 -> Paclitaxel
q2 weeks x 3 (2) E+Paclitaxel q3 weeks x 4.After surgery, all patients received CMF.CONCLUSION: Our results support the efficacy
and short-term safety of IDD as preoperative chemotherapy. IDD was less well
tolerated compared to standard treatment, but improved clinical outcomes in
patients with noninflammatory high-risk primary BC.
Intense
dose-dense sequential chemotherapy with epirubicin, paclitaxel, and
cyclophosphamide compared with conventionally scheduled chemotherapy in
high-risk primary breast cancer: mature results of an AGO phase III study
(2010)
Their dose dense regimen: E (dd) q2 weeks x 3
-> Paclitaxel (dd) q2 weeks x 3 -> C (dd) q2 weeks x 3 compared to
standard q3 week dosing x 4 cycles.Has
been criticized that the standard regimen was a suboptimal comparison.
Cyclophosphamide,
epirubicin, and Fluorouracil versus dose-dense epirubicin and cyclophosphamide
followed by Paclitaxel versus Doxorubicin and cyclophosphamide followed by
Paclitaxel in node-positive or high-risk node-negative breast cancer (2010)
Comparing (1) C (days 1-14), E (days 1, 8), F
(days 1, 8) x6 (28 cycles)(2) EC q2
weeks x 6 -> Paclitaxel q3 weeks x 4(3) AC q3 weeks x 3 -> Paclitaxel q3 weeks x4
Conclusion: (3) is significantly inferior to
(1) and (2)
Dose-dense
doxorubicin and cyclophosphamide followed by dose-dense albumin-bound
paclitaxel plus bevacizumab is safe as adjuvant therapy in patients with early
stage breast cancer (2011)
Able to deliver a higher paclitaxel dose in the
Abraxane formulation with no dose interruptions compared to
cremophor-formulated paclitaxel
Effects
on quality of life, anti-cancer responses, breast conserving surgery and survival
with neoadjuvant docetaxel: a randomised study of sequential weekly versus
three-weekly docetaxel following neoadjuvant doxorubicin and cyclophosphamide
in women with primary breast cancer (2011)
CONCLUSIONS: Weekly docetaxel is well-tolerated
and has less distressing side-effects, without compromising therapeutic
responses, Breast Conserving Surgery (BCS) or survival outcomes in the
neoadjuvant setting.
Triple-negative
phenotype is of adverse prognostic value in patients treated with dose-dense
sequential adjuvant chemotherapy: a translational research analysis in the
context of a Hellenic Cooperative Oncology Group (HeCOG) randomized phase III
trial (2012)
Smallish study from Greece where 298 tumors
were profiled.TNBC tumors were further
characterized by CK5 or EGFR expression (core basal phenotype). Treatment
regimen: E (dd) x 3 -> Paclitaxel (dd) x 3 -> CMF x 3 vs. E (dd) x 4
-> CMF x 4. Conclusion: No benefit from paclitaxel treatment was detected in any of the four
subtypes or the total cohort. (luminal A, B, Her2 enriched and TNBC).
SWOG
0221 Trial comparing (1) DD ACx6 -> DD Taxol x6 (2) A (day1), oral C
(days1-7) repeats q7 days x 15 coursed -> DD Taxol x 6 (3) DD ACx6 ->
weekly Taxol x12
Prospective
multicenter randomized phase III study of weekly versus standard docetaxel (D2)
for first-line treatment of metastatic breast cancer (2011)
Conclusions.The present data support the feasibility of
both weekly and 3-weekly application of docetaxel in combination with
doxorubicin. Nevertheless, given that leukopenia was similar in both arms and
the efficacy parameters were at least numerically inferior with the weekly
schedule, standard 3-weekly application seems to be preferable for patients
requiring combination chemotherapy.
Weekly
docetaxel in metastatic breast cancer patients: no superior benefits compared
to three-weekly docetaxel (2011)
CONCLUSION: Weekly docetaxel is less well
tolerated than a 3-weekly schedule, due to more non-haematological toxicity,
despite less febrile neutropenia. Also, no efficacy benefits can be
demonstrated for weekly docetaxel, which may even be inferior based on
multivariate analysis. Therefore, a 3-weekly schedule should be preferred in
the setting of MBC.
3-16-12 entry
Acety L-carnitine in protecting against taxane-induced neuropathy
Have you ever wondered what the significance is if your path report says only xx % of your cells are positive for a marker (be it hormone receptor, Her2, EGFR, cytokeratin, Ki67)?
A new study from the UK looked in depth at the genetic characteristics of different parts of a renal carcinoma from the same patient and from associated metastatic sites (4 patients total) and found a remarkable degree of intra-tumor heterogeneity.
It means that the idea of characterizing a tumor by a few biomarkers and then basing therapy on those markers is probably too simplistic.
It could explain why cancer drugs stop working after a while if they target only a part of the tumor.
As suggested by the senior author, tumor heterogeneity could explain why some patients with renal cancer have better prognosis if their primary tumors are cut out, even if the tumor has spread. This is because the primary tumor has the "evolutionary reservoir of diversity".
Breast cancer heterogeneity Very likely the same thing is true for BC.
CTEP Meeting: (CTEP=Cancer Therapy Evaluation Program of NCI)
“Preoperative Therapy in Invasive Breast Cancer: Reviewing the State of the Science and Exploring New Research Directions” March 26-27, 2007
Included this link due to pdf and slides from this conference by experts.
Presentations also on surgery/radiation/imaging/research.
NOTE: Info from 2007. One needs to read knowing that one will have to confirm if there is
new info on the subjects addressed.
http://ctep.cancer.gov/highlights/20070326_meeting.htm
updated entry under taxanes http://forum.tnbcfoundation.org/topic9440_post99093.html#99093 on acetyl L-carnitine in protecting against taxane induced neuropathy. My NP said they did a small study at UM for this although the results aren't out and she recommended it. I think others on the forum might also have been taking the supplement. I could only find it in combo form with alpha lipoic acid.
I asked my MO about acetyl L-canitine but because I'm in a clinical trial she said not until I finished with that. She said if something went south, they wouldn't know if it was the PARP or the acetyl L-carnitine. She said I probably could when I'm finished with the trial. Two women in my support group have and are using it and they swear it is helping with the neuropathy.
Nita
DX 09/10 TNBC Stage3c, grade3, Tumor 2.7cm, chemo started 9/29/10, AC x4, Taxol x12, lumpectomy 4/11/11-tumor .6cm, 3+/22 nodes, radiation x 30 finished 6/30/11.Clinical Trial Cisplatin,PARP 8/23/11
BRCA1/BRCA2 and homologous recombination pathway related information
Came across this paper and reminded me of George Sledge's description of smart cancers:
Resistance to therapy caused by intragenic deletion in BRCA2 http://www.nature.com/nature/journal/v451/n7182/full/nature06548.html Researchers isolated PARP inhibitor-resistant clones from a human pancreatic cancer cell line that is BRCA2 deficient (c.617delT) and found that new BRCA2 isoforms were expressed that have deleted the mutation and restored the messenger RNA reading frame. They also found similar restoring mutations in carboplatin-resistant ovarian tumors from c.617delT mutation carriers. (PARP inhibitors depend on the homologous recombination pathway involving BRCA1/2 to be deficient and on the cell to rely on the DNA base excision repair pathway to take over, the latter being targeted by PARP inhibitors).
Good update on PARP inhibitor trials and the road forward (unfortunately not OPEN ACCESS) Stumbling Blocks on the Path to Personalized Medicine in Breast Cancer: The Case of PARP Inhibitors for BRCA1/2-Associated Cancers http://cancerdiscovery.aacrjournals.org/content/1/1/29.abstract
updated entry under novel therapeutics and targets http://forum.tnbcfoundation.org/topic9440_post98426.html#98426 new target from ISPY trial This is the way to go: molecular information from trial --> hypothesis generation --> test in lab --> (hopefully) new target and drug to test in next trial. CDK inhibitors not part of first round of drugs tested in ISPY2 trial -- the trial design is adaptive, meaning that they have a pipeline of new investigational drugs to roll through, without having to file a new trial and get FDA approval.
Possible genetic marker for risk of taxane neuropathy
This is a preliminary finding and subject to significant questions, but potentially an interesting lead on finding genetic markers to help predict who is at risk for taxane induced neuropathy
One big caveat is they only looked at two genes, BRCA1 and FANCD2. They found an association between some variants of FANCD2 and increased risk for taxane neuropathy, but this is not a genome wide search. A second big caveat is that taxane induced neuropathy is more common is women of African descent and the variants in FANCD2 that were associated with increased risk are also more frequently found in women of African descent so at this point it is hard to rule out "true, true and unrelated" as an explanation. Nevertheless, the fact that different populations have different risk for neuropathy does suggest that there is a genetic component and potentially a way to identify people with a higher risk.
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