HER2 Support Group Forums - View Single Post

Lani · 11-04-2012, 05:32 PM

My comments came not from a personal knowledge of Sheila...I had none.. but from your exasperation which I assumed was shared with your mom at her new
doctor not making any suggestions.

Many Stage IVs offer themselves as trial participants in Stage I trials which have virtually no hope of helping them...feeling by doing so they are at least helping the next person to come along. When there are clear reasons and evidence for the drug to be particularly effective, sometimes it proves effective and provides additional quality time.

If your mom was up to it AND WANTED TO ie, is not resigned to giving up/in , and if it were available, I found the following(just published by the Journal of the NCI) There is every evidence that the same dosage which is tolerated well and given to thousands if not millions daily around the world may prove effective :

Selective inhibition of Her2-Positive Breast cancer cells by the HiV Protease inhibitor Nelfinavir
Joong Sup Shim, Rajini Rao, Kristin Beebe, Len Neckers, Inkyu Han, Rita Nahta, Jun O. Liu
Manuscript received July 22, 2011; revised August 8, 2012; accepted August 16, 2012.
Correspondence to: Jun O. Liu, PhD, Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, 725 N Wolfe St, Hunterian Building 516, Baltimore, MD 21205 (e-mail: joliu@jhu.edu).
Background Human epidermal growth factor receptor 2 (HER2)–positive breast cancer is highly aggressive and has higher risk of recurrence than HER2-negative cancer. With few treatment options available, new drug targets specific for HER2-positive breast cancer are needed.
Methods We conducted a pharmacological profiling of seven genotypically distinct breast cancer cell lines using a subset of inhibitors of breast cancer cells from a screen of the Johns Hopkins Drug Library.To identify molecular targets of nelfinavir, identified in the screen as a selective inhibitor of HER2-positive cells, we conducted a genome-wide screen of a haploinsufficiency yeast mutant collection. We evaluated antitumor activity of nelfinavir with xeno- grafts in athymic nude mouse models (n = 4–6 per group) of human breast cancer and repeated mixed-effects regression analysis. All statistical tests were two-sided.
Results Pharmacological profiling showed that nelfinavir, an anti-HIV drug, selectively inhibited the growth of HER2- positive breast cancer cells in vitro. A genome-wide screening of haploinsufficiency yeast mutants revealed that nelfinavir inhibited heat shock protein 90 (HSP90) function. Further characterization using proteolytic footprinting experiments indicated that nelfinavir inhibited HSP90 in breast cancer cells through a novel mechanism. In vivo, nelfinavir selectively inhibited the growth of HER2-positive breast cancer cells (tumor volume index of HCC1954 cells on day 29, vehicle vs nelfinavir, mean = 14.42 vs 5.16, difference = 9.25, 95% confidence interval [CI] = 5.93 to 12.56, P < .001; tumor volume index of BT474 cells on day 26, vehicle vs nelfinavir, mean = 2.21 vs 0.90, dif- ference = 1.31, 95% CI = 0.83 to 1.78, P < .001). Moreover, nelfinavir inhibited the growth of trastuzumab- and/or lapatinib-resistant, HER2-positive breast cancer cells in vitro at clinically achievable concentrations.
Conclusion Nelfinavir was found to be a new class of HSP90 inhibitor and can be brought to HER2-breast cancer treatment trials with the same dosage regimen as that used among HIV patients.
J Natl Cancer Inst 2012;104:1576–1590

Nelfinavir is a first-generation hIV protease inhibitor approved by the uS Food and Drug Administration for an oral dose regimin of 750mg three times daily for AIDS patients. however, it was modified to a regimen of 1250mg twice daily, as recommended
1588 Articles | JNCI
Vol. 104, Issue 20 | October 17, 2012
Downloaded from http://jnci.oxfordjournals.org/ at Periodicals Department/Lane Library on November 4, 2012
by uS Food and Drug Administration in 1999. the efficacy of nelfinavir was proven to be equal in both regimens in a large, ran- domized trial (46). extensive pharmacokinetics studies have shown that nelfinavir has an average peak plasma level of 8–10 μm, which is approximately twice as high as its IC50 for the her2-positive breast cancer cell proliferation (3–6 μm), suggesting that it may be effective in breast cancer patients with the current dosage regimen. With a relatively low toxicity profile and much available informa- tion on its drug–drug interactions and on pharmacokinetics, nelfi- navir is ready for clinical testing in her2 breast cancer patients. In conclusion, the discovery of her2 selective inhibition of breast cancer cells by nelfinavir and the elucidation of its unique mode of action through binding to a new site on hSP90 have important implications in the development of nelfinavir and its analogs as new anticancer agents.

I do not know Sheila but I appreciate her decision to end active treatment and understand it IF INDEED it was made despite being depressed by her new physicians' approach and with knowledge and understanding of whether or not other meaningful options remained.

I provide the following reference to a recent op ed in the NYT on a different but related matter for you to consider. Pass any/all or none of this on to Sheila as you see fit.

NEXT week, voters in Massachusetts will decide whether to adopt an assisted-suicide law. As a good pro-choice liberal, I ought to support the effort. But as a lifelong disabled person, I cannot.

There are solid arguments in favor. No one will be coerced into taking a poison pill, supporters insist. The “right to die” will apply only to those with six months to live or less. Doctors will take into account the possibility of depression. There is no slippery slope.

Fair enough, but I remain skeptical. There’s been scant evidence of abuse so far in Oregon, Washington and Montana, the three states where physician-assisted death is already legal, but abuse — whether spousal, child or elder — is notoriously underreported, and evidence is difficult to come by. What’s more, Massachusetts registered nearly 20,000 cases of elder abuse in 2010 alone.

My problem, ultimately, is this: I’ve lived so close to death for so long that I know how thin and porous the border between coercion and free choice is, how easy it is for someone to inadvertently influence you to feel devalued and hopeless — to pressure you ever so slightly but decidedly into being “reasonable,” to unburdening others, to “letting go.”

Perhaps, as advocates contend, you can’t understand why anyone would push for assisted-suicide legislation until you’ve seen a loved one suffer. But you also can’t truly conceive of the many subtle forces — invariably well meaning, kindhearted, even gentle, yet as persuasive as a tsunami — that emerge when your physical autonomy is hopelessly compromised.

I was born with a congenital neuromuscular weakness called spinal muscular atrophy. I’ve never walked or stood or had much use of my hands. Roughly half the babies who exhibit symptoms as I did don’t live past age 2. Not only did I survive, but the progression of my disease slowed dramatically when I was about 6 years old, astounding doctors. Today, at nearly 50, I’m a husband, father, journalist and author.

Yet I’m more fragile now than I was in infancy. No longer able to hold a pencil, I’m writing this with a voice-controlled computer. Every swallow of food, sometimes every breath, can become a battle. And a few years ago, when a surgical blunder put me into a coma from septic shock, the doctors seriously questioned whether it was worth trying to extend my life. My existence seemed pretty tenuous anyway, they figured. They didn’t know about my family, my career, my aspirations.

Fortunately, they asked my wife, who knows exactly how I feel. She convinced them to proceed “full code,” as she’s learned to say, to keep me alive using any and all means necessary.

From this I learned how easy it is to be perceived as someone whose quality of life is untenable, even or perhaps especially by doctors. Indeed, I hear it from them all the time — “How have you survived so long? Wow, you must put up with a lot!” — even during routine office visits, when all I’ve asked for is an antibiotic for a sinus infection. Strangers don’t treat me this way, but doctors feel entitled to render judgments and voice their opinions. To them, I suppose, I must represent a failure of their profession, which is shortsighted. I am more than my diagnosis and my prognosis.

This is but one of many invisible forces of coercion. Others include that certain look of exhaustion in a loved one’s eyes, or the way nurses and friends sigh in your presence while you’re zoned out in a hospital bed. All these can cast a dangerous cloud of depression upon even the most cheery of optimists, a situation clinicians might misread since, to them, it seems perfectly rational.

And in a sense, it is rational, given the dearth of alternatives. If nobody wants you at the party, why should you stay? Advocates of Death With Dignity laws who say that patients themselves should decide whether to live or die are fantasizing. Who chooses suicide in a vacuum? We are inexorably affected by our immediate environment. The deck is stacked.

Yes, that may sound paranoid. After all, the Massachusetts proposal calls for the lethal dose to be “self-administered,” which it defines as the “patient’s act of ingesting.” You might wonder how that would apply to those who can’t feed themselves — people like me. But as I understand the legislation, there is nothing to prevent the patient from designating just about anyone to feed them the poison pill. Indeed, there is no requirement for oversight of the ingestion at all; no one has to witness how and when the lethal drug is given. Which, to my mind, leaves even more room for abuse.

To be sure, there are noble intentions behind the “assisted death” proposals, but I can’t help wondering why we’re in such a hurry to ensure the right to die before we’ve done all we can to ensure that those of us with severe, untreatable, life-threatening conditions are given the same open-hearted welcome, the same open-minded respect and the same open-ended opportunities due everyone else.

Ben Mattlin is a freelance journalist and the author of “Miracle Boy Grows Up: How the Disability Rights Revolution Saved My Sanity.”

A version of this op-ed appeared in print on November 1, 2012, on page A31 of the New York edition with the headline: Suicide by Choice? Not So Fast.

11-04-2012, 05:32 PM	#178
Lani Senior Member Join Date: Mar 2006 Posts: 4,778	Re: Prayers needed for Sheila My comments came not from a personal knowledge of Sheila...I had none.. but from your exasperation which I assumed was shared with your mom at her new doctor not making any suggestions. Many Stage IVs offer themselves as trial participants in Stage I trials which have virtually no hope of helping them...feeling by doing so they are at least helping the next person to come along. When there are clear reasons and evidence for the drug to be particularly effective, sometimes it proves effective and provides additional quality time. If your mom was up to it AND WANTED TO ie, is not resigned to giving up/in , and if it were available, I found the following(just published by the Journal of the NCI) There is every evidence that the same dosage which is tolerated well and given to thousands if not millions daily around the world may prove effective : Selective inhibition of Her2-Positive Breast cancer cells by the HiV Protease inhibitor Nelfinavir Joong Sup Shim, Rajini Rao, Kristin Beebe, Len Neckers, Inkyu Han, Rita Nahta, Jun O. Liu Manuscript received July 22, 2011; revised August 8, 2012; accepted August 16, 2012. Correspondence to: Jun O. Liu, PhD, Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, 725 N Wolfe St, Hunterian Building 516, Baltimore, MD 21205 (e-mail: joliu@jhu.edu). Background Human epidermal growth factor receptor 2 (HER2)–positive breast cancer is highly aggressive and has higher risk of recurrence than HER2-negative cancer. With few treatment options available, new drug targets specific for HER2-positive breast cancer are needed. Methods We conducted a pharmacological profiling of seven genotypically distinct breast cancer cell lines using a subset of inhibitors of breast cancer cells from a screen of the Johns Hopkins Drug Library.To identify molecular targets of nelfinavir, identified in the screen as a selective inhibitor of HER2-positive cells, we conducted a genome-wide screen of a haploinsufficiency yeast mutant collection. We evaluated antitumor activity of nelfinavir with xeno- grafts in athymic nude mouse models (n = 4–6 per group) of human breast cancer and repeated mixed-effects regression analysis. All statistical tests were two-sided. Results Pharmacological profiling showed that nelfinavir, an anti-HIV drug, selectively inhibited the growth of HER2- positive breast cancer cells in vitro. A genome-wide screening of haploinsufficiency yeast mutants revealed that nelfinavir inhibited heat shock protein 90 (HSP90) function. Further characterization using proteolytic footprinting experiments indicated that nelfinavir inhibited HSP90 in breast cancer cells through a novel mechanism. In vivo, nelfinavir selectively inhibited the growth of HER2-positive breast cancer cells (tumor volume index of HCC1954 cells on day 29, vehicle vs nelfinavir, mean = 14.42 vs 5.16, difference = 9.25, 95% confidence interval [CI] = 5.93 to 12.56, P < .001; tumor volume index of BT474 cells on day 26, vehicle vs nelfinavir, mean = 2.21 vs 0.90, dif- ference = 1.31, 95% CI = 0.83 to 1.78, P < .001). Moreover, nelfinavir inhibited the growth of trastuzumab- and/or lapatinib-resistant, HER2-positive breast cancer cells in vitro at clinically achievable concentrations. Conclusion Nelfinavir was found to be a new class of HSP90 inhibitor and can be brought to HER2-breast cancer treatment trials with the same dosage regimen as that used among HIV patients. J Natl Cancer Inst 2012;104:1576–1590 Nelfinavir is a first-generation hIV protease inhibitor approved by the uS Food and Drug Administration for an oral dose regimin of 750mg three times daily for AIDS patients. however, it was modified to a regimen of 1250mg twice daily, as recommended 1588 Articles \| JNCI Vol. 104, Issue 20 \| October 17, 2012 Downloaded from http://jnci.oxfordjournals.org/ at Periodicals Department/Lane Library on November 4, 2012 by uS Food and Drug Administration in 1999. the efficacy of nelfinavir was proven to be equal in both regimens in a large, ran- domized trial (46). extensive pharmacokinetics studies have shown that nelfinavir has an average peak plasma level of 8–10 μm, which is approximately twice as high as its IC50 for the her2-positive breast cancer cell proliferation (3–6 μm), suggesting that it may be effective in breast cancer patients with the current dosage regimen. With a relatively low toxicity profile and much available informa- tion on its drug–drug interactions and on pharmacokinetics, nelfi- navir is ready for clinical testing in her2 breast cancer patients. In conclusion, the discovery of her2 selective inhibition of breast cancer cells by nelfinavir and the elucidation of its unique mode of action through binding to a new site on hSP90 have important implications in the development of nelfinavir and its analogs as new anticancer agents. I do not know Sheila but I appreciate her decision to end active treatment and understand it IF INDEED it was made despite being depressed by her new physicians' approach and with knowledge and understanding of whether or not other meaningful options remained. I provide the following reference to a recent op ed in the NYT on a different but related matter for you to consider. Pass any/all or none of this on to Sheila as you see fit. NEXT week, voters in Massachusetts will decide whether to adopt an assisted-suicide law. As a good pro-choice liberal, I ought to support the effort. But as a lifelong disabled person, I cannot. There are solid arguments in favor. No one will be coerced into taking a poison pill, supporters insist. The “right to die” will apply only to those with six months to live or less. Doctors will take into account the possibility of depression. There is no slippery slope. Fair enough, but I remain skeptical. There’s been scant evidence of abuse so far in Oregon, Washington and Montana, the three states where physician-assisted death is already legal, but abuse — whether spousal, child or elder — is notoriously underreported, and evidence is difficult to come by. What’s more, Massachusetts registered nearly 20,000 cases of elder abuse in 2010 alone. My problem, ultimately, is this: I’ve lived so close to death for so long that I know how thin and porous the border between coercion and free choice is, how easy it is for someone to inadvertently influence you to feel devalued and hopeless — to pressure you ever so slightly but decidedly into being “reasonable,” to unburdening others, to “letting go.” Perhaps, as advocates contend, you can’t understand why anyone would push for assisted-suicide legislation until you’ve seen a loved one suffer. But you also can’t truly conceive of the many subtle forces — invariably well meaning, kindhearted, even gentle, yet as persuasive as a tsunami — that emerge when your physical autonomy is hopelessly compromised. I was born with a congenital neuromuscular weakness called spinal muscular atrophy. I’ve never walked or stood or had much use of my hands. Roughly half the babies who exhibit symptoms as I did don’t live past age 2. Not only did I survive, but the progression of my disease slowed dramatically when I was about 6 years old, astounding doctors. Today, at nearly 50, I’m a husband, father, journalist and author. Yet I’m more fragile now than I was in infancy. No longer able to hold a pencil, I’m writing this with a voice-controlled computer. Every swallow of food, sometimes every breath, can become a battle. And a few years ago, when a surgical blunder put me into a coma from septic shock, the doctors seriously questioned whether it was worth trying to extend my life. My existence seemed pretty tenuous anyway, they figured. They didn’t know about my family, my career, my aspirations. Fortunately, they asked my wife, who knows exactly how I feel. She convinced them to proceed “full code,” as she’s learned to say, to keep me alive using any and all means necessary. From this I learned how easy it is to be perceived as someone whose quality of life is untenable, even or perhaps especially by doctors. Indeed, I hear it from them all the time — “How have you survived so long? Wow, you must put up with a lot!” — even during routine office visits, when all I’ve asked for is an antibiotic for a sinus infection. Strangers don’t treat me this way, but doctors feel entitled to render judgments and voice their opinions. To them, I suppose, I must represent a failure of their profession, which is shortsighted. I am more than my diagnosis and my prognosis. This is but one of many invisible forces of coercion. Others include that certain look of exhaustion in a loved one’s eyes, or the way nurses and friends sigh in your presence while you’re zoned out in a hospital bed. All these can cast a dangerous cloud of depression upon even the most cheery of optimists, a situation clinicians might misread since, to them, it seems perfectly rational. And in a sense, it is rational, given the dearth of alternatives. If nobody wants you at the party, why should you stay? Advocates of Death With Dignity laws who say that patients themselves should decide whether to live or die are fantasizing. Who chooses suicide in a vacuum? We are inexorably affected by our immediate environment. The deck is stacked. Yes, that may sound paranoid. After all, the Massachusetts proposal calls for the lethal dose to be “self-administered,” which it defines as the “patient’s act of ingesting.” You might wonder how that would apply to those who can’t feed themselves — people like me. But as I understand the legislation, there is nothing to prevent the patient from designating just about anyone to feed them the poison pill. Indeed, there is no requirement for oversight of the ingestion at all; no one has to witness how and when the lethal drug is given. Which, to my mind, leaves even more room for abuse. To be sure, there are noble intentions behind the “assisted death” proposals, but I can’t help wondering why we’re in such a hurry to ensure the right to die before we’ve done all we can to ensure that those of us with severe, untreatable, life-threatening conditions are given the same open-hearted welcome, the same open-minded respect and the same open-ended opportunities due everyone else. Ben Mattlin is a freelance journalist and the author of “Miracle Boy Grows Up: How the Disability Rights Revolution Saved My Sanity.” A version of this op-ed appeared in print on November 1, 2012, on page A31 of the New York edition with the headline: Suicide by Choice? Not So Fast.