Patient-centered elective egg freezing: a binational qualitative study of best practices for women's quality of care.

PURPOSE: How can elective egg freezing (EEF) be made patient centered? This study asked women to reflect on their experiences of EEF, which included their insights and recommendations on the optimal delivery of patient-centered care. METHODS: In this binational, qualitative study, 150 women (114 in the USA, 36 in Israel) who had completed at least one cycle of EEF were recruited from four American IVF clinics (two academic, two private) and three in Israel (one academic, two private) over a two-year period (June 2014-August 2016). Women who volunteered for the study were interviewed by two medical anthropologists. Interviews were audio recorded, transcribed, and entered into a qualitative data management program (Dedoose) for analysis. RESULTS: The majority (85%) of women were without partners at the time of EEF, and thus were undertaking EEF alone in mostly couples-oriented IVF clinics. Following the conceptual framework known as "patient-centered infertility care," we identified two broad categories and eleven specific dimensions of patient-centered EEF care, including (1) system factors: information, competence of clinic and staff, coordination and integration, accessibility, physical comfort, continuity and transition, and cost and (2) human factors: attitude and relationship with staff, communication, patient involvement and privacy, and emotional support. Cost was a unique factor of importance in both countries, despite their different healthcare delivery systems. CONCLUSIONS: Single women who are pursuing EEF alone in the mostly couples-oriented world of IVF have distinct and multifaceted needs. IVF clinics should strive to make best practices for patient-centered EEF care a high priority.

The National Physicians Cooperative: transforming fertility management in the cancer setting and beyond.

Once unimaginable, fertility management is now a nationally established part of cancer care in institutions, from academic centers to community hospitals to private practices. Over the last two decades, advances in medicine and reproductive science have made it possible for men, women and children to be connected with an oncofertility specialist or offered fertility preservation soon after a cancer diagnosis. The Oncofertility Consortium's National Physicians Cooperative is a large-scale effort to engage physicians across disciplines - oncology, urology, obstetrics and gynecology, reproductive endocrinology, and behavioral health - in clinical and research activities to enable significant progress in providing fertility preservation options to children and adults. Here, we review the structure and function of the National Physicians Cooperative and identify next steps.

Ten pathways to elective egg freezing: a binational analysis.

PURPOSE: What are the specific pathways that lead women to freeze their eggs? In this binational study, women were asked directly about the life circumstances that led them on the path to elective egg freezing (EEF). METHODS: From June 2014 to August 2016, 150 women (114 in the USA, 36 in Israel) who had completed at least 1 cycle of EEF were interviewed by two medical anthropologists. Study participants were recruited through four American IVF clinics (two academic, two private) and three in Israel (one academic, two private). Interviews were audio-recorded, transcribed verbatim, and entered into a qualitative data management program (Dedoose) for analysis. RESULTS: The majority (85%) of women in the study were without partners, while 15% had partners at the time of EEF. Six pathways to EEF were found among women without partners (being single, divorced, broken up, deployed overseas, single mother, career planner), with career planning being the least common pathway to EEF. Among women with partners, four pathways to EEF were found (relationship too new or uncertain, partner not ready to have children, partner refusing to have children, or partner having multiple partners). With only one exception, the pathways and their frequencies were similar in both countries. CONCLUSIONS: Partnership problems, not career planning, lead most women on pathways to EEF. These pathways should be studied in a variety of national settings, and fertility clinics should offer patient-centered care for single women pursuing EEF in the couples-oriented world of IVF.

Medical egg freezing: How cost and lack of insurance cover impact women and their families.

Medical egg freezing (MEF) is being recommended increasingly for women at risk of losing their reproductive ability due to cancer chemotherapy or other fertility-threatening medical conditions. This first, binational, ethnographic study of women who had undergone MEF sought to explore women's experiences under two different funding systems: (i) the USA, where the cost of MEF is rarely covered by private or state health insurance; and (ii) Israel, where the cost of MEF is covered by national health insurance. Women were recruited from four American and two Israeli in-vitro fertilization clinics where MEF is offered. In-depth, semi-structured interviews were conducted with 45 women (33 Americans, 12 Israelis) who had completed at least one cycle of MEF. All of the Israeli women had cancer diagnoses, but were not faced with the additional burden of funding an MEF cycle. In marked contrast, the American women - 23 with cancer diagnoses and 10 with other fertility-threatening medical conditions - struggled, along with their families, to 'piece together' MEF funding, which added significant financial pressure to an already stressful situation. Given the high priority that both American and Israeli women in this study placed on survival and future motherhood, it is suggested that insurance funding for MEF should be mandated in the USA, as it is in Israel. This article concludes by describing new state legislative efforts in this regard.

Euploidy in relation to blastocyst sex and morphology.

PURPOSE: The objective of our study is to assess the relationship of embryo ploidy status in relation to embryo sex, morphological characteristics, and transfer parameters. METHODS: This is a retrospective cohort study at an academic medical center of patients who underwent in vitro fertilization with preimplantation genetic screening (PGS) from 2010 to 2015. Embryos were screened with 24-chromosome preimplantation genetic screening with day 5/6 trophectoderm biopsy. We investigated embryo euploidy in relation to morphology (expansion, inner cell mass, trophectoderm), embryo sex, biopsy day, and blastocyst cohort size. We used multivariate logistic regression to calculate odds ratios of euploidy in relation to these parameters. RESULTS: A total of 1559 embryos from 316 cycles and 233 patients (mean maternal age = 37.8 ± 4.2 years) were included in the analysis. Six hundred and twenty-eight blastocysts (40.3%) were found to be euploid. Expansion (p < 0.001), inner cell mass (ICM) (p < 0.01), and trophectoderm grade (p < 0.001) were significantly associated with embryo ploidy in bivariate models controlling for maternal age, while embryo sex, biopsy day, and blastocyst cohort size were not associated with embryo ploidy. In a multivariate model, we found that maternal age (p < 0.001), higher grade of expansion (p < 0.01), and better quality trophectoderm (p < 0.001 for A compared to C grade) remained significantly associated with increased embryo euploidy, but ICM grade was no longer significant. Embryo sex was not associated with ploidy status, though male embryos were found to be associated with higher trophectoderm scores (p < 0.02). CONCLUSIONS: This is the largest study to date to investigate PGS-tested embryo sex and ploidy status. While maternal age and some morphological parameters (expansion, trophectoderm grade) are associated with euploidy in our cohort, other parameters such as embryo sex, biopsy day, and cohort size are not. Though embryo sex was not associated with euploidy, male embryos were found to be associated with higher trophectoderm grades. Additional investigation in larger studies is warranted.

Cross border reproductive care (CBRC): a growing global phenomenon with multidimensional implications (a systematic and critical review).

PURPOSE: Many people travel abroad to access fertility treatments. This growing phenomenon is known as cross border reproductive care (CBRC) or fertility tourism. Due to its complex nature and implications worldwide, CBRC has become an emerging dilemma deserving more attention on the global healthcare agenda. METHODS: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review of the literature was performed for all relevant full-text articles published in PubMed in English during the past 18 years to explore CBRC phenomenon in the new millennium. RESULTS: Little is known about the accurate magnitude and scope of CBRC around the globe. In this systematic and critical review, we identify three major dimensions of CBRC: legal, economic, and ethical. We analyze each of these dimensions from clinical and practical perspectives. CONCLUSION: CBRC is a growing reality worldwide with potential benefits and risks. Therefore, it is very crucial to regulate the global market of CBRC on legal, economic, and ethical bases in order to increase harmonization and reduce any forms of exploitation. Establishment of accurate international statistics and a global registry will help diminish the current information gap surrounding the CBRC phenomenon.

Medical egg freezing: the importance of a patient-centered approach to fertility preservation.

PURPOSE: This binational qualitative study of medical egg freezing (MEF) examined women's motivations and experiences, including their perceived needs for patient-centered care in the midst of fertility- and life-threatening diagnoses. METHODS: Forty-five women who had undertaken MEF were interviewed in the USA (33 women) and in Israel (12 women) between June 2014 and August 2016. Interviews lasted approximately 1 h and were conducted by two senior medical anthropologists, one in each country. Women were recruited from four American IVF clinics (two academic, two private) and two Israeli clinics (both academic) where MEF is being offered to cancer patients and women with other fertility-threatening medical conditions. RESULTS: Women who undertake MEF view their fertility and future motherhood as important components of their identities and recovery and, thus, are grateful for the opportunity to pursue fertility preservation. However, women who undergo MEF have special needs, given that they tend to be a "vulnerable" population of young (age < 30), unmarried, resource-constrained women, who are facing not only fertility loss but also the "double jeopardy" of cancer. Through in-depth, qualitative interviews, these women's MEF stories reveal 10 dimensions of care important to fertility preservation, including five "system factors" (information, coordination and integration, accessibility, physical comfort, cost) and five "human factors" (adolescent issues, male partner involvement, family involvement, egg disposition decisions, emotional support). Together, these dimensions of care constitute an important framework that can be best described as "patient-centered MEF." CONCLUSIONS: Women pursuing MEF have special medical needs and concerns, which require particular forms of patient-centered care. This study outlines 10 dimensions of patient-centered fertility preservation that are appropriate for MEF patients. This approach may help IVF clinics to be better prepared for delivering top-quality care to mostly young, single women facing the daunting prospect of fertility loss and life-threatening medical diagnoses.

Results of a pilot study in the U.S. and Vietnam to assess the utility and acceptability of a multi-level pregnancy test (MLPT) for home monitoring of hCG trends after assisted reproduction.

BACKGROUND: To evaluate the utility and acceptability of using multi-level pregnancy tests (MLPTs) at home to monitor hCG trends following assisted reproductive technology (ART). METHODS: One hundred and four women presenting for ART at either Stanford Medicine Fertility and Reproductive Health Clinic (Stanford, CA) or Hung Vuong Hospital (Ho Chi Minh City, Vietnam) participated in this pilot study. Women were asked to perform the MLPT at home, primarily on days when they were also scheduled to receive standard clinic-based serum hCG testing. These tests were administered up to 6 times over the 6-week period following embryo transfer or intrauterine insemination (IUI). Concordance of serial hCG readings for each time point was assessed by comparing trends in urine MLPT results with trends in serum hCG. Stable or increasing hCG level was interpreted as an indication of a progressing pregnancy, while a declining hCG was interpreted as a lack of established or progressing pregnancy. At study end, all participants were asked about the acceptability and convenience of using the MLPT at home for monitoring hCG trends following ART. RESULTS: Data from both urine and serum testing are available for 156 of 179 clinic visits (87.2%). There was high concordance of serial trend results between the two types of tests: among the 156 sets of serum and urine hCG data points, 150 (96.2%) showed a matching trend in hCG pattern and 6 (3.8%) resulted in a discordant trend. Seventy-three percent of women reported being satisfied or very satisfied with using the MLPTs at home. Almost all (96.6%) said that the MLPT was easy or very easy to use. CONCLUSION: The MLPT offers women and health care providers a client-friendly diagnostic tool to detect very early pregnancy and monitor its progress. TRIAL REGISTRATION: This study was registered on clinicaltrials.gov as NCT01846403 (May 1, 2013), and NCT01919502 (August 5, 2013).

Freeze-only versus fresh embryo transfer in a multicenter matched cohort study: contribution of progesterone and maternal age to success rates.

OBJECTIVE: To compare implantation and ongoing pregnancy rates in freeze-only versus fresh transfer cycles. DESIGN: Retrospective matched cohort study. SETTING: Not applicable. PATIENT(S): Women selected using a matching algorithm for similar distributions of clinical characteristics for a total of 2,910 cycles (1,455 fresh cohort and 1,455 freeze-only cohort). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation and ongoing pregnancy rates. RESULT(S): Implantation and ongoing pregnancy rates were statistically significantly higher in the freeze-only transfer cohort than in the matched fresh transfer cohort: ongoing pregnancy rate for freeze-only was 52.0% (95% confidence interval [CI], 49.4-54.6) and for fresh was 45.3% (95% CI, 42.7-47.9), odds ratio (OR) 1.31 (95% CI, 1.13-1.51). In a stratified analysis, the odds of ongoing pregnancy after freeze-only transfer were statistically significantly higher for women both above and below age 35 with progesterone concentration >1.0 ng/mL (age ≤35: OR 1.38 [1.11-1.71]; age >35: OR 1.73 [1.34-2.24]). For women with progesterone concentration ≤1.0 ng/mL, no statistically significant difference in freeze-only odds of ongoing pregnancy was observed in either age group. The sensitivity analysis revealed that increasing maternal age alone (regardless of progesterone) trended toward a more beneficial effect of freeze-only cycles. A lower progesterone concentration was associated with statistically significantly higher ongoing pregnancy odds for fresh but not freeze-only cycles. CONCLUSION(S): Freeze-only transfer protocols are associated with statistically significantly higher ongoing implantation and pregnancy rates compared with fresh transfer cycles. This effect is most pronounced for cycles with progesterone >1.0 ng/mL at trigger and may also be stronger for older patients.

The role of serum testosterone in early pregnancy outcome: a comparison in women with and without polycystic ovary syndrome.

OBJECTIVE: Hyperandrogenic conditions in women are associated with increased rates of miscarriage. However, the specific role of maternal testosterone in early pregnancy and its association with pregnancy outcome is unknown. The purpose of this study was to compare serum testosterone levels during early pregnancy in women with and without polycystic ovary syndrome (PCOS) who either had successful pregnancies or miscarried. METHOD: We collected serum samples from women attending a university-based fertility centre at the time of their first positive serum beta human chorionic gonadotropin pregnancy test. The samples were subsequently assayed for total testosterone level. We used logistical regression modelling to control for PCOS diagnosis, BMI, and age. RESULTS: Total testosterone levels were available for 346 pregnancies, including 286 successful pregnancies and 78 first trimester miscarriages. We found no difference in total testosterone levels between women who subsequently had an ongoing pregnancy (mean concentration 3.6 ± 2.6 nmol/L) and women with a miscarriage (mean 3.6 ± 2.4 nmol/L). Using the Rotterdam criteria to identify women with PCOS, we also found no differences in serum testosterone between women who had ongoing pregnancies or miscarriages, either with PCOS (P = 0.176) or without PCOS (P = 0.561). CONCLUSIONS: Our findings show that early pregnancy testosterone levels do not predict pregnancy outcome, and they call into question the role of testosterone in causing miscarriage in populations of women with PCOS. Further research is needed to elucidate the normal progression of testosterone levels during pregnancy and to investigate further the relationship between PCOS and miscarriage.

Objectif : Chez les femmes, les troubles liés à l'hyperandrogénie sont associés à des taux accrus de fausse couche. Toutefois, le rôle particulier que joue la testostérone maternelle aux débuts de la grossesse et l'influence qu'elle exerce sur l'issue de la grossesse restent inconnus. L'objectif de la présente étude était de comparer les taux sériques de testostérone aux débuts de la grossesse chez des femmes qui, en présence ou non d'un syndrome d'ovaires polykystiques (SOPK), avaient connu soit une grossesse réussie, soit une fausse couche. Méthode : Nous avons prélevé des échantillons sériques chez des femmes qui fréquentaient un centre de fertilité universitaire, au moment de l'obtention de leur premier résultat positif au test de grossesse fondé sur le taux sérique de bêta-gonadotropine chorionique humaine. Les échantillons ont ensuite été analysés en vue d'établir le taux total de testostérone. Nous avons utilisé un modèle de régression logistique pour neutraliser l'effet du diagnostic de SOPK, de l'IMC et de l'âge. Résultats : Des taux totaux de testostérone étaient disponibles pour 346 grossesses (286 grossesses réussies et 78 fausses couches au premier trimestre). Nous n'avons constaté aucune différence en matière de taux total de testostérone entre les femmes qui ont été en mesure de poursuivre leur grossesse (concentration moyenne de 3,6 ± 2,6 nmol/l) et les femmes qui ont connu une fausse couche (moyenne de 3,6 ± 2,4 nmol/l). En ayant recours aux critères de Rotterdam pour identifier les femmes présentant un SOPK, nous avons constaté qu'il n'existait également aucune différence en matière de taux sérique de testostérone entre les femmes qui ont pu poursuivre leur grossesse et celles qui ont connu une fausse couche, qu'il y ait eu présence d'un SOPK (P = 0,176) ou non (P = 0,561). Conclusions : Les résultats que nous avons obtenus démontrent que les taux de testostérone présents aux débuts de la grossesse ne permettent pas de prévoir l'issue de la grossesse et remettent en question l'influence qu'exerce la testostérone sur la survenue d'une fausse couche chez les femmes qui présentent un SOPK. Des recherches plus poussées sont nécessaires pour élucider l'évolution normale des taux de testostérone pendant la grossesse, ainsi que pour explorer plus à fond le lien qui existe entre le SOPK et la fausse couche.

Comparison of epigenetic mediator expression and function in mouse and human embryonic blastomeres.

A map of human embryo development that combines imaging, molecular, genetic and epigenetic data for comparisons to other species and across pathologies would be greatly beneficial for basic science and clinical applications. Here, we compared mRNA and protein expression of key mediators of DNA methylation and histone modifications between mouse and human embryos, embryos from fertile/infertile couples, and following growth factor supplementation. We observed that individual mouse and human embryos are characterized by similarities and distinct differences in DNA methylation and histone modification patterns especially at the single-cell level. In particular, while mouse embryos first exhibited sub-compartmentalization of different histone modifications between blastomeres at the morula stage and cell sub-populations in blastocysts, differential histone modification expression was detected between blastomeres earlier in human embryos at the four- to eight-cell stage. Likewise, differences in epigenetic mediator expression were also observed between embryos from fertile and infertile couples, which were largely equalized in response to growth factor supplementation, suggesting that select growth factors might prevent alterations in epigenetic profiles during prolonged embryo culture. Finally, we determined that reduced expression via morpholino technologies of a single histone-modifying enzyme, Rps6ka4/Msk2, resulted in cleavage-stage arrest as assessed by time-lapse imaging and was associated with aneuploidy generation. Taken together, data document differences in epigenetic patterns between species with implications for fertility and suggest functional roles for individual epigenetic factors during pre-implantation development.

Fertility issues in cancer survivorship.

Breakthroughs in cancer diagnosis and treatment have led to dramatic improvements in survival and the need to focus on survivorship issues. Chemotherapy and radiotherapy can be gonadotoxic, resulting in impaired fertility. Techniques to help cancer survivors reproduce have been improving over the past decade. Discussion of the changes to a patient's reproductive health after cancer treatment is essential to providing comprehensive quality care. The purpose of this review is to aid in pre- and posttreatment counseling, focusing on fertility preservation and other strategies that may mitigate risks to the patient's reproductive, sexual, and overall health.

Stress and anxiety scores in first and repeat IVF cycles: a pilot study.

BACKGROUND: The role of stress in reproduction, particularly during treatment for infertility, has been of considerable interest; however, few studies have objectively measured stress and anxiety over the course of the IVF cycle or compared the experience of first-time and repeat patients. METHODS: This prospective cohort pilot study enrolled 44 women undergoing IVF at a university-based clinic to complete the State-Trait Anxiety Inventory (STAI), Perceived Stress Scale (PSS) and Infertility Self-Efficacy Scale (ISES) at three time points prior to ovarian stimulation (T1), one day prior to oocyte retrieval (T2), and 5-7 days post embryo transfer (T3). RESULTS: Mean STAI State scores were significantly elevated at all three time points (p<0.01). STAI State and PSS mean values did not change over time and did not differ in first-time vs. repeat patients. Self-efficacy (ISES) scores declined over time, with a greater decline for repeat patients. Of the 36 women who completed a cycle, 15 achieved clinical pregnancy. Using logistic regression modeling, all scores at T2 were correlated with pregnancy outcome with lower scores on the STAI State and PSS and higher scores on the ISES associated with higher pregnancy rates. CONCLUSIONS: Stress and anxiety levels remained elevated across all cycles. Women with lower stress and anxiety levels on the day prior to oocyte retrieval had a higher pregnancy rate. These results emphasize the need to investigate stress reduction modalities throughout the IVF cycle.

Frequency of the male infertility evaluation: data from the national survey of family growth.

PURPOSE: An estimated 7 million American couples per year seek infertility care in the United States. A male factor contributes to 50% of cases but it is unclear what proportion of infertile couples undergoes male evaluation. MATERIALS AND METHODS: We analyzed data from cycles 5 to 7 of the National Survey of Family Growth performed by the Centers for Disease Control to determine the frequency of a male infertility evaluation, and associated reproductive and demographic factors. RESULTS: A total of 25,846 women and 11,067 men were surveyed. Male evaluation was not completed in 18% of couples when the male partner was asked vs 27% when female partners were asked. This corresponds to approximately 370,000 to 860,000 men in the population who were not evaluated at the time of infertility evaluation. Longer infertility duration and white race were associated with increased odds of male infertility evaluation. The male and female samples showed no change in the receipt of male examination with time. CONCLUSIONS: Many men from infertile couples do not undergo male evaluation in the United States. Given the potential implications to reproductive goals and male health, further examination of this pattern is warranted.

Pregnancy During Recovery from Hematopoietic Stem Cell Transplant for Mycosis Fungoides.

We report a case of spontaneous pregnancy with subsequent full-term live birth following hematopoietic stem cell transplantation (HSCT) for mycosis fungoides in a 24-year-old nulligravida with 4 years of prior infertility due to primary ovarian insufficiency. Four months post-transplant, the patient was found to be 10 weeks pregnant. Her pregnancy was complicated by first trimester fetal exposure to mycophenolate mofetil (pregnancy category D), delayed-onset acute gastrointestinal graft-versus-host disease, and multiple systemic infections. This report highlights the importance of discussing potential fertility outcomes in patients undergoing HSCT, including the necessity for adequate contraception post-transplant, even in the setting of previous infertility.

Outcomes of trophectoderm biopsy on cryopreserved blastocysts: a case series.

Preimplantation genetic diagnosis (PGD) is an increasingly common adjunct to IVF. The information gained from PGD may be used to reduce the incidence of chromosomally abnormal pregnancies and augment the current selection process of embryos. As such, patients may choose to utilize PGD in either fresh or cryopreserved IVF cycles. It is a common practice to cryopreserve excess embryos at the blastocyst stage. In these cases, trophectoderm biopsy is the only technique available for PGD. This articles reports this study centre's experience with trophectoderm biopsies of cryopreserved blastocysts in 12 patients who underwent 13 cycles of PGD. The implantation rate per embryo transferred was 46% and the ongoing pregnancy rate per embryo transfer was 63%. The results from this case series demonstrate that trophectoderm biopsy on cryopreserved blastocysts to perform PGD is logistically feasible. In addition, the rate of implantation and ongoing pregnancy were maintained within a reasonable range to justify the procedure. Preimplantation genetic diagnosis (PGD) is an increasingly common adjunct to IVF and is used to evaluate the genetic makeup of the embryo prior to transfer of the embryo into the uterus. The information gained from PGD may be used to identify single-gene disorders that result in genetic disease, reduce the incidence of chromosomally abnormal pregnancies and/or augment the selection process of embryos to be transferred. In order to perform PGD, a biopsy of the embryo is the performed and cells are removed for testing. PGD may be performed in either fresh or frozen (cryopreserved) IVF cycles. Patients who have cryopreserved embryos remaining in storage from a previous fresh cycle may wish to have these embryos tested with PGD. Many embryos are frozen on day 5 of development, referred to as the blastocyst stage. At this stage of development, embryo biopsy is performed via a technique known as 'trophectoderm biopsy', in which 1-3 of the cells destined to become the placenta are removed from the embryo for chromosomal testing. We report our experience with trophectoderm biopsy of frozen blastocysts in 12 patients who underwent 13 cycles of PGD. The implantation rate per embryo transferred was 46% and the ongoing pregnancy rate per embryo transfer was 63%. The results from this case series demonstrate that trophectoderm biopsy on cryopreserved blastocysts to perform PGD is logistically feasible. In addition, the rate of implantation and ongoing pregnancy were maintained within a reasonable range to justify the procedure.

Testosterone concentrations in early pregnancy: relation to method of conception in an infertile population.

This prospective cohort study of infertility patients compared testosterone concentrations in early pregnancy in infertility patients who conceived naturally or after treatment. Although all groups demonstrated some increase in pregnancy testosterone from baseline concentrations, subjects who conceived following ovulation induction showed a significantly increased rise in testosterone as compared with controls (P<0.01).

Integration and safety of fertility preservation in a breast cancer program.

Young women diagnosed with breast cancer typically face systemic treatments that may delay childbearing or permanently impair their fertility. These concerns add to the stress experienced by young cancer survivors. Timely counseling and providing fertility preservation through cryopreservation of eggs or embryos have become an important quality of life issue. We analyzed the impact of fertility preservation procedures on the initiation of treatment for breast cancer and discuss critical aspects of the process.